Basic Principles Of Pharmacology

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] TABLE  OF  CONTENTS       TOPIC   PAGE  NUMBER     Basic  Principles  of  Pharmacology   1     Pharmacodynamics   4     Pharmacokinetics   6     Drug  Metabolism   7     Drug  Evaluation  and  Regulation   8     Autonomic  Pharmacology   9     Cholinoreceptor-­‐Activating  and   11     Cholinesterase-­‐Inhibiting  Drugs     Cholinoreceptor  Blockers   12     Adrenergic  Pharmacology   13     Sympatomimethics   14   BASIC  PRINCIPLES  OF  PHARMACOLOGY   Adrenoreceptor  Blockers   15     Treatment  of  Glaucoma   16   INTRODUCTION   Drugs  for  Hypertension   17     Drugs  Used  in  the  Treatment  of  Angina   19   DEFINITION  OF  TERMS   Pectoris   • DRUGS   Drugs  used  in  Heart  Failure   21   o Any   substance   that   brings   about   a   change   in   Anti-­‐Arrhythmic  Drugs   22   biologic  function  through  its  chemical  actions   Diuretics   25     Drugs  used  in  the  Treatment  of   28   • PHARMACODYNAMICS   Hyperlipidemia   o Actions  of  a  drug  on  the  body   Histamine,  Serotonin,  Ergot  Alkaloids   30    Receptor  interaction   Prostaglandins  and  Other  Eicosanoids   31    Dose-­‐response  phenomena   Bronchodilators  &  Other  Drugs  Used  in   32    Mechanisms   of   therapeutic   and   toxic   Asthma   actions   Agents  Used  in  Anemia  and  Hematopoietic   33     Growth  Factors   • PHARMACOKINETICS   Drugs  Used  in  Coagulation  Disorders   36   o Actions  of  the  body  on  the  drug   NSAIDS,  Acetaminophen,  DMARDS  and   40   o Concerned  with:   Drugs  Used  in  Gout    Absorption   Sedative-­‐Hypnotic  Drugs   44    Distribution   Alcohols   46    Metabolism   Antiseizure  Drugs   48    Elimination   General  Anesthetics   49     Local  Anesthetics   51   MNEMONICS  –  Pharmacodynamics  vs  Pharmacokinetics   Skeletal  Muscle  Relaxants   52   pharmacoDynaMics                                                  pharmacoKineTics     Drugs  Used  in  Parkinsonism   54   (Drug    Man)                                                                        (Katawan    Tableta)                                                 Antiosychotic  Agents  and  Lithium   55     Antidepressants   57   NATURE  OF  DRUGS   Opioid  Analgesics  and  Antagonists   59   • SIZE  AND  MOLECULAR  WEIGHT   Drugs  of  Abuse   60   o Vary   from   MW   7   (lithium)   to   over   MW   50,000   Endocrine  Pharmacology   62   (alteplase,  thrombolytic  enzymes)   Antibiotic  Agents   72   o Majority  have  MW  100  to  1000   o <100  –  rarely  sufficiently  selective  in  their  actions   Antifungal  Agents   80   Antiviral  Chemotherapy  and  Prophylaxis   81   o >1000  –  poorly  absorbed  and  and  poorly  ditributed         Antiprotozoal  Drugs   83   REVIEW  –  Anticoagulants   Antihelminthic  Drugs   85   WARFARIN  –  small   Cancer  Chemotherapy   86   MOA:  Inhibits  Vit  K-­‐dependent  factors  synthesis   Gastrointestinal  Pharmacology   90   Monitor:  PT/INR  (can  cross  the  placenta)   Toxicology   91   Antidote:  Vit  K;  FFP   Management  of  the  Poisoned  Patient   95       HEPARIN   –  large     MOA:  Activates  anti-­‐thrombin  III     Monitor:  aPTT  (cannot  cross  the  placenta)     Antidote:  Protamine  Sulfate         • DRUG-­‐RECEPTOR  BONDS     o Arranged  according  to  decreasing  order  of  strength      Covalent  bonds      Electrostatic  bonds     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 1 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

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• Ionic  bonds   • Hydrogen  bonding   • van  der  Waals      Hydrophobic  bonding   Strength   of   bond   formed   by   drugs   determine   reversibility  of  effects    PRALIDOXIME  (cannot  reverse  insecticide   poisoning   if   the   bonds   formed   by   the   poison  have  aged  and  become  covalent)  

  MOVEMENT  OF  DRUGS  IN  THE  BODY   • Drug   molecules   must   travel   from   the   site   of   administration  to  the  site  of  action   • Permeation   • Fick’s  Law  of  Diffusion   • Water  and  Lipid  solubility  of  Drugs     PERMEATION  –  is  the  movement  of  drug  molecules  into  and  within   biologic  environments   o Aqueous  diffusion   o Lipid  diffusion   o Transport  by  special  carriers   o Endocytosis,  pinocytosis         Aqueous  Diffusion   • Passive   movement   of   non-­‐protein-­‐bound   drugs   between   the   blood   and   extravascular   space   through   small   water-­‐ filled  pores  (exceptions:  Brain,  Testes,  Eye  and  Placenta)   • Affected  by  drug  concentration  and  charge   • Governed  by  Fick’s  Law  of  Diffusion     Lipid  Diffusion   • Movement   of   drugs   through   lipid   memebranes   (i.e.   BBB,   Placenta)  separating  body  compartment,  and  from  the  ECF   to  the  ICF   • Most  important  limiting  factor  for  permeation   • Governed  by  Fick’s  Law  of  Diffusion   • Very   important   for   the   diffusion   of   weak   acids   and   weak   bases     Transport  by  Special  Carriers   • Drugs  that  do  not  readily  cross  through  membranes  may  be   transported   across   barriers   by   mechanisms   that   carry   similar  endogenous  substances     o Ions  through  Na/K  pump   o Neurotransmitter  through  reuptake  transporters   o Metabolites  such  as  glucose  through  GLUT   o Carriers  for  foreign  molecules  or  xenobiotics   • NOT   governed   by   Fick’s   Law   of   Diffusion   and   is   capacity-­‐ limited     Endocytosis   • Endocytosis:   large   drugs   bind   to   receptors,   are   internalized   and   released   after   vesicle   breakdown   (exocytosis   is   the   reverse  process)   • Small   polar   drugs   combine   with   special   proteins   to   form   complexes  which  undergo  endocytosis   o Vitamin  B12  bound  to  Intrinsic  factor   o Iron  bound  to  transferrin    

FICK’S  Law  of  Diffusion   •

Predicts  the  rate  of  movement  of  molecules  across  a  barrier  

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Pharmacologic  Implications:   o Absorption   is   faster   in   organs   with   large   SA   (intestinal  >  stomach)   o Absorption   is   faster   in   organs   with   thinner   membranes  (lung  >  skin)  

  WATER  AND  LIPID  SOLUBILITY  OF  DRUGS   • Aqueous   solubility   is   directly   proportional   to   electrostatic   charge  (ionization,  polarity)   o Ionized  and  polar  drugs  are  more  water-­‐soluble   o Increased   aqueous   solubility   =   increased   clearance   • Lipid   solubility   is   inversely   proportional   to   electrostatic   charge  (ionization,  polarity)   o Non-­‐ionized   and   non-­‐polar   drugs   are   more   lipid-­‐ soluble   o Increase   lipid   solubility   =   increased   capacity   to   cross  biological  membranes     Weak  Acids  and  Bases   • Many  drugs  are  weak  acids  and  weak  bases   • Dissociate  into  ionized  and  non-­‐ionized  forms   • pH   determines   the   fraction   of   drug   molecules   charged   (ionized)  versus  uncharged  (non-­‐ionized)   • predicted  by  Henderson-­‐Hasselbach  equation   • relationship   between   pH,   pKa   (dissociation   constant)   and   concentration  of  charged  and  uncharged  forms     Henderson-­‐Hasselbach  Equation                 Dissocation  of  Weak  Acids       HA   ↔   A-­‐   +   H+                      Protonated   ↔    unprotonated   +   H+                        R  –  COOH   ↔              R  –  COO-­‐   +   H+       • unprotonated   (A-­‐)   form   is   more   water-­‐soluble   and   undergoes  better  clearance   • protonated   (HA)   form   is   more   lipid-­‐soluble   and   more   likely   to  cross  biological  membranes     Dissocation  of  Weak  Bases       BH   ↔   B   +   H+                      Protonated   ↔      unprotonated   +   H+                            R  –  NH3   ↔                  R-­‐  NH2   +   H+     Weak  Acids  and  Bases   Above  pKa:     Unprotonated  >  protonated         At  pH  =  pKa     Unprotonated   =  protonated    

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]     Below  pKa:     Protonated  >  unprotonated             MNEMONIC  –  pKa   • UP  &  Above   • Unprotonated  >  Protonated:  Above  pKa     PRACTICE  PROBLEMS:   1. Aspirin   is   a   weak   organic   acid   with   a   pKa   of   3.5.   What   percentage  of  a  given  dose  will  be  in  the  lipid  soluble  form   at  a  stomach  pH  of  2.5?                                                                    pH  =  pKa    +      log  U/P                                                                  2.5  =  3.5      +      log  U/P                                                                  2.5  –  3.5  =  log  U/P                                                                  -­‐1  =  log  U/P                                                                  10-­‐1  =  U/P                                      Unprotonated  is  10-­‐1  or  0.10  or  10%                                                                      Protonated  is  90%     Since  aspirin  is  a  weak  acid,  the  more  lipid  soluble  form  is     the  protonated  HA  form.  Hence,  the  final  answer  is  90%     2. Atropine   is   a   weak   organic   base   with   a   pKa   of   9.7.   What   percentage  of  a  given  dose  will  be  in  the  lipid  soluble  form   at  a  pH  of  7.7?                             Application  of  Henderson-­‐Hasselbach  Equation   • Excretion  of  a  weak  acid  may  be  accelerated  by  alkalinizing   the  urine  with  bicarbonate  (HCO3-­‐)   • Excretion  of  a  weak  base  may  be  accelerated  by  acidifying   the  urine  with  ammonium  chloride  (NH4Cl)     MNEMONICS  –  BICARBONATE  and  AMMONIUM  CHLORIDE   Alkalinizing  Agent  =  Basic  =  give  Bicarbonate   Acidifying  Agent  =  ACid  =  give  Ammonium  Chloride     DRUG  ABSORPTION     Absorption   • Transfer   of   a   drug   from   its   site   of   administration   to   the   bloodstream   • Affected  by  3  major  factors:   o Route  of  administration   o Blood  flor   o Concentration    

ROUTES  OF  ADMINISTRATION     Oral  Route   • Offers  maximum  convenience   • Most  common  route  of  drug  administration   • Absorption  is  slow  and  less  complete   o Gastric  contents   o First-­‐pass  effect    A   significant   amount   of   the   drug   is   metabolized   in   the   gut   wall,   portal   circulation   and   liver   before   it   reaches   the  ssystemic  circulation     Intravenous  Route   • Instantaneous   and   complete   absorption   that   bypasses   first-­‐ pass  effect  (100%  bioavailability)   • Potentially  more  dangerous:   o High  blood  levels  reached  on  rapid  administration   o Inadvertent   systemic   introduction   of   bacteria   through  the  IV  line  (line  sepsis)     Intramuscular  Route   • Absorption   is   faster   and   more   complete   than   oral   (higher   bioavailability)   o Bypasses  first-­‐pass  effect   • Large   volumes   may   be   delivered   if   drug   is   not   too   irritating   (i.e.  5g  of  MgSO4)   • Anticoagulant   cannot   be   given   by   this   route   because   they   may  cause  bleeding  (hematomas)     KEY  LEARNING  POINTS  –  IM  Injections  to  Buttocks   Which   quadrant   of   the   buttocks   is   safest   for   IM   drug   administration?                         • Superolateral  =  safe   • Superomedial  =  gluteus  medius  gait   • Inferomedial  =  sciatic  nerve         Subcutaneous  Route   • Slower  absorption  than  intramuscular  route   o NO  blood  vessels  in  the  subcutaneous  space   • Large  volume  doses  are  less  feasible   • Bypasses  the  first-­‐pass  effect     • Anticoagulants   do   NOT   cause   hematomas   when   administered  via  this  route     Buccal  and  Sublingual  Route   • Buccal:  pouch  between  the  gums  and  cheek   • Sublingual:  under  the  tongue   • Direct   absorption   into   the   systemic   venous   circulation   bypassing  the  first-­‐pass  effect     CORRELATIONS  –  Anatomy  –  Sublingual  Drugs   Through   which   blood   vessels   do   drugs   administered   SL   pass  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] before  reaching  the  heart?   Lingual   vein      Internajugular   vein      Brachiocephalic   (innominate)  vein    Superior  vena  cava    Right  atrium     Rectal  (Suppository)  Route   • Partial  avoidance  of  the  first  pass  effect   • Useful   for   large   amounts   of   drugs   with   unpleasant   tastes   and  for  patients  who  are  vomiting     CORRELATIONS  –  Anatomy  –  Rectal  Route   Why   is   there   only   partial   bypass   of   the   first-­‐pass   effect   on   rectal   administration?   Review  the  VENOUS  DRAINAGE  OF  THE  RECTUM   • Superior  Rectal  vein:  IMV  PV  (first-­‐pass)   • Middle  Rectal  vein:  IIV    IVC   • Inferior  Rectal  vein:  IPV    IIV    IVC     Inhalational  Route   • Offers  delivery  closest  to  the  target  in  respiratory  diseases   • Rapid  absorption  with  minimal  systemic  effects   • Convenient   for   drugs   that   are   gases   at   room  temperature   (nitrous   oxide,   nitric   oxide)   or   easily   volatilized   (anesthetics)     Topical  Route   • Application   to   skin,   mucous   membranes   of   the   eye,   ear,   nose,  throat,  airway,  or  vagina  for  local  effect   • Absorption   varies   with   the   area   of   application   and   drug   formulation   o Increasing  ability  to  retard  evaporation    (more   evaporation)   tinctures   >   wet   dressings   >   lotions   >   gels   >   aerosols   >   powders   >   pastes   >   creams   >   foams   >   ointments  (less  evaporation)   • Slowest  route  of  drug  administration     KEY  LEARNING  POINTS  –  Topical  Preparations   Describe   the   utility   of   dermatologic   drug   preparations   for   skin   inflammation:   • Acute   inflammation   =   drying   agents   (tinctures,   wet   dressings,  and  lotions)   • Chronic   inflammation   =   lubricating   agents   (creams,   ointments)     Transdermal  Route   • Application  to  the  skin  for  systemic  effect   • Absorption   occurs   very   slowly   but   bypasses   the   first-­‐pass   effect     DRUG  DISTRIBUTION     Distribution   • Drug   reversibly   leaves   the   bloodstream   and   enters   the   target  organ   • Depends  upon  4  major  factors:   o Size  of  the  organ   o Blood  flow   o Solubility   o Binding     SIZE  OF  THE  ORGAN   • Determines  concentration  gradient  between  blood  and  the   organ   o Skeletal  muscles  is  very  large  organ  

Large   doses   are   required   to   actually   change  the  concentration  gradient   The  brain  is  a  small  and  compact  organ    Only   a   small   amount   of   drugs   is   required   to   change   concentration   gradients   

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  BLOOD  FLOW   • Important  determinant  of  the  rate  of  drug  uptake   • Well-­‐perfused   organs   will   achieve   high   tissue   concentrations  sooner  than  poorly  perfused  tissues   • Concentration   of   drugs   with   rapid   elimination   will   not   significantly  rise  in  poorly  perfused  tissues           SOLUBILITY   • Influences  the  concentration  of  the  drug  in  the  extracellular   fluid  surrounding  blood  vessels   • Most   barriers   in   the   body   (BBB,   placenta,   glomerulus)   are   lipid-­‐barriers   o Non-­‐ionized,   non-­‐polar   drugs   are   more   lipid-­‐ soluble  and  undergo  more  extensive  distribution     BINDING   • Binding  to  macromolecules  in  the  blood  or  tissue  will  tend   to  increase  the  drug’s  concentration  in  that  compartment   o Acidic  drugs  are  bound  to  albumin   o Basic  drugs  are  bound  to  orosomucoid   • Bound   drugs   CANNOT   cross   membranes   and   exert   their   effect   • Only  unbound  drugs  CAN  cross  membranes  and  exert  their   effect     DRUG  METABOLISM     Metabolism   • Drugs  are  chemically  altered  in  the  body   • Drugs  may  undergo  3  metabolic  fates:   o Termination  of  drug  action   o Drug  activation   o Elimination  without  metabolism     TERMINATION  OF  DRUG  ACTION   • Drugs  are  metabolized  into  biologically  inactive  derivatives   • Conversion  to  a  metabolite  is  a  form  of  elimination     DRUG  ACTIVATION   • Prodrugs  are  metabolized  in  the  body  to  become  active   • Some   drugs   are   metabolically   active   but   still   have   active   metabolites     ELIMINATION  WITHOUT  METABOLISM   • Some   drugs   are   not   modified   by   the   body   and   continue   to   act  until  they  are  excreted     DRUG  ELIMINATION     Elimination   • Elimination:  termination  of  drug  action   • Excretion:  release  of  drugs  or  their  metabolites  in  the  urine,   stool,  bile,  exhaled  air,  etc.  

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Duration  of  drug  action  is  determined  by:   o Dose  administered   o Rate  of  elimination  following  the  last  dose  

  PHARMACODYNAMICS     Receptors   • Specific   molecules   in   a   biologic   system   with   which   drugs   interact  to  produce  changes  in  the  function  of  the  system   • Must  be  selective  in  their  ligand-­‐binding  characterstic     • Must   be   modified   when   they   bind   an   agonist   to   bring   about   functional  change   • Most  are  proteins     Receptor  Sites  or  Recognition  Sites   • Specific  binding  region  of  the  macromolecule   • High  and  selective  affinity  for  the  drug  molecule     Effectors   • Translate   the   drug-­‐receptor   interaction   into   a   change   in   cellular  activity   • Some  receptors  are  also  effectors   o A   single   molecule   may   incorporate   both   the   drug   binding  site  and  the  effector  mechanism    Tyrosine   kinase   receptor   in   insulin   receptor  molecule    Na/K  channel  in  nicotinic  Ach  receptor     Graded  Dose-­‐Response  Relationships   • Dose-­‐response  curve   o Response  of  a  particular  receptor-­‐effector  system   measured  against  increasing  drug  concentrations   o Yields   a   sigmoid   curve   if   plotted   on   a   semilogarithmic  axis   • Efficacy   (Emax)   and   Potency   (EC50)   are   derived   from   this   curve     Binding  Affinity   • Fraction   of   receptors   bound   by   a   drug   plotted   against   the   log  of  the  drug  concentration   • Kd   is   the   concentration   required   to   bind   50%   of   the   receptors   o The   smaller   the   Kd,   the   greater   the   affinity   of   a   drug  for  its  receptor         Graded-­‐Dose  Response  Curves                       Definitios   Emax   =   maximal   effect   achievable   with   increasing   concentration   of  a  drug   EC50   =   concentration   of   the   drug   wherein   half   of   the   maximal   effect  is  achieved   Bmax   =   maximum   percentage   of   receptors   with   increasing   concentration  of  a  drug   Kd  =  concentration  wherein  50%  of  receptors  is  occupied    

  Elimination  and  Drug  Metabolites   • Elimination   of   parent   molecule   does   not   terminate   the   drug’s  action  for  drugs  with  active  metabolites   • Excretion  is  the  mode  of  elimination  for  drugs  that  are  not   metabolized     FIRST-­‐ORDER  ELIMINATION   • Rate  of  elimination  is  proportionate  to  the  concentration   o Concentration  decreases  exponentially  over  time   • Characteristic  half-­‐life  elimination   o Concentration   decreases   by   50%   for   every   half-­‐ life   • Most  common  type  of  elimination     ZERO-­‐ORDER  ELIMINATION   • Rate  of  elimination  is  constant  regardless  of  concentration   o Concentration  decreases  linearly  over  time   • Occurs   when   drugs   have   saturated   their   elimination   mechanisms                     MNEMONICS  –  Zero  Order  Kinetics   What  drugs  display  zero-­‐order  elimination  kinetics?   WHAT  PET   • Warfarin   • Heparin   • Aspirin   • Tolbutamide   • Phenytoin   • Ethanol   • Theophylline       PRACTICE  PROBLEM  –  Elimination  Kinetics   1. Which   drug   displays   first-­‐order   elimination?   Zero-­‐order   elimination     0h   1h   2h   3h   4h   A   80mg   60mg   40mg   20mg   0mg   B   80mg   40mg   20mg   10mg   5mg     2. Compute  the  remaining  concentration  of  Drug  A  and  B  every   hour  for  4  hours   First-­‐order  elimination:  Drug  A  t1/2  =  2h   Zero-­‐order  elimination:  Drug  B  Rate  =  50  mg/2h     0h   1h   2h   3h   4h   A   100mg           B   100mg                         TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 5 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Quantal  Dose-­‐Response  Relationships   • Minimum   dose   require   to   produce   a   specified   response   is   determined  in  each  member  of  a  population   • Quantal  dose-­‐response  curve   o Fraction   of   the   population   that   responds   to   each   dose  against  the  log  of  the  dose  administered   • No  attempt  is  made  to  determine  maximal  effect     Quantal-­‐Dose  Response  Curves                                   Therapeutic  Index                                             Efficacy   • Maximal  efficacy  or  Emax   • Maximal  effect  an  agonist  can  produce  if  the  dose  taken  to   very  high  levels   • Determined   mainly   by   the   nature   of   the   receptor   and   its   associated  effector  system   • Measured   with   graded   dose-­‐response   curves   NOT   with   quantal  dose-­‐response  curves   • Partial   agonists   have   lower   maximal   efficacy   than   full   agonists     Potency   • Denotes  the  amount  of  the  drug  needed  to  produce  a  given   effect   • Determined   mainly   by   the   affinity   of   the   receptor   for   the   drug   • Measurement:  

o o

In   grade   dose-­‐response   curves,   it   is   the   dose   required  to  produce  50%  of  the  maximal  effect   In   quantal   dose-­‐response   curves,   three   potency   variables  are  measurable  (ED50,  TD50,  LD50)  

                          Factors  Affecting  Dose  Response  Curves                         Full  Agonists   • Capable  of  fully  activating  the  effector  system  when  it  binds   to  the  receptor   • High  affinity  for  the  activated  receptor  conformation   • Sufficiently   high   concentrations   result   in   all   the   receptor   achieving  the  activated  state     Partial  Agonists   • Produce   less   than   the   full   effect,   even   when   it   has   saturated   the  receptors   • In   the   presence   of   an   agonist,   a   partial   agonist   acts   as   an   inhibitor                               Antagonists   • Do   not   provoke   a   biological   response   by   themselves   upon   binding  to  a  receptor   • Blocks   or   dampens   drug   response   in   the   presence   of   an   agonist   • Classification:   o Competitive  (reversible)   o Non-­‐competitive  (irreversible)   o Physiologic   o Chemical   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 6 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]               Competitive  or  Reversible  Antagonists   • Bind  to  receptors  in  a  reversible  way  without  activating  the   effector  system   • Shift   DRCs   to   the   RIGHT   (increase   ED50)   but   same   maximal  effect  is  reached   • Effects  overcome  by  adding  more  agonist   • Examples:   o β-­‐blockers  (Propranolol)   o β-­‐agonists  (Isoproterenol)       Non-­‐competitive  or  Irreversible  Antagonists   • Causes  DOWNWARD  shift  of  the  DRC   • No  horizontal  shift  of  DRC  (ED50  unchanged)  unless  spare   receptors  are  present   • Not  overcome  by  adding  more  agonists   • Examples:   o Norepinephrine   o Phenoxybenzamine     Physiologic  Antagonists   • Binds   to   a   different   receptor,   producing   an   effect   opposite   to  that  produced  by  the  drug  it  is  antagonizing   • Examples:   o Histamine  &  Epinephrine   o Propranolol  &  Thyroid  hormone     Chemical  Antagonists   • Interact  directly  with  the  drug  being  antagonized  to  remove   it  or  to  prevent  it  from  reaching  its  target   • Does  not  depend  on  interaction  with  agonist  receptors   • Examples:   o Dimercaprol  for  lead  poisoning   o Pralidoxime  for  organophosphate  poisoning     Variations  in  Drug  Response     Tachyphylaxis   • Responsiveness   diminishes   rapidly   after   administration   of   drug   • Frequent   or   continuous   exposure   to   agonists   often   results   in  short-­‐term  diminution  of  the  receptor  response     MNEMONICS  –  Tachyphylaxis   What  drugs  display  tachyphylaxis?   MEDical  students  Love  to  watch  CNN  in  HD!   Metoclopramide   Ephedrine   Dobutamine   LSD   Calcitonin   Nitroglycerin   Nicotine   Hydralazine   Desmopressin     Tolerance  

• • •

Continuous   activation   may   lead   to   depletion   of   essential   substrates   Reversed  by  repletion  of  missing  substrates   EXAMPLE:   depletion   of   thiol   cofactors   in   nitroglycerin   tolerance,  reversible  with  administration  of  glutathione  

  Idiosyncratic  Drug  Response   • One  that  is  infrequently  observed  in  most  patients   • EXAMPLES:   o Aplastic  anemia  with  chloramphenicol   o Cataracts  with  allopurinol    

PHARMACOKINETICS     Effective  Drug  Concentration    Concentration  of  a  adrug  at  the  receptor  site  (target  organ)    Except  for  topically  applied  agents,  the  concentration  at  the   receptor   site   is   usually   proportional   to   the   drug’s   concentration  in  the  plasma  or  whole  blood  at  equilibrium       Apparent  Volume  of  Distribution   • Volume   at   which   drug   would   need   to   be   uniformly   distributed  to  produce  an  observed  blood  concentration       • Purely   pharmacokinetic   parameter   with   no   direct   physical   equivalent   • Can  be  altered  by  liver  and  kidney  disease     Volume  of  Distribution     Low  Vd   Distribute  in  blood   Medium  Vd   Distribute  in  extracellular   space  or  body  water   High  Vd   Distribute  in  tissues                                               Clearance   • Relates  the  rate  of  elimination  to  the  plasma  concentration        

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] •

• • •

Depends   on   the   drug   and   the   condition   of   the   organs   of   elimination   o For  a  drug  that  is  very  effectively  extracted  by  an   organ,  clearance  is  flow-­‐limited   For   drugs   eliminated   with   first-­‐order   kinetics,   clearance   is   a  constant  proportion   For  drugs  eliminated  with  zero-­‐order  kinetics,  clearance  is   a  constant  amount   Most   important   pharmacokinetic   parameter   to   be   considered   in   defining   a   rational   steady   state   during   dosage  regimen  

                                    Steady  State   • Condition  in  which  the  average  total  amount  of  drug  in  the   body  does  not  change  over  multiple  dosing  intervals   • Rate  of  drug  input  equals  the  rate  of  elimination   • Reached  in  4-­‐5  half-­‐lives  of  the  drug       Half-­‐life       • Constant  for  drugs  following  first-­‐order  kinetics   • Disease,  age,  and  other  variables  usually  alter  clearance  of  a   drug  much  more  then  Vd   • Half-­‐life   may   not   change   despite   a   decreased   cleareance   if   the  Vd  decreases  at  the  same  time                       Bioavailability   • Fraction  of  the  administered  dose  that  reaches  the  systemic   circulation   • Drugs   administered   intravenously   have   100%   bioavailability   • Reduced   by   incomplete   absorption,   first-­‐pass   metabolism,   and  pre-­‐systemic  redistribution   • Determined   by   computing   the   area   under   the   plasma   concentration  curve  (AUC)    

                    PRACTICE  PROBLEM  –  Bioavailability   After   oral   administration   of   500mg   of   Drug   A,   only   300mg   were   absorbed   into   the   patient’s   systemic   circulation.   What   is   its   bioavailability?     Dosage  Regimen   • Plan  for  drug  administration  over  a  time  period   • Results   in   the   achievement   of   therapeutic   levels   of   the   drug   in   the   blood   without   exceeding   the   minimum   toxic   concentration   • Based  on  knowledge  of  both  the  minimum  therapeutic  and   minimum   toxic   concentrations   for   the   drug,   as   well   as   its   clearance  and  Vd     Maintenance  Dose   • Equal  to  the  rate  of  elimination  at  steady  state         • Vd  is  NOT  involved  in  calculating  MD   • Important   to   maintain   concentration   above   minimum   therapeutic  level:   o Give  large  doses  at  long  intervals   o Smaller  doses  at  more  frequent  intervals     Loading  Dose   • If   the   therapeutic   concentration   must   be   achieved   rapidly   and  the  volume  of  distributin  is  large         • Clearance  is  NOT  involved  in  calculating  LD   • If   the   LD   is   very   large,   dose   should   be   given   slowly   to   prevent  toxicity   o Due   to   excessively   high   plasma   levels   during   the   distribution  phase           Therapeutic  Window   • Safe   range   between   the   minimum   therapeutic   concentration   and   the   minimum   toxic   concentration   of   a   drug   o Minimum   effective   concentration   usually   determines     the   desired   trough   levels   of   a   drug   given  intermittently   o Minimum   toxic   concentration   determines   the   permissible  peak  plasma  concentration            

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]             Adjustment  of  Dosage   • Renal   disease   or   reduced   cardiac   output   often   reduces   the   clearance  of  drugs  that  depend  on  renal  function   • Impairment   of   hepatic   clearance   occurs   when   liver   blood   flow  is  reduced   o EXAMPLES:   heart   failure,   severe   cirrhosis,   other   forms  of  liver  failure     Adjustment  of  Dosage  in  Renal  Impairment       • If   a   drug   is   cleared   partly   by   the   kidney   and   partly   by   other   routes,  apply  the  equation  only  to  the  part  of  the  dose  that   is  eliminated  by  the  kidney     Cockroft  –  Gault  Equation   • To   calculate   the   patient’s   creatinine   clearance,   use   the   Cockroft-­‐Gualt  equation       PRACTICE  PROBLEM  –  Corrected  Dosage   A   drug   is   50%   cleared   by   the   kidney   and   50%   by   the   liver.   Its   normal   dosage   is   200   mg/dL.   What   is   the   corrected   dosage   in   a   patient  with  a  creatinine  clearance  of  20  mL/min    

    Phase  2  Reactions   • Involve   conjugation   of   subgroups   to   –OH,   –NH2,   and   –SH   functions  on  the  drug  molecule   o Makes   the   drug   more   polar   and   less   lipid-­‐soluble   than  the  original  drug  molecule   o EXAMPLES:   glucoronate,   acetate,   glutathione,   glycine,  sulfate,  and  methyl  group   • Phase  II  enzymes  are  NOT  very  selective     • Drugs   may   undergo   phase   II   metabolism   before   or   after   phase  I     Examples  of  Phase  2  Reactions  

DRUG  METABOLISM     Drug  Metabolism   • All   organs   are   exposed   to   foreign   chemical   compounds   (xenobiotics)   • Metabolic   pathways   alter   drug   activity   and   their   susceptibility  to  excretion     Phase  1  Reactions     • Convert  the  parent  drug  to  a  more  polar  (water-­‐soluble)  or     more   reactive   product   by   unmasking   or   inserting   a   polar   Sites  of  Drug  Metabolism   functional  group   • LIVER   • EXAMPLES:  oxidation,  reduction,  deamination,  hydrolysis   o Most  important  organ  for  drug  metabolism     • KIDNEYS   MNEMONICS  –  Phase  I  Reactions   • TISSUE  COMPARTMENTS   A  HORDe  of  PHASE  I  REACTIONS   o Few   drugs   (eg,   esters)   are   metabolized   in   many   Hydrolysis   tissues  (eg,  liver,  blood,  intestinal  wall)  because  of   Oxidation   the  broad  distribution  of  their  enzymes   Reduction     Deamination   Drug  Biotransformation     • Most  often  due  to  genetic  or  drug-­‐induced  differences   Cytochrome  P450  Enzymes   • Gender  is  important  for  only  a  few  drugs   • Also  called  mixed-­‐function  oxidases   o First-­‐pass  metabolism  of  alcohol  (M>F)   • High  concentration  in  the  smooth  endoplasmic  reticulum  of   • Primary  determinant  of  clearance   the  liver   o Variations   must   be   considered   carefully   when   • Not  highly  selective  in  their  substrates   designing  or  modifying  a  dosage  regimen   • Of   the   drugs   metabolized   by   phase   I   cytochrome   P450s,     approximately  75%  are  metabolized  by  just  two:   Genetic  Factors   o CYP3A4  or  CYP2D6   • Drug-­‐metabolizing   systems   differ   among   families   or     populations  in  genetically  determined  ways     • Recent   advances   in   genomic   techniques   allow   screening   for     a  huge  variety  of  polymorphisms  (pharmacogenomics)   Examples  of  Phase  1  Reactions   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 9 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]   Examples  in  Pharmacogenomics   • HYDROLYSIS  OF  ESTERS                Succinylcholine  metabolism  by  pseudocholinesterase   • ACETYLATION  OF  AMINES                Fast  and  slow  acetylation  of  isoniazid,  hydralazine                                                          and  procainamide   • OXIDATION                Debrisoquin,  Sparteine,  Phenformin,                                    Dextromethorphan,  Metoprolol,  and                  Tricyclic  antidepressants             Enzyme  Induction   • Results   from   increased   synthesis   of   cytochrome   P450   enzymes  and  heme   • Several   days   are   usually   required   to   reach   maximum   induction   • Most   common   strong   inducers   are   carbamazepine,   phenobarbital,  phenytoin,  and  rifampin     MNEMONIC  –  CYTOCHROME  P450  INDUCERS   Ethel  Booba  takes  Phen-­‐phen  and  Refuses  Greasy  Carb  Shakes!   Ethanol   Barbiturates   Phenytoin   Rifampicin   Griseofulvin   Carbamazepine   St.  John’s  Wort  /  Smoking     Enzyme  Inhibition   • Most   significant   inhibitors   are   Amiodarone,   Cimetidine,   Furanocoumarins   present   in   grapefruit   juice,   azole   antifungals,  and  the  HIV  protease  inhibitor  (Ritonavir)   • Metabolism  may  be  decreased  by  reduction  in  blood  flow  to   metabolizing  organ   o EXAMPLE:   Propranolol   reduces   hepatic   blood   flow       Suicide  Inhibitors   • Metabolized   to   products   that   irreversibly   inhibit   the   metabolizing  enzyme   o EXAMPLES:   Ethinyl   estradiol,   Norethindrone,   Spironolactone,   Secobarbital,   Allopurinol,   Fluroxene,  PTU     MNEMONICS  –  CYTOCHROME  P450  INHIBITORS   Inhibitors  Stop  Cyber  Kids  from  Eating  GRApefruit  OV!   Isoniazid   Sulfonamides   Cimetidine   Ketoconazole   Erythromycin   Grapefruit  Juice   Ritonavir   Amiodarone   Quinidine   Valproic  acid   _______________________________________________________________________________  

DRUG  EVALUATION  AND  REGULATION     Animal  Testing   • Required  before  human  studies  begin  

•

Function   of   the   proposed   use   and   the   urgency   of   the   application   o Drug   proposed   for   nonsystemic   use   requires   less   extensive  testing   o Anticancer   drugs   and   drugs   proposed   for   use   in   AIDS  require  less  evidence  of  safety  

  Acute  Toxicity   • Required  for  all  new  drugs   • Involve  administration  of  single  doses  of  the  agent  up  to  the   lethal   level   in   at   least   2   species   (eg,   1   rodent   and   1   nonrodent)     Subacute  and  Chronic  Toxicity   • Required   for   most   agents,   especially   those   intended   for   chronic  use   • Duration:   2   –   4   weeks   (subacute)   or   6   –   24   months   (chronic),  in  at  least  2  species     Pharmacologic  Profile   • Description  of  all  the  pharmacologic  effects   o Effects   on   cardiovascular   function,   gastrointestinal   activity,   respiration,   renal   function,  and  endocrine  function,  CNS   • Both  graded  and  quantal  dose-­‐response  data  are  gathered     Reproductive  Toxicity    Involves   the   study   of   the   fertility   effects   of   the   candidate   drug  and  its  teratogenic  and  mutagenic  toxicity    FDA   uses   a   5-­‐level   descriptive   scale   to   summarize   information  regarding  the  safety  of  drugs  in  pregnancy     FDA  Drug  Categories   Category   A  

B  

C  

D  

X  

Description   Controlled  studies  in  women  fail  to  demonstrate  a  risk  to  the   fetus  in  the  first  trimester  (and  ther  is  no  evidence  of  a  risk  in   later   trimesters),   and   the   possibility   of   fetal   harm   appears   remote   Either   animal   reproduction   studies   have   not   demonstrated   a   fetal   risk   but   there   are   no   controlled   studies   in   pregnant   women,   or   animal   reproduction   studies   have   shown   an   adverse   effect   (other   than   a   decrease   fertility)   that   was   not   confirmed  in  controlled  studies  in  women  in  the  first  trimester   (and  ther  is  no  evidence  of  a  risk  in  later  trimesters)   Either  studies  in  animals  have  revealed  adverse  effects  on  the   fetus   (teratogenic   or   emryocidal   or   other)   and   there   are   no   controlled  studies  in  women,  or  studies  in  women  and  animals   are   not   available.   Drugs   should   be   given   only   when   the   potential  benefit  justifies  the  potential  risk  to  the  fetus     There   is   positive   evidence   of   human   fetal   risk,   but   the   benefits   from   use   in   pregnant   women   may   be   acceptable   despite   the   risk  (eg,  if  the  drug  is  needed  in  a  life-­‐threatening  situation  or   for  a  serious  disease  for  which  safer  drugs  cannot  be  used  or   are  ineffective)   Studies   in   animals   or   human   beings   have   demonstrated   fetal   abnormalities   or   ther   is   evidence   of   fetal   risk   based   on   human   experience   or   both,   and   the   risk   of   the   use   of   the   drug   in   pregnant   women   clearly   outweighs   any   possible   benefit.   The   drug   is   contraindicated   in   women   who   are   or   may   become   pregnant  

    Drugs  and  Pregnancy     Class   A   B  

Pregnant   Human     Studies   safe   no  studies   safe  

Pregnant   Animal   Studies   safe   safe   unsafe  

  Examples   Folic  acid,  thyroid  hormones   Zidovudine    

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] C   D   X  

no  studies   no  studies   unsafe   unsafe  

unsafe   no  studies   unsafe   unsafe  

Aspirin     ACE  inhibitors,  Anticonvulsants   Statins,  OCPs,  Clomiphene,   Misoprostol,  High-­‐dose  vitamin  A  

  Teratogenesis    Induction  of  developmental  defects  in  the  somatic  tissues  of   the  fetus    Studied   by   treating   pregnant   female   animals   of   at   least   2   species   at   selected   times   during   early   pregnancy   when   organogenesis  is  known  to  take  place   o EXAMPLES:   thalidomide,   isotretinoin,   valproic   acid,   ethanol,   glucocorticoids,   warfarin,   lithium,  and  androgens     COMMON  TERATOGENS   TERATOGEN   ACE  inhibitors   Antiepileptic  Drugs   Phenytoin   Oral  hypoglycemic  agents   Barbiturates   Diethylstilbestrol  (DES)   Ethanol   Lithium   Isotretinoin   Iodide   Misoprostol   Penicillamine   Thalidomide   Smoking   Tetracycline   Streptomycin   Methimazole   Sulfonamides   Fluoroquinolones   Warfarin                                    1st  trimester                                                                        2nd  trimester                                                                        3rd  trimester    

EFFECT   Fetal  renal  damage   Neural  tube  defects   Fetal  hydantoin  syndrome   Neonatal  hypoglycemia   Neonatal  dependence   Vaginal  clear  cell  adenocarcinoma   Fetal  alcohol  syndrome   Ebstein’s  anomaly   Craniofacial  malformations   Congenital  hypothyroidism   Mobius  sequence   Cutis  laxa   Phocomelia   Intrauterine  growth  restriction  (IUGR)   Tooth  discoloration   Ototoxicity   Aplasia  cutis  congenita   Kernicterus   Cartilage  damage   Chondrodysplasia   CNS  malformations   Bleeding  diatheses  

  Mutagenesis   • Induction   of   changes   in   the   genetic   material   of   animals   of   any  age  and  therefore  induction  of  heritable  abnormalities   o EXAMPLES:  aflatoxin,  cancer  chemotherapeutic   drugs,  and  other  agents  that  bind  to  DNA     Ames  Test   • Standard  in  vitro  test  for  mutagenicity   • Uses  a  special  strain  of  Salmonella  that  naturally  depends   on  specific  nutrients   • Loss  of  this  dependence  signals  a  mutation     Dominant  Lethal  Test   • In  vivo  mutagenicity  test  carried  out  in  mice   • Male   animals   are   exposed   to   the   test   substance   before   mating   • Abnormalities   in   the   results   fo   the   subsequent   mating   signal  a  mutation  in  the  male’s  germ  cells     Carcinogenesis   • Induction  of  malignant  characteristics  in  cells   • Difficult  and  expensive  to  study   • High   degree   of   correlation   between   mutagenicity   in   the   Ames  test  and  carcinogenicity  in  some  animal  tests  

o

EXAMPLES:   coal   tar,   aflatoxin,   nitrosamines,   urethane,   vinyl   chloride,   polycyclic   aromatic   hydrocarbons  in  tobacco  smoke  

Clinical  Trial   • Requires  approval  by  institutional  committees  that  monitor   the   ethical   (informed   consent,   patient   safety)   and   scientific   aspects   (study   design,   statistical   power)   of   the   proposed   tests     Investigational  New  Drug  (IND)   • Includes  all  the  preclinical  data  colleceted  up  to  the  time  of   submission  and  the  detailed  proposal  for  clinical  trials     New  Drug  Application  (NDA)   • Constitutes   the   request   for   approval   of   general   marketing   of   the   new   agent   for   prescription   usa   and   includes   all   the   results  of  preclinical  and  clinical  testing     PHASE  1  TRIAL   • Careful   evaluation   of   the   dose-­‐response   relationship   and   pharmacokinetics   among   normal   human   volunteers   (25-­‐ 50)   o EXCEPTION!   In   cancer   and   highly   toxic   agents   (volunteer  patients  with  target  disease)   • Acute   effects   of   the  agent   are   studied   over   a   broad   range   of   dosages     PHASE  2  TRIAL   • Evaluation  of  a  drug  in  a  moderate  number  of  patients  (eg,   100-­‐300)  with  the  target  disease   • Placebo  or  positive  control  durg  is  included  in  a  sigle-­‐blind   or  double-­‐blind  design   • Under   carefully   controlled   conditions   with   close   monitoring  usually  in  hospital  ward   • Determine   whether   the   agent   has   the   desired   efficacy   at   doses  that  are  tolerated  by  sick  patients     PHASE  3  TRIAL   • Large   design   involving   many   patients   (1000-­‐5000)   and   many  clinicians   • Include   placebo   and   positive   control   in   a   double-­‐blind   crossover  design   • Explore   further   the   spectrum   of   beneficial   actions   of   the   new   drug   to   compare   it   with   older   therapies,   and   to   discover  toxicities   • Large  amounts  of  data  are  collected   • Usually  very  expensive     PHASE  4  TRIAL   • Post-­‐marketing  surveillance  phase   • Detects  toxicities  that  occur  very  infrequently   • Findings   reported   early   enough   to   prevent   major   therapeutic  disasters       Drug  Patents   • Usually  submitted  around  the  time  that  a  new  drug  enters   animal  testing   • Right   to   market   the   drug   without   competition   from   other   firms  for  a  period  of  20  years   • After   expiration   of   patent,   any   company   may   apply   to   the   FDA  for  permission  to  market  a  generic  version  of  the  same   drug  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] o

Must   demonstrate   that   their   generic   drug   molecule  is  bioequivalent  

  Bioequivalence   • Two   related   drugs   are   bioequivalent   if   they   show   comparable   bioavailability   and   similar   times   to   achieve   a   peak  blood  concentrations   • Used  in  determining  safety  and  efficacy  of  generic  drugs    

             

    Orphan  Drug   • Drug   for   a   rare   disease   (one   affecting   fewer   than   200,000   people)   • Often   neglected   because   the   sales   of   an   effective   agent   for   an   uncommon   ailment   might   not   pay   the   costs   of   development      

AUTONOMIC  PHARMACOLOGY     Autonomic  Nervous  System   • Major   involuntary,   unconscious,   automatic   portion   of   the   nervous  system   • Major  divisions:   o Parasympathetic  ANS  (PANS)   o Sympathetic  ANS  (SANS)   o Enteric  nervous  system  (ENS)    Consists   of   myenteric   plexus   (plexus   of   Auerbach)   and   submucous   plexus   (plexus  of  Meissner)       SANS   PANS     Thoracic  (T1-­‐T12)  and   CN  III,  VII,  IX  and  X   Spinal  Roots     Lumbar  (L1-­‐L5)   Sacral  segments  of   of  Origin   segments  of  the  spinal   spinal  cord   cord     Paraventral  chains  that   Most  are  located  in   Location  of     lie  along  the  spinal   the  organs   Ganglia   column,  some  along  the   innervated,  more   anterior  aspects  of  the   distant  from  the   abdominal  aorta   spinal  cord   Preganglionic   Short   Long   Fibers     Postganglionic   Long   Short     Fibers          

 

    ORGAN   Pupils   Heart  rate   Heart  contractility   Blood  vessels   Skin,  splanchnic   Skeletal   Bronchi   GIT  walls   GIT  sphincters   GIT  secretions   Bladder  wall   Bladder  sphincter   Uterus   Penis   Sweat  glands   Liver  

EFFECT   Sympathetic   Parasympathetic     Mydriasis  (α1)   Miosis  (M3)   Tachycardia  (β1)   Bradycardia  (M2)   Increased  (β1)   Decreased  (M2)     NO  EFFECT   Constriction  (α1)   NO  EFFECT   Dilation  (β2,  M3)   NO  EFFECT   Dilation  (β2)   Contraction  (M3)   Relaxation  (α2,  β2)   Contraction  (M3)   Contraction  (α1)   Relaxation  (M3)   NO  EFFECT   Increased  (M1,  M3)   Relaxation  (β2)   Contraction  (M3)   Contraction  (α1)   Relaxation  (M3)   Contraction  (α1)   Contraction  (M3)   Relaxation  (β2)   Ejaculation  (α)   Erection  (M)   ↑  sweating  (α)   NO  EFFECT   Gluconeogenesis   NO  EFFECT  

Glycogenolysis  (α,  β2)  

Fat  cells   Lipolysis  (β3)   NO  EFFECT   Kidnets   ↑  renin  (β1)   NO  EFFECT       MNEMONIC  –  for  Parasympathetic  Nervous  System   PLASMA!   Parasympathetic   NS,   Long   preganglionic   fiber,   Acetylcholine,   Short  postgalionic  fibers,  Acetylcholine  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]     MNEMONIC  –  Point  and  Shoot!   Point  (Erection)  =  Parasympathetic  NS   Shoot  (Ejection)  =  Sympathetic  NS                         CHOLINERGIC  PHARMACOLOGY     Acetycholine   • Primary   transmitter   in   all   autonomic   ganglia   and   at   the   synapses  between  parasympathetic  postganglionic  neurons   and  their  effector  cells   • Primary   transmitter   at   the   somatic   (voluntary)   skeletal   muscle  neuromuscular  junction                                                     STEP  1  –  SYNTHESIS   • ACh   is   synthesized   from   Acetyl   CoA   and   choline   by   the   enzyme  acetyltransferase  (ChAT)   o Choline  transport  inhibited  by  HEMICHOLINIUM     STEP  2  –  STORAGE   • ACh   is   actively   transported   (endocytosis)   into   vesicles   for   storage  by  vesicle-­‐associated  transport  (VAT)   o Inhibited  by  VESAMICOL     STEP  3  –  RELEASE   • Entry   of   calcium   triggers   interaction   among   SNARE   proteins  (VAMPs  and  SNAPs)   o BOTULINUM   toxins   alter   synaptobrevins   to   prevent  release  of  ACh  

  STEP  4  –  TERMINATION   • Degradation   of   ACh   into   choline   and   acetate   by   acetylcholinesterase   o Inhibited   by   INDIRECT-­‐ACTING   CHOLINOMIMETICS   (CARBAMATES,   ORGANOPHOSPHATES,  and  NEOSTIGMINE)       Cholinergic  Drug  Effects   • Not   very   useful   for   systemic   therapy   because   their   effects   are  not  sufficiently  selective   o PANS   and   SANS   ganglia   and   somatic   neuromuscular  junctions  all  may  be  blocked   • Botulinum  toxin  is  a  very  alrge  molecule  and  diffuses  very   slowly     o Injection  for  relatively  selective  local  effects     Cholinoreceptors   Receptor   M1   M2  

Location   Nerve  endings   Heart,  some  nerve  endings  

M3   NN  

Effector   cells:   smooth   muscle,  glands,  endothelium   ANS  ganglia  

Ion  channel  

NM  

Neuromuscular  end  plate  

Ion  channel  

       

 

Mechanism   Gq-­‐coupled   Gl-­‐coupled   Gq-­‐coupled  

Major  functions   ↑  IP3,  DAG  cascade   ↓   cAMP,   activates   K+   channels   ↑  IP3,  DAG  cascade   Depolarizes,   evokes   action  potential   Depolarizes,   evokes   action  potential  

 

CHOLINORECEPTOR-­‐ACTIVATING  AND   CHOLINESTERASE-­‐INHIBITING  DRUGS                           DIRECT  –  ACTING  CHOLINOMIMETICS,  MUSCARINIC     BETANECHOL   Class   Cholinomimetic  (direct  –  acting,  muscarinic)   MOA   Activates  muscarinic  (M3)  receptors   Uses   Bladder  and  bowel  atony  (post-­‐surgery  or  spinal  cord   injury)   SE   Cyclospasm,   Diarrhea,   Urinary   urgency,   Vasodilation,   Reflex  tachycardia,  Sweating     MNEMONICS  –  Betanechol   B  =  Betanechol  =  Bowel  and  Bladder  Atony     PILOCARPINE   Class   Cholinomimetic  (direct  –  acting,  muscarinic)   MOA   Activates  muscarinic  (M3)  receptors  in  ciliary  muscle   (increasing   aqueous   humor   outflow)   and   salivary   glands  (increasing  salivation)   Uses   Glaucome,  Sjogren’s  syndrome,  Sicca  syndrome  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SE   Miosis,  Blurring  of  vision  (due  to  cyclospasm)     KEY  LEARNING  POINTS  –  Sjogren’s  Syndrome!   What  is  Sjogren  Syndrome?   Autoimmune  disorder  characterized  by:   • XEROSTOMIA  (dry  mouth)   • XEROPHTHALMIA  (dry  eys)   • RHEUMATOID  ARTHRITIS     DIRECT  –  ACTING  CHOLINOMIMETICS,  NICOTINIC     NICOTINE   SimD   VARENICLINE   Class   Cholinomimetic  (direct  –  acting,  nicotinic)   MOA   Activates  nicotinic  ACh  receptors  (NN  and  NM)   Uses   Smoking  Cessation   SE   Generalized   ganglionic   stimulation   (hypertension,   tachycardia,  nausea,  vomiting,  diarrhea)   Notes   Overdose  leads  to  convulsions,  paralysis  and  coma     Muscarinic  Toxicity   • CNS  stimulation   • EYE:  miosis,  spasm  of  accommodation   • LUNGS:  bronchoconstriction   • GIT/GUT:   excessive   gastrointestinal   and   genitourinary   smooth  muscle  activity   • Increased   secretory   activity   (sweat   glands,   airway,   gastrointestinal  tract,  lacrimal  glands)   • Vasodilation     Mushroom  Posoning   • Muscarine   and   similar   alkaloids   found   in   mushrooms   (Inocybe  and  Amanita  muscaria)   o Responsible   for   the   short-­‐acting   form   of   mushroom   poisoning   (nausea,   vomiting   and   diarrhea)     Nicotinic  Toxicity   • Ganglionic  stimulation   • Blockade  of  neuromuscular  end  plate  depolarization   o Leading  to  fasciculations  and  paralysis   • CNS   toxicity:   stimulation   (convulsions)   followed   by   CNS   depression   INDIRECT  –  ACTING  CHOLINOMIMETICS         MOA  of  Indirect-­‐Acting  Cholinomimetics   • Bind  to  cholinesterase  and  undergo  prompt  hydrolysis   o Alcohol  portion  released   o Acidic  portion  retained  and  released  slowly    Prevents   the   binding   and   hydrolysis   of   endogenous  acetylcholine    Amplify   acetylcholine   effects   wherever   ACh  is  released   • No   significant   actions   at   uninnervated   sites   where   ACh   is   NOT  normally  released     EDROPHONIUM   Class   Cholinomimetic  (indirect  –  acting)   MOA   Inhibits   acetylcholinesterase.   Amplifies   endogenously   released  acetylcholine   Uses   Myasthenia   gravis   (diagnosis   –   Tensilon   test),   Differentiation  of  cholinergic  crisis  and  mysthenic  crisis   SE   Miosis,   Salivation,   Nausea,   Vomiting,   Diarrhea,  

Notes  

Bradychardia   Very  short-­‐acting  upon  intravenous  administration  

  NEOSTIGMINE   SimD   PYRIDOSTIGMINE,  PHYSOSTIGMINE   Class   Cholinomimetic  (indirect  –  acting)   MOA   Inhibits   acetylcholinesterase.   Amplifies   endogenously   released  acetylcholine   Uses   Myasthenia   gravis   (treatment),   Reversal   of   nondepolarizing   neuromuscular   blockade,   Ogilvie   syndrome,  Glaucoma  (physostigmine  ONLY)   SE   Miosis,   Salivation,   Nausea,   Vomiting,   Diarrhea,   Bradychardia   Notes   Muscarinic  effects  are  blocked  by  ATROPINE     CORRELATIONS  –  Myasthenia  Gravis!   What  is  myasthenia  gravis?   Autoimmune   destruction   of   nicotinic   ACh   receptors,   characterized  by:   • Fluctuating  muscle   • Weakness   • Ocular  symptoms   • Bulbar  symptoms   • Proximal  muscle  weakness     Differentiate  myasthenic  crisis  from  cholinergic  crisis.   MYASTHENIC  CRISIS   • Acute   worsening   of   symptoms   due   to   infection,   stress   or   UNDERmedication     CHOLINERGIC  CRISIS   • Excessive   activation   of   cholinoceptors   (skeletal   muscle   weakness   and   parasympathetic   signs)   due   to   OVERmedication     How   does   EDROPHONIUM   differentiate   myasthenic   crisis   from   cholinergic  crisis?   • IMPROVES  muscle  strength  in  MYASTHENIC  CRISIS   • WEAKENS  muscle  strength  in  CHOLINERGIC  CRISIS     RIVASTIGMINE   SimD   GALANTAMINE,  DONEPEZIL,  TACRINE   Class   Cholinomimetic  (indirect  –  acting)   MOA   Inhibits   acetylcholinesterase.   Amplifies   endogenously   released  acetylcholine   Uses   ALZHEIMER’S  DISEASE   SE   Miosis,   Salivation,   Nausea,   Vomiting,   Diarrhea,   Bradychardia       MNEMONICS  –  ORGANOPHOSPHATE  POISONING!   What  are  the  signs  and  symptoms  of  organophosphate  poisoning?   DUMBBELSS!   Diarrhea   Urination   Miosis   Bronchospasm     Bradycardia   Excitation  (skeletal  muscle  and  CNS)   Lacrimation   Sweating   Salivation     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 14 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] TREATMENT  OF  ORGANOPHOSPHATE  POISONING     ATROPINE   Class   Cholinergic  Antagonist  (muscarinic)   MOA   Competitively  blocks  ALL  muscarinic  receptors   Uses   Mydriatic,   Cycloplegic,   Antidote   for   organophosphate   poisoning   (first   choice),   Bradycardia,  Hypersalivation   SE   Tachycardia,   Mydriasis,   Cycloplegia,   Skin   flushing,   Delirium,  Hallucinations   Notes   No  effect  on  the  nicotinic  signs  of  toxicity     PRALIDOXIME   Class   Cholinesterase  Regenerator,  Antidote   MOA   Binds   phosphorus   of   organophosphate.   Breaks   organophosphate  bond  with  cholinesterase   Uses   Antidote   for   organophosphate   poisoning   and   nerve   gas  poisoning  (sarin,  tabun)   SE   Muscle  weakness   Notes   Must   be   administerd   before   6–8   hours   of   organophosphate  bond  with  cholinesterase  occurs    

CHOLINOCEPTOR  BLOCKERS                     Atropine   • Prototype  nonselective  muscarinic  blocker   • Found  in  Atropa  belladonna   • Tertiary  amine  that  readily  crosses  membrane  barriers     MNEMONICS  –  Cytoplegia  and  Mydriasis   C  =  Cycloplegia  =  Ciliary  muscle  paralysis  =  loss  of  Accomodation   M  =  Mydriasis  =  Dilate  (or  you  dilate  your  mouth  when  you  say   mydriasis)     ATROPINE   SimD   HOMATROPINE,  CYCLOPENTOLATE,  TROPICAMIDE   Class   Cholinergic  antagonists  (muscarinic)   MOA   Competitively  blocks  ALL  muscarinic  receptors   Uses   Mydriatic,   Cycloplegic,   Antidote   for   organophosphate   poisoning,   (first   choice),   Bradycardia,  Hypersalivation   SE   Tachycardia,   Mydriasis,   Cycloplegia,   Skin   flushing,   Delirium,  Hallucinations     BENZTROPINE   SimD   BIPERIDEN,  TRIHEXYPHENIDYL   Class   Cholinergic  antagonists  (muscarinic)   MOA   Competitively   blocks   ALL   muscarinic   receptors.   Restores   neurotransmitter   balance   in   the   basal   ganglia   Uses   PARKINSON’S  DISEASE   SE   Blurring  of  vision,  Dry  eyes,  Constipation,  Dry  mouth,   Urinary  retention   Notes   Reduces  tremors  more  than  bradykinesia  or  rigidity    

MNEMONICS  –  Muscarinic  Antagonists  for  Parkinsonism   Try  to  park  your  Benz,  Beep  here!   TRIhexyphenidyl   BENZtropine   BIPeriden     IPRATROPIUM   SimD   TIOTROPIUM   Class   Cholinergic  anragonists  (muscarinic)   MOA   Blocks   muscarinic   receptors   in   bronchial   smooth   muscle.  Prevents  vagal-­‐stimulated  bronchoconstriction.   Uses   ASTHMA,  COPD   SE   Dry  mouth,  Cough,  Nasal  dryness   Notes   More   effective   and   less   toxic   than   beta-­‐agonists   in   patients  with  COPD  and  Heart  disease       KEY  LEARNING  POINTS  –  Ipratropium  in  COPD   Why  is  ipratropium  the  preferred  bronchodilator  in  patients  with   comorbid  COPD  and  heart  disease?    Less  likely  to  cause  tachycardia;  and    Cardiac  arrhythmias     SCOPOLAMINE   Class   Cholinergic  antagonists  (muscarinic)   MOA   Competitively   blocks   ALL   muscarinic   receptors.   Antagonizes  histamine  and  serotonin   Uses   MOTION  SICKNESS   SE   Drowsiness,   Blurring   of   vision,   Dry   eyes,   Constipation,   Dry  mouth,  Urinary  retention   Notes   Applied  as  a  transdermal  patch     Atropine  Toxicity   • Atropine  fever  (hyperthermia)   • Atropine  flush  (cutaneous  vasodilation)   • Decreased  secretions   • Tachycardia   • Arrhythmias  (intravenous  conduction  block)   • Constipation   • Blurred  vision   • CNS  toxicity     MNEMONICS  –  Atropine  Toxicity    HOT  as  a  hare    DRY  as  a  bone    RED  as  a  beet    BLIND  as  a  bat    MAD  as  a  hatter     Contraindications  to  Muscarinic  Blockers!   • Cautious  use  in  infants   • Hyperthermia  due  to  decreased  sweating   • Acute  angle-­‐closure  glaucoma   • Benign  prostatic  hyperplasia     Ganglion  Blockers   • Competitive   pharmacologic   antagonists   at   nicotinic   acetylcholine  receptors   • First   successful   agents   for   the   treatment   of   hypertension   but  were  abandoned   • Adverse  effects   of   ganglion   blockade   in   hypertension   are   so   severe     HEXAMETHONIUM  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SimD   Class   MOA   Uses   SE  

TRIMETHAPHAN   Cholinergic  antagonists  (nicotinic)   Completitively  blocks  NN  nicotinic  ACh  receptors   Hypertension  (obsolete),  Hypertensive  emergencies     POSTURAL  HYPOTENSION,  Dry  mouth,  Blurred  vision,   Constipation,  Sexual  dysfunction  

  Neuromuscular  Blockers   • Important   for   producing   complete   skeletal   muscle   relaxation  in  surgery   • Classification:   o NONDEPOLARIZING  –  Tubocurarine,   Pancuronium,  Atracurium,  Vecuronium   o DEPOLARIZING  –  Succinylcholine   MNEMONICS  –  Succinylcholine   Kapag  nakapag-­‐DEPOsit  ka  sa  toilet,  SUCCess  yun!   (DEPOlarizing  =  SUCCinylcholine      

ADRENERGIC  PHARMACOLOGY  

STEP  2  –  STORAGE   • Norepinephrine   and   dopamine   are   transported   into   vesicles   o Inactivated   by   monoamine   oxidase   in   the   cytoplasm   • MAOIs  increase  stores  of  Norepinephrine  and  Dopamine   • Vesicular  transport  inhibited  by  RESERPINE     STEP  3  –  RELEASE   • Entry   of   calcium   triggers   interaction   among   SNARE   proteins  (VAMPs  and  SNAPs)   o Inhibited  by  GUANETHIDINE   o Promoted  by  AMPHETAMINES  and  TYRAMINE     STEP  4  –  TERMINATION   • Diffusion  and  reuptake  via  NET  and  DAT  in  synaptic  cleft   o Inhibited  by  COCAINE  and  TCAs   • Metabolized   by   MAO   and   COMT   into   metanephrine   and   VMA   o Inhibited  by  MAOIs  and  COMT  INHIBITORS       SITES  OF  AUTONOMIC  DRUG  ACTION   STEPS   INHIBITORS   CHOLINERGIC   ADRENERGIC   SYNTHESIS   Hemicholinium   Metyrosine   STORAGE   Vesamicol   Reserpine   RELEASE   Botulinum   Guanethidine   TERMINATION     Metabolism   Neostigmine   MAOIs,  COMTIs   Reuptake   NONE   Cocaine,  TCAs     Drug  Effects  on  Adrenergic  Transmission   • Used  in  treatment  of  several  diseases  (pheochromocytoma,   hypertension)   o Block   sympathetic   but   NOT   parasympathetic   functions   • Other  drugs  promote  catecholamine  release   o Predictably  cause  sympathomimetic  effects     Adrenoceptors  

  NOREPINEPHRINE   • Primary   transmitter   at   the   sympathetic   post-­‐ganglionic   neuron-­‐effector  cell  synapses  in  most  tissues   o EXCEPTIONS!    Eccrine  sweat  galnds    Vasodilator   sympathetic   fibers   in   skeletal  muscle     MNEMONICS  –  Dopamine  /  Norepinephrine   Dopamine  vasoDILATES  renal  blood  vessel  while;     Norepinephrine  vasoCONSTRICTS  them                       Receptor   Location   G   2nd   Messenger     Alpha1  (α1)   Effector     ↑  IP3,  DAG     tissues   Gq     Smooth  muscle     Glands     Alpha2  (α2)   Nerve  endings   Gi   ↓  cAMP     Smooth  muscle       Beta1  (β1)   Cardiac  muscle   Gs   ↑  cAMP     JG  apparatus     Beta2  (β2)   Smooth  muscle   Gs   ↑  cAMP     Liver     Heart       Beta3  (β3)   Adipose  cells   Gs   ↑  cAMP     Dopamine   Smooth  muscle   Gs   ↑  cAMP   STEP  1  –  SYNTHESIS   (D1)   • Tyrosine   is   hydroxylated   by   tyrosine   hydroxylase   to   DOPA     o Inhibited  by  METYROSINE     • DOPA  is  decarboxylated  to  Dopamine   Alpha  –  1  (α1)  Adrenergic  Effects   • Dopamine  is  hydroxylated  to  Norepinephrine   Tissue   Actions     Most  vascular  smooth  muscle   Contracts   (↑   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 16 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

Major   Functions   ↑   Ca2+,   causes   contraction,   secretion   ↓   transmitter   release,   causes   contraction   ↑   heart   rate,   force   ↑   renin   release   Relax   smooth   muscle,   ↑   glycogenolysis,   ↑  HR,  force   ↑  lipolysis   Relax   renal   vascular   smooth  muscle  

vasacular  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] MOA  of  Sympathomimetics   • Direct  activation  of  adrenoceptors   • Indirect  activation  by  increasing  concentration  of  available   catecholamines  in  the  synapse   o Release  of  stored  catecholamines   o Inhibition  of  reuptake     EPINEPHRINE   Class   Sympathomimetic  (non-­‐selective,  direct-­‐acting)   MOA   Activates  α  and  β  adrenergic  receptors   α1:vasoconstriction,  increases  BP   β1:  increased  HR,  conduction  and  contractility   β2:    bronchodilation     Uses   Cardiac  arrest,  Anaphylaxis,  Asthma,  COPD,  Hemostasis   SE   Hypertension,  Tachycardia,  Ischemia,  Hyperglycemia     NOREPINEPHRINE   Class   Sympathomimetic  (non-­‐selective,  direct-­‐acting)   MOA   Activates  α  and  β  adrenergic  receptors   α1:vasoconstriction,  increases  BP   β1:  increased  HR,  conduction  and  contractility   β2:    bronchodilation   Uses   Neurogenic  shock,  Cardiogenic  shock  (last  resort)   SE   Extreme   vasospasm,   Tissue   necrosis,   Excessive   blood   pressure   increase,   Arrhythmias,   Infarction,   Reflex   bradycardia   Notes   Compensatory   vagal   reflexes   tend   to   overcome   the   direct  positive  chronotropic  effects     DOPAMINE   Class   Sympathomimetic  (non-­‐selective,  direct-­‐acting)   MOA   Activates  α,  β  and  D1  adrenergic  receptors   α1:vasoconstriction,  increases  BP   β1:  increased  HR,  conduction  and  contractility   D1:  vasodilation  in  splanchnic  and  renal  vessels   Uses   Shock,  Heart  failure   SE   Cardiovascular  disturbance,  Arrhythmias     Dose-­‐Dependent  Actions  of  Dopamine   • LOW  DOSE  (1-­‐5  mcg/kg/min)   o Vasodilation   in   the   splanchnic   and   renal   vascular   beds  via  D1  receptors   o Increased  renal  blood  flow  and  urine  output     • MEDIUM  DOSE  (5-­‐15  mcg/kg/min)   o Increased   renal   blood   flow,   heart   rate,   cardiac   contractility,  and  cardiac  output  via  β1  receptors     • HIGH  DOSE  (>15  mcg/kg/min)   o Vasoconstriction   and   increased   blood   pressure   via  α  receptors     ISOPROTERENOL   SYMPATHOMIMETICS   Class   Sympathomimetic  (beta  non-­‐selective)     MOA   Non-­‐selectively  activates  β  adrenergic  receptors     β1:  increased  HR,  conduction  and  contractility     β2:    bronchodilation     Uses   ASTHMA       SE   Cardiovascular  disturbance,  Arrhythmias         Selective  Alpha-­‐1  (α1)  Agonists         PHENYLEPHRINE     SimD   PSEUDOEPHEDRINE   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 17 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected] resistance)   Pupillary  dilator  muscle   Contracts  (mydriasis)   Pilomotor  smooth  muscle   Contracts  (erects  hair)   Liver   (in   some   species,   eg,   Stimulates  glycogenolysis   rat)     Alpha  –  2  (α2)  Adrenergic  Effects   Tissue   Actions   Adrenergic   and   Cholinergic   Inhibits  transmitter  release   nerve  terminals   Platelets   Stimulates  aggregation   Some   vascular   smooth   Contracts   muscle   Fat  cells   Inhibits  lipolysis   Pancreatic  B  cells   Inhibits  insulin  release     Beta  –  1  (β1)  Adrenergic  Effects   Tissue   Action   Heart   Stimulates  rate  and  force   JG  cells  of  kidney   Stimulates  renin  release     Beta  –  2  (β2)  Adrenergic  Effects       Tissue   Action   Airways,   uterine,   and   Relaxes   vascular  smooth  muscle     Liver  (human)   Stimulates  glycogenolysis   Pancreatic  (B)  cells   Stimulates  insulin  release   Somatic   motor   neuron   Causes  tremor   terminals  (voluntary  muscle)   Heart   Stimulates  rate  and  force     MNEMONIC  –  Beta  Receptors   You  have  1  HEART  and  2  LUNGS!   β1  for  the  heart;   β2  for  the  lungs     Miscellaneous  Adrenergic  Effects   • Beta  –  3  (β3)  Adrenergic  Effects   Tissue   Actions   fat  cells   Stimulates  lipolysis     • Dopamie  –  1  (D1)  Adrenergic  Effects   Tissue   Actions   Renal  and  other  splanchnic   Dilates  (↓  resistance)   blood  vessels     • Dopamine  –  2  (D2)  Adrenergic  Effects   Tissue   Action   Nerve  terminals   Inhibits  adenylyl  cyclase      

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Class   MOA   Uses   SE   Notes  

Sympathomimetic  (alpha-­‐1  selective)   Selectively  activates  α1  adrenergic  receptors   α1:  vasoconstriction,  increase  BP   Decongestants,   Mydriatic,   Drug-­‐induced   hypotension,   Spinal  shock   REBOUND   NASAL   CONGESTION,   Hypertension,   Stroke,  Myocardial  Infarction   Ocular   administration   causes   mydriasis   WITHOUT   CYCLOPLEGIA  

  Selective  Alpha-­‐2  (α2)  Agonists     CLONIDINE     Class   Sympathomimetic  (alpha-­‐2  selective)   MOA   Activates  α2  adrenergic  receptors   α2:  decreases  central  sympathetic  outflow   Uses   Hypertension,  Cancer  pain,  Opioid  withdrawal   SE   Sedation,  Rebound  hypertension,  Dry  mouth   Notes   Taper   use   prior   to   discontinuation   to   avoid   rebound   hypertension   To   treat   rebound   hypertension,   administer   PHENTOLAMINE     METHYLDOPA   Class   Sympathomimetic  (alpha-­‐2  selective)   MOA   Activates  α2  adrenergic  receptors   α2:  decreases  central  sympathetic  outflow   Uses   PRE-­‐ECLAMPSIA   SE   Sedation,  Hemoyltic  anemia  (positive  Coomb’s  test)     APRACLONIDINE   SimD   BRIMONIDINE   Class   Sympathomimetic  (alpha-­‐2  selective)   MOA   Activates  α2  adrenergic  receptors   α2:  decreases  secretion  of  aqueous  humor   Uses   GLAUCOMA   SE   Blurring  of  vision,  Dry  mouth,  Conjunctivitis     Selective  Beta-­‐1  (β1)  Agonists       DOBUTAMINE   Class   Sympathomimetic  (beta-­‐1  selective)   MOA   Activates  β1  adrenergic  receptors   β1:  increases  HR  and  contractility   Uses   Acute  heart  failure,  Cardiogenic  shock   SE   Tachycardia,  Arrhythmias,  Tachyphylaxis   Notes   May  also  be  used  in  cardiac  stress  testing       Selective  Beta-­‐2  (β2)  Agonists     ALBUTEROL/SALBUTAMOL   SimD   TERBUTALINE,  RITODRINE   Class   Sympathomimetic  (beta-­‐2  selective)   MOA   Activates   β2   receptors   in   bronchial   smooth   muscle.   Causes  bronchodilation.   Uses   Acute   asthma   attacks   (drug   of   choice),   TOCOLYSIS   for  preterm  labor  (terbutaline  and  ritodrine)   SE   Tachycardia,   Tremors,   Nervousness,   Restlessness,   Arrhythmias   when   used   excessively,   Loss   of   responsiveness  (tolerance,  tachyphylaxis)   Notes   May   precipitate   arrhythmias   in   patients   with   concurrent  COPD  and  heart  disease  

  Clinical  Applications  of  Sympathomimetics   Clinical  Condition   Acute  heart  failure   Septic  shock   Hemostasis   Decongestion   Spinal  shock   Bronchospasm   Premature  labor   Hypertension   Glaucoma  

Desired  Parameter   Increased  cardiac   output   Vasoconstriction   Temporary   maintenance  of  BP   Bronchodilation   Uterine  smooth   muscle  relaxation   Decrease  BP  

Sympathomimetic  of   choice   β1  &  D1  agonists  

α1  agonists   β2  agonists   α2  agonists  

 

ADRENOCEPTOR  BLOCKERS                               Non-­‐selective  Alpha  Blockers     PHENOXYBENZAMINE   Class   Adrenergic  antagonist  (alpha  non-­‐selective)   MOA   Irreversibly  blocks  α  adrenergic  receptors  (α1  >  α2)     Uses   PHEOCHROMOCYTOMA  (pre-­‐surgical)   SE   Orthostatic   hypotension,   Reflex   tachycardia,   Gastrointestinal  irritation   Notes   Forms   covalent   bond   with   α   receptors   (effects   last   for   several  days)     PHETOLAMINE   Class   Adrenergic  antagonist  (alpha  non-­‐selective)   MOA   Reversibly  blocks  α  adrenergic  receptors  (α1  >  α2)   Uses   Pheochromocytoma   (pre-­‐surgical),   Antidote   to   α1   agonist  oerdose,  REBOUND  HYPERTENSION   SE   Orthostatic   hypotension,   Reflex   tachycardia,   Gastrointestinal  irritation     Selective    Alpha1  (α1)  Blockers     PRAZOSIN   SimD   DOXAZOSIN,  TERAZOSIN,  TAMSULOSIN,  SILODOSIN   Class   Adrenergic  antagonist  (alpha-­‐1  selective)   MOA   Selectively  blocks  α1  adrenergic  receptors   Uses   Benign  prostatic  hyperplasia,  Hypertension   SE   First   dose   orthostatic   hypotension,   Reflex   tachycardia   (less  chance)   Notes   Tamsulosin   is   most   selective   for   prostatic   smooth   muscle       KEY  LEARNING  POINTS  –  Alpha-­‐1  Selectivity   What  is  the  pharmacologic  advantage  of  α1  selectivity?  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 18 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  Relax  tachycardia  is  less  common  and  less  severe     MNEMONICS  –  Isoproterenol   ISOproterenol  is  NOT  a  beta  blocker!   It  is  a  non-­‐selective  beta  agonist.   I  SOrry  ka!  Akala  ko  beta  blocker  ka!     Non-­‐selective  Beta  Blockers     PROPRANOLOL   SimD   PINDOLOL,   TIMOLOL,   LABETALOL,   CARVEDILOL,   NADOLOL   Class   Adrenergic  antagonists  (beta  non-­‐selective)   MOA   Blocks  β1  and  β2  receptors.  Blocks  sympathetic  effects   on  heart  and  BP.  Reduces  renin  release   Uses   Angina   prophylaxis,   Hypertension,   Arrhythmias,   Migraine,  Performance  anxiety,  Hyperthyroidism   SE   Bronchospasm,   AV   block,   Heart   failure,   CNS   sedation,   Erectile  dysfunction   Notes   Masks  symptoms  of  hypoglycemia  in  diabetics   CARVEDILOL   and   LABETALOL   has   combined   α   and   β   blockade  (may  be  used  in  pheochromocytoma)     Beta-­‐Blockers  in  Diabetic  Patients   • Masking   of   premonitory   symptoms   of   hypoglycemia   from   insulin  overdosage  (tachycardia,  tremor,  anxiety)   • Impaired  hepatic  mobilization  of  glucose     Intrinsic  Sympathomimetic  Activity   • Parital  agonist  activity   • Advantage   in   treating   patients   with   asthma   because   these   drugs  are  less  likely  to  cause  bronchospasm   • PINDOLOL  ,  ACEBUTOLOL     MNEMONICS  –  Beta  Blockers  with  ISA   ISA  PA!  Isa  pa!  Isa  pang  CHICKEN  JOY!   Intrinsic  Sympathomimetic  Activity  =  PINDOLOL,  ACEBUTOLOL     Local  Anesthetic  Activity   • Membrane-­‐stabilizing  activity   • Disadvantage  when  beta-­‐blockers  are  used  topically  in  the   eye:   o Decreases  protective  reflexes   o Increases  the  risk  of  corneal  ulceration   • Absent   from   TIMOLOL   and   BETAXOLOL   making   them   useful  in  Glaucoma!     MNEMONICS  –  Nadolol   NADOLOL  =  NAsa  DOLO  =  longest  half  life!     Selective  Beta-­‐1  (β1)  Blockers     ATENOLOL   SimD   BETAXOLOL,  ESMOLOL,  ACEBUTOLOL,  METOPROLOL   Class   Adrenergic  antagonists  (beta-­‐1  selective)   MOA   Selectively   blocks   β1   receptors.   Blocks   sympathetic   effects  on  heart  and  BP   Uses   Angina,   Hypertension,   Heart   failure,   Supraventricular   tachycardia  (ESMOLOL  ONLY)   SE   Bronchospasm   (less   chance),   AV   block,   Heart   failure,   CNS  sedation,  Erectile  dysfunction   Notes   Masks  symptoms  of  hypoglycemia  in  diabetics   ESMOLOL  has  shortest  half-­‐life  

  MNEMONICS  –  Esmolol   ESMOLOL  =  ESMOL  (small)  =  shortest  half-­‐life!    

TREATMENT  OF  GLAUCOMA     Complex  Organ  Control:  The  Eye!   • Reciprocal  control  of  the  PUPIL   o SANS  (pupillary  dilator  muscle)   o PANS  (pupillary  constrictor)     • CILIARY  MUSCLE  (controls  accommodation)   o PANS  (primary  control  of  muscarinic  receptors   o Insignificant  contributions  from  the  SANA     • CILIARY  EPITHELIUM   o Important   receptors   with   permissive   effect   on   aqueous  humor  secretion                                                   FLOW  OF  AQUEOUS  HUMOR   Ciliary   body      Posterior   chamber      Anterior   chamber   angle      Pupil      Anterior   chamber      Trabecular   meshwork      Canal   of   Schlemm    Uveoscleral  veins     Treatment  of  Glaucoma   Drug  Class   Beta  blockers   Osmotic  agents   α2  –  agonist     Carbonic   anhydrase   inhibitors   Cholinomimetics  

Examples   TIMOLOL   MANNITOL   APRACLONIDINE   ACETAZOLAMIDE   DORZOLAMIDE   PILOCARPINE   PHYSOSTIGMINE  

P                                                                                            LATANOPROST                                 rostaglandins   Non-­‐selective     EPINEPHRINE   α  –  agonists    

                                                                                                                   

 

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Mechanism   Decreased   secretion   of   aqueous   humor   from   the   ciliary  epithelium  

Ciliary  muscle  contraction,   opening  of  trabecular   meshwork,  increased   outflow   Increased   outflow   through   canal  of  Schlemm   Increased   outflow   via   uveoscleral  veins  

 

 

         .  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

DRUGS  FOR  HYPERTENSION                                       KEY  LEARNING  POINTS  –  Target  BP   What  is  the  blood  pressure  goal  in  hypertensive  patients  with:    No  comorbidities?  <  140/90    Diabetes  mellitus?  <  130/80    Chronic  kidney  disease?  <  130/80                                           DIURETICS     HYDROCHLOROTHIAZIDE   SimD   CHLORTHALIDONE,  INDAPAMIDE,  METOLAZONE   Class   Thiazide  Diuretics   MOA   Inhibit   Na/Cl   transporter   in   distal   convoluted   tubule.   Cause   moderate   diuresis   and   reduced   excretion   of   calcium   Uses   Hypertension   (first   line),   Heart   failure,   Hypercalciuria,   Renal  calcium  stones,  Nephrogenic  diabetes  insipidus   SE   Hypokalemic  metabolic  alkalosis,     Dilutional  hyponatremia,  Potassium  wasting,   Hyperglycemia,  Hyperlipidemia,  Hyperuricemia,     Sulfa  allergy     FUROSEMIDE   SimD   BUMETANIDE,   TORSEMIDE,   ETHACRYNIC   ACID*   (greatest  diuretic  effect)     Class   Loop  Diuretics   MOA   Inhibit   Na/K/2Cl   transporter   in   thick   ascending   limb   of  

Uses   SE  

loop  of  Henle.  Cause  powerful  diuresis  and  increase  Ca+   excretion.   Heart  failure,  Pulmonary  edema,  Hypertension,   Hypercalcemia,  Acute  renal  failure,  Anion  overdose   Hypokalemic   metabolic   alkalosis,   Potassium   wasting,   Dehydration,   Ototoxicity,   Sulfa   allergy,   Hyperuricemia,   Hypomagnesemia,  Nephritis,  Hypocalcemia  

  SYMPATHOPLEGICS       CNS Sympathetic Outflow Blockers (Centrally-Acting Agents)                               1. CNS  Sympathetic  Outflow  Blockers     CLONIDINE   Class   Sympathetic  Outflow  Blocker   MOA   Activates  α2  adrenergic  receptors.   α2:  decreases  central  sympathetic  outflow     Uses   Hypertension,  Cancer  pain,  Opioid  withdrawal   SE   Sedation,  Rebound  hypertension,  Dry  mouth   Notes   Taper   use   prior   to   discontinuation     to   avoid   rebound   hypertension   To   treat   rebound   hypertension,   administer   PHENTOLAMINE     METHYLDOPA   Class   Sympathetic  Outflow  Blocker   MOA   Activates  α2  adrenergic  receptors.   α2:  decreases  central  sympathetic  outflow   Uses     PRE-­‐ECLAMPSIA   SE   Sedation,  Hemolytic  anemia  (positive  Coomb’s  test)     2. Ganglion  Blockers     HEXAMETHONIUM   SimD   TRIMETHAPHAN   Class   Ganglion  Blocker   MOA   Competitively  blocks  Nn  nicotinic  ACh  receptors   Uses   Hypertension  (obsolete),  Hypertensive  emergencies   SE   POSTURAL  HYPOTENSION,  Dry  mouth,  Blurred  vision,   Constipation,  Sexual  dysfunction     3. Nerve  Terminal  Blockers     RESERPINE   SimD   GUANETHIDINE   Class   Nerve  Termina  Blocker   MOA   Irreversibly   blocks   the   vesicular   monoamine   transporter  (VMAT)  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Uses   SE  

Hypertension  (obsolete)   Sedation,  Severe  psychiatric  depression,     Suicidal  ideation  

  4. Adrenergic  Blockers     PRAZOSIN   SimD   DOXAZOSIN,  TERAZOSIN,  TAMSULOSIN,  SILODOSIN   Class   Adrenergic  antagonists  (alpha-­‐1  selective)   MOA   Selectively  blocks  α1  adrenergic  receptors   Uses   Benign  prostatic  hyperplasia,  Hypertension   SE   FIRST  DOSE  Orthostatic  hypotension,     Reflex  tachycardia  (less  chance)   Notes   Tamsulosin   is   most   effective   for   prostatic   smooth   muscle!     PROPRANOLOL   SimD   PINDOLOL,   TIMOLOL,   LABETALOL,   CARVEDILOL,   NADOLOL   Class   Adrenergic  antagonists  (beta  non-­‐selective)   MOA   Blocks  β1  and  β2  receptors.  Blocks  sympathetic  effects   on  heart  and  BP.  Reduces  renin  release     Uses   Angina   prophylaxis,   Hypertension,   Arrhythmias,   Migraine,  Performance  anxiety,  Hyperthyroidism   SE   Bronchospasms,   AV   block,   Heart   failure,   CNS   sedation,   Erectile  dysfunction,  Asthma,  DM   Notes   Masks   symptoms   of   hypoglycemia   in   diabetics.   LABETALOL   has   combined   α   and   β   blockade   (may   be   used  in  Pheochromocytoma)     KEY  LEARNING  POINTS  –  Pheochromocytoma   What  drugs  are  used  to  control  blood  pressure  in   pheochromocytoma?    PHENOXYBENZAMINE  (irreversible  alpha  selective)    PHENTOLAMINE  (reversible)    LABETALOL     CARDIOACTIVE  DRUGS!   Singh  –  Vaughan  Williams  Classification    Class  I  –  Rapid  Sodium  channel  Blockers    Class  II  –  Beta  receptor  Blockers    Class  III  –  Potassium  channel  Blockers    Class  IV  –  Calcium  channel  Blockers     VASODILATORS     1. Older  Oral  Vasodilators     HYDRALAZINE   Class   Vasodilator   MOA   Alters  intracellular  Ca2+  metabolism.     Relaxes  arteriolar  smooth  muscle,  causing  vasodilation.   Decreases  afterload.   Uses   Hypertension,   Heart   failure   (in   combination   with   Isosorbide  Dinitrate  –  ISDN),  Pre-­‐eclampsia   SE   Edema,   Reflex   tachycardia,   Myocardial   ischemia,   Drug-­‐induced  lupus   Notes   Combination   treatment   with   ISDN   for   Heart   failure   is   more  effective  than  ACE  Inhibitors  in  Blacks!     MNEMONICS  –  Drug-­‐induced  Lupus!   What  medications  may  cause  drug-­‐induced  lupus?   It’s  HIPP  to  have  LUPUS!!!  

   

HYDRALAZINE   ISONIAZID   PROCAINAMIDE   PENICILLAMINE  

  MINOXIDIL   Class   Vasodilator   MOA   Opens   K+   channels   in   vascular   smooth   muscles,   causing   hyperpolarization,  muscle  relaxation  and  vasodilation   Uses   Hypertension,  ALOPECIA   SE   Edema,   Reflex   tachycardia,   Angina,   Pericarditis,   Pulmonary  hypertension,  HYPERTRICHOSIS     KEY  LEARNING  POINTS  –  Hypertrichosis  and  Minoxidil  Use   How  does  minoxidil  cause  excessive  hair  growth?    Minoxidil   stimulates   hair   follicles   (telogen   phase)   to   differentiate  into  growth  follicles  (anagen  phase)     2. Calcium  Channel  Blockers     VERAPAMIL   SimD   DILTIAZEM   Class   Non-­‐dihydropyridine  Calcium  channel  Blocker   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (cardiac  >  vascular)   Uses   Angina,   Hypertension,   Supraventricular   tachycardia,   Migraine   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,  Gingival  hyperplasia,  Heart  failure,  AV  block,   Sinus  node  depression   NIFEDIPINE   SimD   AMLODIPINE,   FELODIPINE,   NICARDIPINE,   NISOLDIPINE   Class   Dihydropyridine  Calcium  channel  Blockers   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (vascular  >  cardiac)   Uses   Angina,  Hypertension   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,  Gingival  hyperplase  (less  chance)     3. Parenteral  Vasodilators     NITROPRUSSIDE   Class   Vasodilator   MOA   Relaxes   venous   and   arteriolar   smoth   muscle.   Decreases   both   preload   and   afterload.   Activate   guanidyl   cyclase.   Increases  cGMP  release   Uses   Hypertensive   emergency,   Acute   heart   failure,   Cardiogenic  shock,  Controlled  hypotension   SE   Hypotension,  Headache,  CYANIDE  TOXICITY     FENOLDOPAM   Class   Dopamine  agonist   MOA   Causes   arteriolar   vasodilation   of   the   afferent   and   efferent  arterioles.  Increases  renal  blood  flow.   Uses   Hypertensive  emergency  (2nd  type  of  hypertension)   SE   Hypotension,  Hypokalemia   Notes   Duration  of  action:  10  minutes            

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] ANGIOTENSIN  ANTAGONISTS                                       1. ACE  Inhibitors     CAPTOPRIL   SimD   ENALAPRIL,   BENAZEPRIL,   FOSINOPRIL,   LISINOPRIL,   QUINAPRIL,  RAMIPRIL,  TRANDOLAPRIL   Class   Angiotensin  Converting  Enzyme  (ACE)  –  Inhibitors   MOA   Inhibits  ACE  and  formation  of  Angiotensin  II.  Decreases   aldosterone  secretion.   Uses   Hypertension,  Heart  failure,  Post-­‐myocardial  infarction,   Diabetic  nephropathy   SE   Cough,   Taste   disturbance,   Angioedema,   Hypotension,   Teratogen,  Hyperkalemia   Notes   Slow   ventricular   remodeling   and   increases   survival   in   heart  failure   Delays  progression  of  diabetic  nephropathy!   FIRST  LINE  DRUG  FOR  CHRONIC  HEART  FAILURE!!     KEY  LEARING  POINTS  –  ACE-­‐Inhibitors   Why   are   patients   with   diabetic   nephropathy   treated   with   ACE-­‐ Inhibitors?    ACE   inhibitors   decrease   albumin   excretion   and   slow   progression   from   micro-­‐   to   macroalbuminuria   (renoprotective  effect)     2. Angiotensin  Receptor  Blockers     LOSARTAN   SimD   CANDESARTAN,   VALSARTAN,   IRBESARTAN,   EPROSARTAN,  TELMISARTAN     Class   Angiotensin  Receptor  Blockers  (ARB)   MOA   Blockes   Angiotensin   (AT1   receptors)   in   vascular   smooth   muscle   and   adrenal   cortex.   Decreases   aldosterone  secretion.   Uses   Hypertension,  Heart  failure,  Diabetic  nephropathy   SE   Hypotension,  Teratogen,  Hyperkalemia   Notes   Slows  ventricular  remodeling  and  increases  survival  in   heart  failure   Delays  progression  of  diabetic  nephropathy!     KEY  LEARNING  POINTS  –  Hyperkalemia   Why   do   patients   taking   Angiotensin   antagonists   (ACE-­‐Is/ARBs)   develop  hyperkalemia?    ACE-­‐Is/ARBs   reduce   aldosterone   levels   and   causes   potassium  retention    

3. Renin  Antagonists     ALISKIREN   Class   Renin  Antagonist   MOA   Inhibits  renin.  Prevents  conversion  of  Angiotensinogen   to  Angiotensin  I   Uses   HYPERTENSION   SE   Headache,  Diarrhea,  Angioedema,  Renal  impairment   Notes   Not  used  with  ACE-­‐Is/ARBs,  may  lead  to  hyperkalemia     Malignant  Hypertension  (>  210/150)   • Accelerated   form   of   severe   hypertension   associated   with   rising   blood   pressure   and   rapidly   progressing   end-­‐organ   damage   • MANAGEMENT!   o Powerful   vasodilators   (nitroprusside,   fenoldopam,   or   diazoxide)   combined   with   diuretics   (furosemide)   and   beta   blockers   to   lower  BP  to  140-­‐160/90-­‐110    

DRUGS  USED  IN  THE  TREATMENT  OF   ANGINA  PECTORIS     Atherosclerotic  Angina   • Angina  of  effort  or  “Classic  Angina”   • Associated   with   atheromatous   plaques   that   partially   occlude  1  or  more  coronary  arteries   • Constitutes  about  90%  of  angina  cases     Vasospastic  Angina   • Rest  angina,  Variant  angina,  or  “Prinzmetal’s  Angina”   • Responsible  for  less  than  10%  of  cases   • Involves  reversible  spasm  of  coronaries,  usually  at  the  site   of  an  atherosclerotic  plaque   • May  deteriorate  into  unstable  angina     Unstable  Angina   • Unstable/crescendo  angina  /  “Acute  Coronary  Syndrome”   • Increase  frequency  and  severity  of  attacks  that  result  form   a   combination   of   atherosclerotic   plaques,   platelet   aggregation  and  vasospasms   • Immediate  precursor  of  Myocardial  infarction     Therapeutic  Strategies  in  Angina   • Defect   that   causes   anginal   pain   is   inadequate   coronary   oxygen   delivery   relative   to   the   myocardial   oxygen   requirement   • Can  be  corrected  in  2  ways:   o Increasing  oxygen  delivery   o Reducing  oxygen  requiremen                            

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                   VASODILATORS     1. Nitrates     AMYL  NITRITE   Class   Ultra  short-­‐acting  Nitrate   MOA   Releases   nitric   oxide   (NO),   increases   cGMP   (cyclic   Guanosine   Monophosphate)   and   relaxes   smooth   muscles,  especially  vascular   Uses   CYANIDE  POISONING   SE   Reflext   tachycardia,   Orthostatic   hypotension,   Headache,  METHEMOGLOBINEMIA     KEY  LEARNING  POINTS  –  Cyanide   Which   portion   of   the   electron   transport   chain   is   affectec   by   Cyanide?    Complex   IV   (cytochrome   oxidase)   of   the   Electron   Transport  Chain     What  is  the  antidote  for  Cyanide  poisoning?    Inhaled   amyl   nitrite   +   IV   sodium   nitrite   +   IV   sodium   thiosulfate     MONDAY  DISEASE   • Due  to  occupational  exposure  to  nitrates   • Alternating   development   of   tolerance   (during   the   work   week)   and   loss   of   tolerance   (over   the   weekend)   every   Monday!     NITROGLYCERIN   SimD   ISOSORBIDE  DINITRATE,  ISOSORBIDE  MONONITRATE   Class   Short-­‐acting  Nitrate   MOA   Releases   Nitric   oxide   (NO),   increases   cGMP   (cyclic   Guanosine   Monophosphate)   and   relaxes   smooth   muscles,  especially  vascular   Uses   ANGINA,  ACUTE  CORONARY  SYNDROME   SE   Reflex  tachycardia,  Orthostatic  hypotension,  Headache,   TOLERANCE  (transdermal)   Notes   Dangerous  hypotension  with  PDE  inhibitors                  

                          KEY  LEARNING  POINTS  –  Nitrate-­‐Induced  Headache   Why   do   patients   taking   nitrates   usually   experience   throbbing   headaches?    Due  to  meningeal  artery  vasodilation!     2. Calcium  Channel  Blockers     NIFEDIPINE   SimD   AMLODIPINE,   FELODIPINE,   NICARDIPINE,   NISOLDIPINE   Class   Dihydropyridine  Calcium  channel  Blockers   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (vascular  >  cardiac)   Uses   Angina,  Hypertension   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,  Gingival  hyperplasia  (less  chance)     VERAPAMIL   SimD   DILTIAZEM   Class   Non-­‐dihydropyridine  Calcium  channel  Blocker   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (cardiac  >  vascular)   Uses   Angina,   Hypertension,   Supraventricular   tachycardia,   Migraine   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,  Gingival  hyperplasia,  Heart  failure,  AV  block,   Sinus  node  depression     DILTIAZEM   Class   Non-­‐dihydropyridine  Calcium  channel  Blocker   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (cardiac  >  vascular)   Uses   Angina,   Hypertension,   Supraventricular   tachycardia,   Vasospasm,  RAYNAUD’S  PHENOMENON   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,   Heart   failure,   AV   block,   Sinus   node   depression     KEY  LEARNING  POINTS  –  Calcium  Channel  Blockers   Why   is   calcium-­‐dependent   neurotransmission   or   hormone   release  not  affected  by  Calcium  Channel  Blockers?    CCBs  block  L-­‐type  calcium  channels  ONLY!    Other  functions  use  N-­‐,  P-­‐  and  R-­‐types     What  drug  can  cause  gingival  hyperplasia?   NapaCa-­‐Pangit  ng  gingiVa  mo!    NIFEDIPINE    CYCLOSPORINE    PHENYTOIN    VERAPAMIL    

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] CARDIAC  DEPRESSANTS     1. Beta  Blockers     PROPRANOLOL   SimD   ATENOLOL,  METOPROLOL,  other  beta-­‐blockers   Class   Beta  Receptor  Blocker   MOA   Blocks   sympathetic   effects   on   heart   and   Blood   Pressure.  Reduces  renin  release     Uses   Angina   prophylaxis,   Hypertension,   Arrhythmias,   Migraine,  Performance  anxiety   SE   Excessive  β  blockade:  Bronchospasms,  AV  block,  Heart   failure,   CNS   sedation,   Masks   hypoglycemia   in   diabetic   patients,  Erectile  dysfunction     Effects  of  Drug  Combinations    

Nitrates   Alone  

BB  or  CCB   Alone  

Heart  rate   Arterial  pressure   End-­‐diastolic   pressure   Contractility  

Reflex  increase   Decrease   DECREASE  

DECREASE   DECREASE   Increase  

Reflex  increase  

DECREASE  

Ejection  time   Net   myocardial   O2  requirement  

Reflex  increase   DECREASE  

Increase   DECREASE  

Combined   Nitrate  and     BB  or  CCB   DECREASE   DECREASE   DECREASE   No  effect  or   decrease   No  effect   DECREASE  

  METABOLISM  MODIFIERS     TRIMETAZIDINE   SimD   VASTAREL   Class   Metabolism  Modifier   MOA   Impairs   glucose   utilization   through   Fatty   acid   metabolism.   Inhibit   beta   oxidation   of   Fatty   acids   by   inhibiting   3-­‐ ketoacyl  thiolase  which  enhances  glucose  oxidation   Notes   FIRST  CYTOPROTECTIVE  ANTI-­‐ISCHEMIC  AGENT      

DRUGS  USED  IN  HEART  FAILURE     Pathophysiology  of  Congestive  Heart  Failure   • Fundamental   physiologic   defect   is   decrease   in   cardiac   output  relative  to  the  needs  of  the  body   • Frequently   associated   with   chronic   hypertension,   valvular   disease,  coronary  artery  disease,  and  cardiomyopathies     Therapeutic  Strategies  for  CHF   • Removal  of  retained  salt  and  water  with  diuretics   • Reduction   of   afterload   and   salt   and   water   retention   by   means  of  ACE  Inhibitors   • Reduction   of   excessive   sympathetic   stimulation   by   means   of  beta-­‐blockers   • Reduction  of  preload  or  afterload  with  vasodilators   • Direct  augmentation  of  depressed  cardiac  contractility  with   positive  inotropic  drugs     Current  Clinical  Evidence  for  CHF   • ACUTE  HEART  FAILURE   o Should  be  treated  with  loop  diuretics  

If   very   severe,   use   prompt-­‐acting   positive   inotropes  (beta-­‐agonists  or  PDE  inhibitors)  and   vasodilators         CHRONIC  HEART  FAILURE   o Treated   with   diuretics   (often   loop   +   spironolactone)   plus   an   ACE   Inhibitor;   and   if   tolerated,  add  a  beta-­‐blocker   o DIGITALIS   may   be   helpful   if   systolic   dysfunction   is  prominent!  (cardio/renal-­‐protective)   o

•

  KEY  LEARNING  POINTS  –  Heart  Failure   Which  type  of  heart  failure  presents  with:    LEFT  HEART  FAILURE   o Orthopnea   o Paroxysmal  Nocturnal  Dyspnea  (PND)   o Pulmonary  congestion      RIGHT  HEART  FAILURE   o Hepatomegaly   o Edema   o Engorged  Neck  Veins                       DIGOXIN   Class   Cardiac  glycoside   MOA   Inhibits   Na/K   ATPase,   Increases   intracellular   Ca,   increasing  cardiac  contractility   Uses   Heart  failure,  Nodal  arrhythmias   SE   Narrow   therapeutic   index,   Arrhythmias,   Vomiting,   Diarrhea,  VISUAL  CHANGES   Intxn   Reduced   clearance   with   Quinidine,   Amiodarone,   Cyclosporine,  Diltiazem,  and  Verapamil   Notes   Arrhythmogenesisincreased   by   hypokalemia,   hypomagnesemia,  and  hypercalcemia       MNEMONICS  –  Narrow  Therapeutic  Index   What  drugs  have  narrow  therapeutic  index?   WALA  na  Cyang  PaPa!!  VasTeD  na!!!    Warfarin      Aminoglycosides    Lithium    Amphotericin  B    Carbamazepine    Phenobarbital    Phenytoin    Vancomycin    Theophylline    Digoxin     Digitalis  Toxicity   • Increased   by   HYPOKALEMIA,   HYPOMAGNESEMIA   and   HYPERCALCEMIA  (same  as  Thiazide)   o Loop   diuretics   and   Thiazides   may   significantly   reduce   serum   potassium   and   precipitate   digitalis   toxicity  

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Digitalis-­‐induced   vomiting   may   deplete   serum   magnesium  and  similarly  facilitate  toxicity  

  Treatment  of  Digitalis  Toxicity   • CORRECTION  OF  POTASSIUM/MAGNESIUM  DEFICIENCY   • ANTI-­‐ARRHYTHMIC  DRUGS   o Drug  of  choice  is:  LIDOCAINE   o Electronic   pacemaker   may   be   required   in   severe   cases   • DIGOXIN  ANTIBODIES   o Digoxin  antibodies  (Fab  fragments;  Digibind)   o May  save  patients  who  would  otherwise  die     OTHER  DRUGS  FOR  CONGESTIVE  HEART  FAILURE     1. Diuretics   • First-­‐line  therapy  for  both  systolic  and  diastolic  failure!   • FUROSEMIDE   for   immediate   reduction   of   the   pulmonary   congestion   and   severe   edema   associated   with   acute   heart   failure   • SPIRONOLACTONE   (aldosterone   antagonists)   and   EPLERENONE   have   significant   long-­‐term   benefits   and   can   reduce  mortality  in  chronic  failure     2. Angiotensin  Antagonists   • First-­‐line  drugs  for  Chronic  Heart  Failure!   • Reduce  aldosterone  secretion,  salt  and  water  retention,  and   vascular  resistance   • Decrease  ventricular  remodeling  (cardiprotective)   • Reduce  morbidity  and  mortality  in  chronic  heart  failure   • ARBs  have  the  same  benefits  as  ACE-­‐Inhibitors     3. Beta1-­‐Selective  Sympathomimetics   • DOBUTAMINE   (β1   –   selective)   and   DOPAMINE   are   useful   in  Acute  heart  failure   • NOT   appropriate   for   chronic   failure   because   of   tolerance,   lack  of  oral  efficacy  and  significant  arrhythmogenic  effects.       4. Beta-­‐Blockers   • CARVEDILOL,   LABETALOL,   and   METOPROLOL   reduce   progression  of  chronic  heart  failure   • Beta-­‐blockers  are  NOT  of  value  in  acute  failure  and  may  be   detrimental  if  systolic  dysfunction  is  marked     5. Phosphodiesterase  Inhibitors   • Examples:  INAMRINONE,  MILRINONE   • Mechanism  of  Action:   o Increase   cAMP   by   inhibiting   its   breakdown   by   phosphodiesterase;     o Increase  intracellular  Ca2+   o Vasodilation   • Should   NOT   be   used   in   chronic   failure   because   they   increase  morbidity  and  mortality     6. Vasodilators   • NITROPRUSSIDE   or   NITROGLYCERIN   for   acute   severe   failure  with  congestion   • Dramatically   effective   in   CHF   due   to   increased   afterload   (eg,   continuing   hypertension   in   an   individual   who   has   just   had  an  infarct)   • HYDRALAZINE   and   ISOSORBIDE   DINITRATE   has   been   shown  to  reduce  mortality  in  African  Americans   • Calcium  channel  blockers  are  of  NO  VALUE  in  CHF  

  MNEMONICS  –  Survival  in  CHF   What   drugs   have   been   shown   to   improve   survival   in   cases   of   heart  failure?   ABA!!  Buhay  ka  pa!!    ACE  Inhibitors    Beta-­‐blockers    Aldosterone  Antagonists      

ANTI-­‐ARRHYTHMIC  DRUGS                     Arrhythmogenic  Mechanisms   • ABNORMAL  AUTOMATICITY   o Pacemaker   acitivity   that   originates   anywhere   other  than  in  the  sinoatrial  node   • ABNORMAL  CONDUCTION   o Conduction  of  an  impulse  that  does  not  follow  the   defined  path  or  re-­‐enters  tissue  previously  excited     TORSADES  DE  POINTES   • Often   induced   by   anti-­‐arrhythmics   and   other   drugs   that   change   the   shape   of   action   potential   and   prolong   QT   interval   • “All  anti-­‐arrhythmics  are  PRO-­‐ARRHYTHMICS”                 ECG  Morphology   • Polymorphic   ventricular   tachycardia,   often   displaying   WAXING  and  WANING  QRS  AMPLITUDE   • Associated  with  Long  QT  Syndrome   o Heritable   abnormal   prolongation   of   the   QT   interval   caused   by   mutations   in   the   IK   or   INa   channel  proteins     Singh–Vaughan  Williams  Classification   • Based  loosely  on  the  channel  or  receptor  affected:   o CLASS  1:  Sodium  channel  Blockers   o CLASS  2:  Beta-­‐adrenoceptor  Blockers   o CLASS  3:  Potassium  channel  Blockers   o CLASS  4:  Calcium  channel  Blockers       CLASS  1  ANTI-­‐ARRHYTHMICS   • Have  local  anesthetic  activity   • Acts  on  PHASE  0  of  cardiac  action  potential   • Further  subdivided  based  on  their  effects  on  AP  duration   o GROUP  1A  drugs  prolong  the  AP  duration   o GROUP  1B  drugs  shorten  the  AP  duration   o GROUP  1C  drugs  have  NO  EFFECT  on  AP  duration      

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]   MNEMONICS  –  Class  1A  Anti-­‐arrhythmics!     Class  1A:   MOA  of  CLASS  1  Anti-­‐arrhythmics   I  Am  the  Queen  who  Proclaimed  Diso’s  pyramid!!    QUINIDINE   • ALL   group   1   drugs   slow   or   block   conduction   in   ischemic   and   depolarized   cells;   and   slow   or   abolish   abnormal    PROCAINAMIDE   pacemakers    DISOPYRAMIDE     • Most   selective   agents   (GROUP   1B)   have   significant   effects   on   sodium   channels   in   ischemic   tissue,   BUT   negligible   Treatment  of  Class  A1  Overdose   effects  on  normal  cells   • SODIUM  LACTATE  to  reverse  drug-­‐induced  arrhythmias   • Use  dependent  or  state  dependent  in  their  action!   • PRESSOR   SYMPATHOMIMETICS   to   reverse   drug-­‐induced   o Selectively   depress   tissues   that   are   frequently   hypotension,  if  indicated:   depolarizing     o Selectively   depresses   tissues   that   are   relatively   2. Class  1B  Anti-­‐arrhythmics   depolarized  during  rest     • AMIODARONE  has  class  A1  activity   MOA  of  GROUP  1B  Anti-­‐arrhythmics     • REDUCES  AP  duration   KEY  LEARNING  POINTS  –  CLASS  1  Anti-­‐arrhythmics   • Slows   recovery   of   sodium   channels   from   inactivation   What   are   the   effects   of   class   1   anti-­‐arrhythmics   on   action   leading  to  prolonged  ERP   potential  duration?   • Selectively   affects   ischemic   or   depolarized   Purkinje   and   • CLASS  1A:  prolongs  AP  duration   ventricular  tissue   • CLASS  1B:  shortens  AP  duration   o Because   these   agents   have   little   effect   on   normal   • CLASS  1C:  no  effect  on  AP  duration   cardiac   cells,   they   have   LITTLE   EFFECT   on   the     ECG     1. Class  1A  Anti-­‐arrhythmics   LIDOCAINE     SimD   MEXILETINE,  TOCAINIDE,  PHENYTOIN   PROCAINAMIDE   Class   Class  1B  Anti-­‐arrhythmics   Class   Class  1A  Anti-­‐arrhythmic   MOA   Highly-­‐selective  use-­‐  and  state-­‐dependent  INa  block;   MOA   Use-­‐   and   State-­‐dependent   block   INachannels;   Some   Minimal  effect  in  normal  tissue;  NO  EFFECT  on  IK   block  of  IK  channels.     Slowed   conduction   velocity   and   pacemaker   activity;   Uses   Drug   of   choice   for   Ventricular   arrhythmias   post-­‐ Prolonged   action   potential   duration   and   refractory   myocardial  infarction;  Digoxin-­‐induced  arrhythmias   period   SE   CNS   stimulation,   Cardiovascular   depression,   Uses   Atrian   and   Ventricular   arrhythmias,   especially   after   Arrhythmias,   Allergy,   Seizure,   AGRANULOCYTOSIS*   Myocardial  Infarction   (Tocainide)   SE   Arrhythmias,  Hypotension,  Lupus-­‐like  syndrome   Notes   Hyperkalemia  exacerbates  cardiac  toxicity   Lidocaine   is   the   LEAST   cardiotoxic   among   Notes   Hyperkalemia  exacerbates  cardiac  toxicity;   conventional  anti-­‐arrhythmias   Duration  of  action:  2-­‐3  hours       DISOPYRAMIDE   MNEMONICS  –  Class  1B  Anti-­‐arrhythmics!   Class  1B:   Class   Class  1A  anti-­‐arrhythmic   I  Buy  Mexican  Taco’s  from  Lily   MOA   Use-­‐   and   State-­‐dependent   block   INachannels;   Some    MEXILETINE   block  of  IK  channels.      TOCAINIDE   Slowed   conduction   velocity   and   pacemaker   activity;    LIDOCAINE   Prolonged   action   potential   duration   and   refractory     period   What  are  the  drugs  that  can  cause  AGRANULOCYTOSIS?   Uses   Atrial  and  Ventricular  arrhythmias   AGRANULOCYTOSIS!!  CCCAPPIT!   SE   Arrhythmias,   Hypotension,   Marked   anti-­‐muscarinic    CLOZAPINE   effects,  Heart  failure    CO-­‐TRIMOXAZOLE   Notes   Hyperkalemia  exacerbates  cardiac  toxicity    COLCHICINE      AMINOPYRINE   QUINIDINE    PHENYLBUTAZONE   Class   Class  1A  anti-­‐arrhythmic    PROPYLTHIOURACIL  (PTU)   MOA   Use-­‐   and   State-­‐dependent   block   INachannels;   Some    INDOMETHACIN   block  of  IK  channels.      TOCAINIDE   Slowed   conduction   velocity   and   pacemaker   activity;     Prolonged   action   potential   duration   and   refractory   3. Class  1C  Anti-­‐arrhythmics   period     Uses   Atrial  and  Ventricular  arrhythmias,  MALARIA   MOA  of  GROUP  1C  Anti-­‐arrhythmics   SE   Arrhythmias   (torsades),   Hypotension,   CINCHONISM   • Powerful  depressant  of  Sodium  current   (headache,   vertigo,   tinnitus),   Cardiac   depression,   GI   • Can   markedly   slow   conduction   velocity   in   atrial   and   upset,  Autoimmune  reactions  (ITP)   ventricular  cells   Notes   Hyperkalemia  exacerbates  cardiac  toxicity.   • ECG  effects:   Reduces  clearance  of  digoxin!     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 26 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

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NO  EFFECT  on  ventricular  AP  duration  or  the  QT   interval   Increases  the  QRS  duration  (pro-­‐arrhythmics)  

Uses  

Acute   perioperative   and   thyrotoxic   arrhythmias,   Supraventricular  tachycardia   Bronchospasms,  Cardiac  depression,  AV  block,   Hypotension  

o SE     FLECAINIDE     SimD   PROPAFENONE,  ENCAINIDE,  MORICIZINE   KEY  LEARNING  POINTS  –  Beta  Blockers!   Class   Class  1C  anti-­‐arrhythmic   What  are  the  major  subgroups  of  Beta  blockers?   MOA   Selective  use-­‐  and  state-­‐dependent  block  INachannels;     Slowed  conduction  velocity  and  pacemaker  activity.   Non-­‐selective   PROPRANOLOL,     Uses   REFRACTORY  ARRHYTHMIAS   TIMOLOL  (Glaucoma)   SE   Increased   arrhythmias   (pro-­‐arrhythmic   effects),   CNS   Beta1-­‐selective   ACEBUTOLOL   excitation   ATENOLOL   Notes   Hyperkalemia   exacerbates   cardiac   toxicity,   BETAXOLOL   contraindicated  for  post-­‐MI  arrhythmias   ESMOLOL   METOPROLOL     Partial  agonist   PINDOLOL,  ACEBUTOLOL   MNEMONICS  –  Class  1C  Anti-­‐arrhythmics!   Class  1C:   Lacking  local  anesthetic  effect   TIMOLOL   Chicken  ay  Pagain  For  Enrico!!   Low  lipid  solubility   ATENOLOL    PROPAFENONE   Shortest-­‐acting   ESMOLOL    FLECAINIDE   Longest-­‐acting   NADOLOL    ENCAINIDE   Combined  α  and  β  blockade   CARVEDILOL,  LABETALOL       Summary  of  the  Clinical  Uses  of  Class  I  Anti-­‐arrhythmics     • Class  1A     o All  types  of  Arrhythmias   CLASS  3  ANTI-­‐ARRHYTHMICS   o Arrhythmias   in   acute   phase   of   Myocardial     Infarction   MOA  of  CLASS  3  Anti-­‐arrhythmics   o Procainamide   and   Amiodarone   for   • Act  on  PHASE  3   __________________     • Hallmark  is  PROLONGATION  of  the  AP  Duration   • Class  1B   o Caused  by  blockade  of  IK  potassium  channels  that   o Acute  ventricular  arrhythmias,  especially  post-­‐MI   are  responsible  for  the  repolarization  of  the  AP   o Atrial  arrhythmias  due  to  Digitalis   o Results   in   an   increase   in   ERP   and   reduces   the   • Class  1C   ability   of   the   heart   to   respond   to   rapid   o Refractory  arrhythmias   tachycardias     • ECG  Morphology   CLASS  2  ANTI-­‐ARRHYTHMICS   o Increase  in  QT  interval       MOA  of  CLASS  2  Anti-­‐arrhythmics   DOFETILIDE   • Primarily   cardiac   beta-­‐adrenoceptor   blockade   and   SimD   IBUTILIDE   reduction  in  cAMP   Class   Class  3  Anti-­‐arrhythmics   o Reduction  of  both  sodium  and  calcium  currents   MOA   Selective   IK   block;   Prolonged   action   potential   and   QT   o Suppression  of  abnormal  pacemakers   interval   • AV  node  is  particulary  sensitive  to  blockers   Uses   Treatment  and  prophylaxis  of  ATRIAL  FIBRILLATION     o PR  interval  is  usually  prolonged   SE   Torsades  de  Pointes   • Act  on  PHASE  4     • SOTALOL  and  AMIODARONE  also  have  group  2  effects   SOTALOL     Class   Class  3  Anti-­‐arrhythmics   PROPRANOLOL   MOA   IK  block  and  beta-­‐adrenoceptor  block   SimD   METOPROLOL,  TIMOLOL   Uses   Ventricular   arrhythmias,   Atrial   fibrillation,   Class   Class  2  Anti-­‐arrhythmics   Supraventricular  tachycardia   MOA   Block  off  beta-­‐receptors;  Slowed  pacemaker  activity       SE   Dose-­‐related   torsade   de   pointes,   Excessive   beta-­‐ Uses   Post-­‐MI  prophylaxis  against  sudden  death,   blockade  (sinus  bradycardia,  asthma)   Thyrotoxicosis     SE   Bronchospasms,  Cardiac  depression,  AV  block,   AMIODARONE   Hypotension   SimD   DRONEDARONE   Notes   In  CHF,  reduces  progression  and  decreases  incidence  of   Class   Class  3  Anti-­‐arrhythmics   potentially  fatal  arrhythmias.   MOA   Strong  IK  block  produces  marked  prolongation  of  action   SOTALOL  is  a  beta-­‐blocker  anti-­‐arrhythmic  that  has   potential  and  refractory  period.   Class  3  properties.   Group  1  activity  slows  conduction  velocity;     Group   2   and   4   activity   confer   additional   anti-­‐ ESMOLOL   arrhythmic  activity   Class   Class  2  Anti-­‐arrhythmics   Uses   REFRACTORY  ARRHYTHMIAS,  Used  off-­‐label  in  many   MOA   Selectively  block  off  beta-­‐1  receptors,     arrhythmias   Slowed  pacemaker  activity   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 27 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SE   Notes  

Microcrystalline   deposits   in   cornea   and   skin,   Thyroid   dysfunction   (hyper-­‐   or   hypo-­‐),   Paresthesias,   Tremor,   Pulmonary  fibrosis   MOST  EFFICACIOUS  of  all  Anti-­‐arrhythmic  drugs  

  KEY  LEARNING  POINTS  –  Amiodarone  Toxicity   AMIODARONE  TOXICITY    Pulmonary  fibrosis    Paresthesias    Tremors    Thyroid  dysfunction    Corneal  deposits    Skin  deposits     MNEMONICS  –  Class  3  Anti-­‐arrhythmics   AIDS!!    AMIODARONE    IBUTILIDE    DOFETILIDE    SOTALOL     CLASS  4  ANTI-­‐ARRHYTHMICS     MOA  of  CLASS  4  Anti-­‐arrhythmics   • Effective   in   arrhythmias   that   must   traverse   calcium-­‐ dependent  cardiac  tissue  (eg,  the  AV  Node)   • Cause   a   state-­‐   and   use-­‐dependent   selective   depression   of   calcium  currents   • AV   conduction   velocity   is   decreased   and   effective   refractory  period  increased   • ECG  morphology   o PR  interval  is  consistently  INCREASED!     KEY  LEARNING  POINTS  –  Dihydropyridine  CCBs   Why   are   dihydropyridine   calcium   channel   blocker   NOT   useful   as   anti-­‐arrhythmics?    Dihydropyridine  CCBs  evoke  compensatory  sympathetic   discharge   which   facilitates   arrhythmias   rather   than   terminating  them    >  vascular    vasodilator    ↑  HR  response     VERAPAMIL   Class   Non-­‐dihydropyridine  Calcium  channel  Blocker   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (cardiac  >  vascular)   Uses   Angina,   Hypertension,   Supraventricular   tachycardia,   Migraine   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,  Gingival  hyperplasia,  Heart  failure,  AV  block,   Sinus  node  depression     DILTIAZEM   Class   Non-­‐dihydropyridine  Calcium  channel  Blocker   MOA   Block  voltage-­‐gated  L-­‐type  calcium  channels     (cardiac  >  vascular)   Uses   Angina,   Hypertension,   Supraventricular   tachycardia,   Vasospasm,  RAYNAUD’S  PHENOMENON   SE   Constipation,   Pretibial   edema,   Nausea,   Flushing,   Dizziness,   Heart   failure,   AV   block,   Sinus   node   depression     Summary  of  the  Effects  of  Anti-­‐arrhythmics  Drugs   Class  

Prototype  

Effects  on  AP   duration  

Effects  on   ECG  

1A  

Procainamide  

PROLONGS  

1B   1C   2   3   4  

Lidocaine   Flecainide   Propranolol   Dofetilide   Verapamil  

SHORTENS   NO  EFFECT   NO  EFFECT   PROLONGS   NO  EFFECT  

PROLONGS  PR  interval,   PROLONGS  QRS  duration,   PROLONGS  QT  interval   NO  EFFECT  on  normal  cells   PROLONGS  QRS  duration   PROLONGS  PR  interval   PROLONGS  QT  interval   PROLONGS  PR  interval  

  MISCELLANEOUS  ANTI-­‐ARRHYTHMICS     ADENOSINE   Class   Miscellaneous  Anti-­‐arrhythmic   MOA   Increase   in   diastolic   Ik   of   AV   node   that   causes   marked   hyperpolarization  and  conduction  block;  Reduced  ICa   Uses   AV   donal   arrhythmias;   Drug   of   Choice   for   PAROXYSMAL  SUPRAVENTRICULAR  TACHYCARDIA   SE   Flushing,  Hypotension,  Transient  chest  pain,  Dyspnea   Notes   Potent  bronchoconstrictor!     Potassium  Ion   • MOA:  Depresses  ectopic  pacemaker,  including  those  caused   by  digitalis  toxicity   • When   treating   arrhythmias,   serum   potassium   should   be   measured  and  normalized  if  ABNORMAL   o Hypokalemia   is   associated   with   an   increased   incidence   of   arrhythmias,   especially   in   patients   receiving  Digitalis   o Excessive   Potassium   levels   depress   conduction   and  can  cause  re-­‐entry  arrhythmias     Magnesium  Ion   • MOA:   Poorly   understood,   possible   increase   in   Na+/K+   ATPase  activity   • Similar   depressant   effects   as   potassium   on   digitalis-­‐ induced  arrhythmias   • Effective  in  some  cases  of  torsades  de  pointes     NON-­‐PHARMACOLOGIC  TREATMENT   • Electrical  Methods   o External  Defibrillator   o Implanted  Defibrillator   o Implanted  pacemaker   o Radiofrequency  Ablation  of  Arrhythmogenics      

DIURETICS                                    

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                             CARBONIC  ANHYDRASE  INHIBITORS     Proximal  Convoluted  Tubule   • Carries   out   isosmotic   reabsorption   of   amino   acids,   glucose,  and  numerous  cations   o Major   site   for   sodium   chloride   and   sodium   bicarbonate  reabsorption  (60-­‐70%)     • Site  of  uric  acid  transport   • Site  of  action  of  carbonic  anhydrase  inhibitors                                       ACETAZOLAMIDE   SimD   DORZOLAMIDE,   BRINZOLAMIDE,   METHAZOLAMIDE   DICHLORPHENAMIDE   Class   Carbonic  Anhydrase  Inhibitors   MOA   Inhibits  carbonic  anhydrase  in  proximal  tubule.   In   Glaucoma,   secretion   of   aqueous   humor   is   reduced,   and  in  Mountain  sickness,  metabolic  acidosis  increases   respiration.   Uses   Glaucoma,  Mountain  Sickness,  Edema  with  alkalosis   SE   Drowsiness,   Paresthesia,   Sulfa   allergy,   Renal   calcium   stones,   Potassium   wasting,   Hyperchloremic   metabolic   acidosis,  Hepatic  encephalopathy  in  cirrhotic  patients     MNEMONICS  –  Metabolic  Acidosis   ACIDazolamide  causes  ACIDosis  

  LOOP  DIURETICS     Thick  Ascending  Limb  of  the  Loop  of  Henle   • Responsible  for  a  significant  percentage  of  sodium  chloride   reabsorption  via  the  Na+/K+/2Cl-­‐  transporter   • Site  of  calcium  and  magnesium  reabsorption   • Site  of  action  of  loop  diuretics   • Prostaglandins   are   important   in   maintaining   glomerular   filtration   • NSAIDs  decrease  the  efficacy  of  loop  diuretics                                         FUROSEMIDE   SimD   BUMETANIDE,  TORSEMIDE,     ETHACRYNIC  ACID  (Phenoxy-­‐  derivative)   Class   Loop  Diuretic   MOA   Inhibit   Na/K/2Cl   transporter   in   thick   ascending   limb   of   loop   of   Henle.   Causes   powerful   diuresis   and   increased   calcium  excretion   Uses   Heart   failure,   Pulmonary   edema,   Hypertension,   Hypercalcemia,  Acute  renal  failure,  ANION  OVERDOSE   SE   Hypokalemic   metabolic   alkalosis,   Potassium   wasting,   Dehydration,   Ototoxicity,   Sulfa   allergy,   Hyperuricemia,   Hypocalcemia,  Hypomagnesemia,  Nephritis   Notes   Synergistic  ototoxicity  with  aminoglycosides.   Efficacy  decreased  by  NSAIDs     MNEMONICS  –  Loop  Diuretic  Toxicities   What  are  the  adverse  effects  associated  with  loop  diuretics?   OH  DANG!!    Ototoxicity    Hypokalemia    Dehydration    Allergy  to  Sulfa    Nephritis    Gout     THIAZIDE  DIURETICS     Distal  Convoluted  Tubule   • Actively  pumps  sodium  and  chloride  out  of  the  lumen  of  the   nephron  via  the  Na+/Cl-­‐  carrier   • Site  of  action  of  thiazide  diuretics   • Responsible   for   approximately   5-­‐8%   of   sodium   reabsorption  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] •

Calcium   is   also   reabsorbed   in   this   segment   under   the   control  of  PARATHYROID  HORMONE  (PTH)  

                                        GYNECOMASTIA,  IMPOTENCE,  STERILITY!!    Ketoconazole    Spironolactone    Cimetidine     HYDROCHLOROTHIAZIDE   SimD   CHLORTHALIDONE,  INDAPAMIDE,  METOLAZONE   Class   Thiazide  Diuretics   MOA   Inhibit   Na/Cl   transporter   in   distal   convoluted   tubule.   Causes   moderate   diuresis   and   reduced   excretion   of   calcium.   Uses   Hypertension,   Heart   failure,   Hypercalciuria,   Renal   calcium  stones,  Nephrogenic  diabetes  insipidus   SE   Hypokalemic   metabolic   alkalosis,   Dilutional   hyponatremia,   Potassium   wasting,   Hyperglycemia,   Hyperlipidemia,   Hyperuricemia,   Hypercalcemia,   Sulfa   allergy   Notes   Synergistic  effect  with  loop  diuretics.     Efficacy  decreased  by  NSAIDs.     MNEMONICS  –  Thiazide  Diuretics   HYPER  GLUC!!    HyperGlycemia    HyperLipidemia    HyperUricemia    HyperCalcemia     POTASSIUM  –  SPARING  DIURETICS     Cortical  Collecting  Ducts   • Last  tubular  site  of  sodium  reabsorption   o Responsible  for  reabsorption  of  2-­‐5%  of  the  total   filtered  Sodium   • Under   the   influence   of   ALDOSTERONE,   reabsorption   of   sodium  occurs  via  channels   o Accompanied   by   an   equivalent   loss   of   potassium   or  hydrogen  ions   • Primary  site  of  Acidification  of  the  Urine!   • Last  site  of  Potassium  excretion   o Sites  of  action  of  the  potassium-­‐sparing  diuretics     SPIRONOLACTONE  

SimD   Class   MOA   Uses   SE   Notes  

EPLERENONE   Potassium-­‐sparing   Diuretic   (Aldosterone   antagonists)   Steroid   inhibitors   of   cytoplasmic   aldosterone   receptor   in  cortical  collectind  ducts.  Reduces  K+  excretion.   Hyperaldosteronism,   Hypertension,   Heart   failure,   Hypokalemia   Hyperkalemia,  GYNECOMASTIA  (spironolactone  only),   Impotence,   Benign   prostatic   hyperplasia,   Hyperchloremic  metabolic  acidosis   Eplerenone   reduces   progression   of   DM   nephropathy   and  reduces  mortality  post-­‐MI  

  AMILORIDE   SimD   TRIAMTERENE   Class   Potassium-­‐sparing  Diuretic  (Sodium  blocker)   MOA   Inhibit   ENaC   epithelial   sodium   channels   in   cortical   collecting   duct,   reduces   Na+   reabsorption   and   K+   excretion   Uses   HYPOKALEMIA   SE   Hyperkalemia,   Acute   renal   failure   (with   indomethacin),   Kidney  stones,  Metabolic  acidosis   Notes   Should  never  be  given  with  potassium  supplements!     MNEMONICS  –  Potassium-­‐sparing  Diuretics   The  K+  STAEs  (stays)  with  K-­‐sparing  diuretics!!    SPIRONOLACTONE    TRIAMTERENE    AMILORIDE    EPLERENONE     Which  drugs  can  cause  GYNECOMASTIA?   Some  Drugs  Create  Awesome  Knockers!    SPIRONOLACTONE    DIGOXIN    CIMETIDINE    ALCOHOL    KETOCONAZOLE     OSMOTIC  DIURETICS   MOA  of  Osmotic  Diuretics   • Remains   in   the   lumen   and   “holds”   water   by   virtue   of   its   osmotic  effect   • Reabsorption   of   water   is   also   reduced   in   the   descending   limb  of  the  loop  of  Henle  and  the  collecting  tubule     MANNITOL   SimD   GLYCERIN,  ISOSORBIDE,  UREA   Class   Osmotic  Diuretic   MOA   Osmotically   retains   water   in   tubule   by   reducing   reabsorption   in   proximal   tubule,   descending   limb   of   Henle’s  loop,  and  collecting  ducts;     In  the  periphery,  mannitol  extracts  water  from  cells     Uses   RHABDOMYOLYSIS,   Hemolysis,   Increased   intracranial   pressure,  Acute  glaucoma   SE   Transient   volume   expansion   (hyponatremia,   pulmonary   edema;   followed   by   hypernatremia),   Headache,  Nausea,  Vomiting,  Diarrhea     ADH  AGONISTS  /  ANTAGONISTS   Medullat  Collecting  Duct   • Reabsorption   of   water   occurs   under   the   control   of   ANTI-­‐ DIURETIC  HORMONE  (ADH)   • Site  of  action  of  ADH  agonists  and  antagonists   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 30 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] ANTIDIURETIC  HORMONE   SimD   DESMOPRESSIN   Class   ADH  Agonist   MOA   Agonists  at  V1  and  V2  ADH  receptor.  Activate  insertion   of   aquaporin   water   channels   in   collecting   tubule.   Vasoconstriction     Uses   Central   diabetes   insipidus,   Nocturnal   enuresis,   Hemophilia,  von  Willebrand’s  disease   SE   Hyponatremia,  Hypertension     CONIVAPTAN   SimD   TOLVAPTAN,   LIXIVAPTAN,   DEMECLOCYCLINE,   LITHIUM   Class   ADH  Antagonist   MOA   Antagonist  at  V1a  and  V2  receptors   Uses   SIADH,  Hyponatremia   SE   Infusion   site   reactions,   Hyperkalemia,   Nephrogenic   diabetes   insipidus,   Renal   failure   (lithium,   demeclocycline),   Bone   and   teeth   abnormalities   (demeclocycline)   Notes   CENTRAL   PONTINE   MYELINOLYSIS   may   occur   with   rapid  correction  of  hyponatremia     QUICK  MEMORY  TIPS!     Urine  Na+:  INCREASES  (all  diuretics);  serum  NaCl  may  decrease   as  a  result!     Urine   K+:   INCREASES   (ALL,   except   K-­‐sparing   Diuretics);   serum   K+  may  decrease  as  a  result!     Urine  Ca2+:  INCREASES  (in  loop  diuretics);  decrease  serum  Ca2+   DECREASES  (in  thiazide  diuretics);  increase  serum  Ca2+     Blood  pH:  DECREASES  pH  (acidemia)    Furosemide      Carbonic   anhydrase   inhibitors,   decreases   HCO3   reabsorption;  prevents  K+  secretion  and  H+  secretion    K-­‐sparing  diuretics,  aldosterone  blockade     Blood  pH:  INCREASES  pH  (alkalemia)    Both  loop  diuretics  and  thiazide  diuretics     SUMMARY  TABLE!   DRUG   MOA/   Urinary   Blood   LOCATION   Electryolytes   pH   ACETAZOLAMIDE   Inhibition  of   ↑Na,  K   Acidosis   carbonic   ↓HCO3   anhydrase  in   PCT   FUROSEMIDE   Inhibition   of   ↑Na,  K,  Ca,   Alkalosi Na/K/Cl   co-­‐ Mg,  Cl   s   transporter   in   Thick   ascending   limb   of   the   loop   of   Henle   HYDROCHLORO-­‐ Inhibition   of   ↑Na,  K,  Cl   alkalosis   THIAZIDE   NaCl   co-­‐ ↓Ca   transporter   in  DCT   SPIRONOLACTONE   Blocks   Na   ↓K+   acidosis   channels,   ↑Na  (small)  

Blocks   aldosterone   in   collecting   tubules    

DRUGS  USED  IN  THE  TREATMENT  OF   HYPERLIPIDEMIAS                 Pathogenesis  of  Hyperlipoproteinemia   • Premature   atherosclerosis   is   strongly   associated   with   elevated  concentrations  of  lipoproteins   o Elevated  level  of  low-­‐density  lipoproteins  (LDL)   o Depressed   level   of   high-­‐density   lipoproteins   (HDL)   o Hypertriglyceridemia     • Hyperchylomicronemia  is  associated  with  a  high  incidence   of  acute  pancreatitis     Treatment  Strategies:  DIET!   • Cholesterol   and   saturated   fats   are   the   primary   dietary   factors  that  contribute  to  elevated  plasma  lipoproteins   • Dietary   measures   constitute   the   first   method   of   management   o May  be  sufficient  to  reduce  lipoprotein  levels  to  a   safe  range   • ALCOHOL  raises  triglyceride  and  VLDL  levels   o Should   be   avoided   by   patients   with   hypertriglyceridemia!     Treatment  Strategies:  DRUGS!   • Choice  of  drug  is  based  on  the  lipid  abnormality   • Drugs  most  effective  at  lowering  LDL  cholesterol   o Statins,  Resins,  Ezetimibe,  Niacin     • Drugs   most   effective   at   lowering   triglyceride   and   VLDL   and   raising  HDL   o Niacin,  Fibrates                                 STATINS/HMG-­‐COA  REDUCTASE  INHIBITORS     MOA  of  Statins   • Inhibition   of   hepatic   cholesterol   synthesis   contributes   a   small  amount  to  drug  effect   • Greater   cholesterol-­‐lowering   effect   derived   from   the   compensatory  response  of  the  liver  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Increased    number  of  high-­‐affinity  LDL  receptors,   which   clear   LDL   and   VLDL   remnants   from   the   blood   Direct  anti-­‐atherosclerotic  effects   Prevent  bone  loss  

Avoid  in  patients  with  diverticulitis!     KEY  LEARNING  POINTS  –  Bile  Acids   • 90%  of  bile  is  reabsorbed  in  the  DISTAL  ILEUM!!     •     CHOLESTEROL  ABSORPTION  BLOCKERS   SIMVASTATIN     SimD   ATORVASTATIN,   ROSUVASTATIN,   FLUVASTATIN,   MOA  of  Ezetimibe   PRAVASTATIN,  LOVASTATIN,  PITAVASTATIN   • Converted  in  the  liver  to  the  active  glucuronide  form   Class   Reversible   competitive   inhibitor   of   HMG-­‐COA   • Inhibits  NPC1L1  transporter  (a  specific  transport  process   reductase   in   jejunal   enterocyte)   that   mediates   gastrointestinal   uptake   MOA   Inhibits   rate-­‐limiting   enzyme   in   cholesterol   of  cholesterol  and  phytosterols   biosynthesis.   Increased   hepatic   cholesterol   uptake.   • Prevents   absorption   of   dietary   cholesterol   and   cholesterol   Increased   high-­‐affinity   LDL   receptors.   Decreased   LDL   that  is  excreted  in  bile   levels.   o Reduces   cholesterol   in   tightly   regulated   hepatic   Uses   Hypercholesterolemia   (high   LDL),   Acute   coronary   pool   syndromes,  Ischemic  stroke   o Compensatory   increase   in   the   synthesis   of   high-­‐ SE   Hepatotoxicity,   Myopathy,   Rhabdomyolysis,   affinity   LDL   receptors     increases   the   removal   of   Gastrointestinal  distress,  Teratogen   LDL   Notes   Increased   risk   of   Myopathy   and   Rhabdomyolysis     when  used  with  FIBRATE.     EZETIMIBE   Given   before   bedtime   because   cholesterol   synthesis   Class   Sterol  Absorption  Blocker   predominantly  occurs  at  night   MOA   Selective   inhibitor   of   the   NPC1L1   transporter,     decreasing   intestinal   absorption   of   cholesterol   and   KEY  LEARNING  POINTS  –  Statins  in  Coronary  Artery  Disease!   other  phytosterols   Why   are   statins   used   in   the   management   of   coronary   artery   Uses   Hypercholesterolemia  (high  LDL),  Phytosterolemia   disease?   SE   HEPATOTOXICITY   (increased   with   statin   use),    For  the  stabilization  of  atherosclerotic  plaques   Myositis     Notes   Synergistic  LDL-­‐lowering  effect  with  statins   For   which   biochemical   pathway   are   the   following   rate-­‐limiting     enzymes:   SITOSTEROL    HMG-­‐CoA  Synthase?  KETOGENESIS   Class   Sterol  Absorption  Blocker    HMG-­‐CoA  Reductase?  CHOLESTEROL  BIOSYNTHESIS   MOA   Cholesterol   analog,   takes   the   place   of   dietary   and     biliary   cholesterol,   decreasing   intestinal   absorption   of   BILE  ACID  –  BINDING  RESINS  (BARs)   cholesterol  and  other  phytosterols     Uses   Hypercholesterolemia  (high  LDL),  Phytosterolemia   MOA  of  Resins   SE   Gastrointestinal   upset,   bloating,   IMPOTENCE   (rare),   • Over  90%  of  bile  acids  are  reabsorbed  and  returned  to  the   Coronary  events   liver  for  reuse  (enterohepatic  circulation)     • Resins   bind   bile   acids   and   prevent   their   intestinal   NIACIN   absorption     o Divert   hepatic   cholesterol   to   synthesis   of   new   bile   MOA  of  Niacin   acids   • Multiple  mechanisms  of  actions  in  various  tissues   o Reduce   amount   of   cholesterol   in   a   tightly   o Inhibits  lipolysis  by  hormone  sensitive  lipase   regulated  pool   o In  the  liver,  niacin  reduces  VLDL  synthesis   o Compensatory   increase   in   high-­‐affinity   LDL   o In   adipose   tissue,   niacin   reduces   hormone-­‐ receptors  increases  LDL  removal   sensitive   lipase   activity,   decreases   plasma   fatty   • Modest   reduction   in   LDL   cholesterol   but   have   little   effect   acids  and  triglyceride  levels   on  HDL  or  Triglycerides   o In   capillary   endothelial   cells,   niacin   causes     increased  clearance  of  VLDL  by  lipoprotein  lipase   CHOLESTYRAMINE   o Niacin  reduces  the  catabolic  rate  for  HDL   SimD   COLESEVELAM,  COLESTIPOL   o Decreases   circulating   fibrinogen   and   increases   Class   Bile  acid-­‐binding  Resins   tPA  activity   MOA   Binds   bile   acids,   preventing   their   reabsorption   and   • Net  effect  on  lipid  profile   increasing   cholesterol   utilization   for   replacement.   o Most  effective  agent  for  increasing  HDL  levels   Modestly  lowers  LDL  levels.   o Reduces  LDL  cholesterol,  triglycerides,  and  VLDL   Uses   Hypercholesterolemia   (high   LDL),   Pruritus   in     Cholestasis,  Digitalis  toxicity   NIACIN   SE   Constipation,  BLOATING,  Gritty  taste,  Steatorrhea,  Gall   Class   Vitamin,  Anti-­‐hyperlipidemic  drug   stones  (rare),  Malabsorption  (vitamin  K)   MOA   Decreases   VLDL   synthesis   and   LDL   cholesterol   Notes   Increases  TGs  and  VLDL  in  patients  with  high  TGs   concentrations.  Increases  HDL  cholesterol     Uses   Hypercholesterolemia  (low  HDL,  high  HDL/VLDL)   Treat  constipation  with  fiber  supplements/psyllium   SE   Flushing,   Pruritus,   Rashes,   Acanthosis   nigricans,     Gastrointestinal   irritation,   Hepatotoxicity   (mild),   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 32 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected] o

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

Notes  

Hyperuricemia,   Impaired   glucose   tolerance,   Arrhythmias,  Amblyopia   ASPIRIN  pre-­‐treatment  reduces  flushing.     Avoid  in  patients  with  peptic  ulcer  disease.  Potentiates   effects   of   anti-­‐hypertensives   (vasodilators,   ganglion   blockers)  

  MNEMONICS  –  Cutaneous  Flushing   What  are  the  drugs  that  cause  flushing?   V  –  A  –  N  –  C    Vancomycin    Adenosine    Niacin    Calcium-­‐channel  Blockers     “slap  cheek”  –  Parvovirus  B19     FIBRATES     MOA  of  Fibrates   • Ligands  for  the  peroxisome  proliferator-­‐activated  receptor-­‐ alpha  (PPAR-­‐α)  protein   o Increased   synthesis   by   adipose   tissue   of   lipoprotein  lipase    Enhances  clearance  of  triglycerides   • In  the  liver,  fibrates  stimulate  fatty  acid  oxidation   o Limits   supply   of   triglycerides   and   decreases   VLDL   synthesis   • Decreases  expression  of  apoC-­‐III   o Impedes  the  clearance  of  VLDL   o Increases   the   expression   of   apoA-­‐I   and   apoA-­‐II,   which  in  turn  increases  HDL  levels   • Little  or  no  effect  on  LDL  concentrations     GEMFIBROZIL   SimD   FENOFIBRATE,  BEZAFIBRATE   Class   Fibric  Acid  Derivative   MOA   Activates   PPAR-­‐α   and   increases   expression   of   lipoprotein   lipase   and   apolipoproteins   (apoA-­‐I   and   apoA-­‐II).  Lowers  triglycerides.  Increases  HDL   Uses   Drug   of   choice   for   HYPERTRIGLYCERIDEMIA,   Hypercholesterolemia   (low   HDL,   high   LDL),   Fat   redistribution  syndrome   SE   Nausea,   Rashes,   Leukopenia,   Hemoconcentration,   Increased  risk  of  cholesterol  gallstones   Notes   Increased   risk   of   myopathy   and   rhabdomyolysis   when   used  with  STATINS!     Avoided  in  patients  with  hepatic  or  renal  dysfunction.     MNEMONICS  –  Fibrates   FULL:  Fibrates  Upregulate  Lipoprotein  Lipase!!     Combination  Therapy   • All   patients   with   hyperlipidemia   are   treated   first   with   dietary  modification   • Certain   drug   combinations   provide   advantages   whereas   others  present  specific  challenges     SYNERGISTIC  ANTI-­‐HYPERLIPIDEMIC  COMBINATIONS!   Synergistic   CLINICAL  USE   Combinations   Niacin  +  Statin   Familial  hypercholesterolemia  

Statin  +  Ezetimibe   Familial  hypercholesterolemia   Niacin  +  Resin   Familial  combined  hypercholesterolemia   Statin  +  Fibrate   Familial  combined  hypercholesterolemia     STILL   STILL     HIGH   HIGH         Diet  and   High  LDL   STATIN   EZETIMIBE     Excercise       Diet  and     High  VLDL   FIBRATE   STATIN   Excercise         Diet  and   NIACIN     High  TAG   FIBRATE   Excercise         Diet  and     Low  HDL   STATIN   Excercise         EZETIMIBE   Diet  and   STATIN     High  LDL   or  NIACIN   Excercise     High  VLDL         High  LDL,   STATIN  +   Diet  and     HIGH  TGs,   NIACIN  +   Excercise   FIBRATE     Low  HDL       DISADVANTAGEOUS  ANTI-­‐HYPERLIPIDEMIC  COMBINATIONS!   COMBINATION   DISADVANTAGE   Fibrate  +  Resin   Increased  risk  of  cholelithiasis   Statin  +  Resin   Impaired  statin  absorption   Statin  +  Fibrate   Increased  risk  of  myopathy  and   rhabdomyolysis       CORRELATIONS  –  Biochemistry  –  Lipoproteins   Which   anti-­‐hyperlipidemic   drugs   are   indicated   for   the   inherited   lipoproteinemias?    

I   IIA       IIB  

Condition  

Cause  

Primary   hyperchylomicronemi a   Familial   hypercholesterolemia  

Deficiency  in   LPL     or  ApoC-­‐II  

    Familial   combined   hypercholesterolemia  

Defect   in   LDL   receptors       Over-­‐ production   of  VLDL  

III  

Familial   dysbeta-­‐ lipoproteinemia  

Deficiency  in   ApoE  

IV  

Familial   hypertriglyceridemia  

Decreased   clearance   of   VLDL  

V  

Familial   combined   hypertriglyceridemia  

Decreased   clearance   of   VLDL  

Lipid   Profile   ↑  CM   ↑  TGs  

10  Tx  

20  Tx  

Low-­‐ fat  diet  

Niacin   Fibrate  

↑  LDL   N.    VLDL  

Statin  

Niacin   Ezetimibe  

↑  VLDL  

Statin  

↑  LDL  

Statin  

↑  VLDL   ↑LDL   ↑VLDL   remnant   ↑  CM   ↑  TGs   ↑  VLDL   ↓/N.  LDL   ↑  TGs   ↑  CM   ↑  VLDL   ↓/N.  LDL  

Statin  

Niacin   Fibrate   Niacin   Ezetimibe   Niacin   Ezetimibe   Statin  

      TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 33 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

Fibrate   Niacin   Fibrate   Niacin  

 

Fibrate   Niacin  

 

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                                                                                                                  

                 

HISTAMINE,  SEROTONIN  AND     THE  ERGOT  ALKALOIDS                                                                     AUTACOIDS   • Endogenous   molecules   with   powerful   pharmacologic   effects  that  do  not  fall  into  traditional  autonomic  groups   • HISTAMINE   and   SEROTONIN   are   the   most   important   amine  autacoids                 HISTAMINERGIC  AGENTS     HISTAMINE   • Formed  from  the  amino  acid  HISTIDINE   • Metabolized   by   the   enzyme   monoamine   oxidase   and   diamine  oxidase   • Excess   production   detected   by   measurement   of   IMIDAZOLE  ACETIC  ACID  in  the  Urine  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Important  pathophysiologic  roles:   o Seasonal   rhinitis   (hay   fever),   Urticaria,   and   Angioedema   o Control  of  acid  secretion  in  the  stomach   Triple  Response  (WHEAL,  FLUSH  and  FLARE)   • Classic  demonstration  of  histamine  effect   o Redness   o Swelling   o Itch  and  Pain   • Mediated  mainly  by  H1  and  H2  receptors   • Involves   a     small   red   spot   at   the   center   of   an   intradermal   injection   of   histamine   surrounded   by   a   red   edematous   wheal     Histamine  Receptors  and  Effects   •

Type  

Distribution  

Mechanism  

  H1  

  Smooth   muscle  

  Gq;  ↑  IP3,   DAG  

H2  

Stomach,   Heart,   Mast   cells   Nerve   endings,  CNS   Leukocytes  

Gs;  ↑  cAMP  

Cimetidine  

Gi;  ↓  cAMP  

Clobenpropit    

Gi;  ↓  cAMP  

-­‐-­‐-­‐  

H3   H4  

Prototype   Antagonists       Diphenhydramine  

Effects   Pain   and   itching,   bronchoconstriction,   vasodilation,   local   edema     Gastric   acid   secretion,   cardiac   stimulation   Modulation   of   other   NTs   Leukocyte   chemotaxis  

  DIPHENHYDRAMINE   SimD   CHLORPHENIRAMINE,   CYCLIZINE,   MECLIZINE,   PROMETHAZINE   Class   H1-­‐receptor  Antagonists  (first  generation)   MOA   Competitive   pharmacologic   block   of   peripheral   and   CNS  H1  receptors  plus  α-­‐  and  M-­‐receptor  block.     “Anti-­‐motion  Sickness  Effect”   Uses   Hay   fever,   Angioedema,   Motion   sickness,   Insomnia,   Dystonia   SE   DROWSINESS,   Blurred   vision,   Dry   mouth,   Urinary   retention,   Anorexia,   Orthostatic   hypotension,   anti-­‐ cholinergic  effect     CETIRIZINE   SimD   LORATADINE,   FEXOFENADINE,   DESLORATADINE,   TERFENADINE,  ASTEMIZOLE,  LEVOCETIRIZINE   Class   H1-­‐receptor  Antagonists  (second  generation)   MOA   Competitive   pharmacologic   block   of   peripheral   H1   receptors.  No  autonomic  or  anti-­‐motion  sickness  effects   Uses   Hay  fever,  Angioedema,  Urticaria   SE   NONE   Notes   Fatal   arrhythmias   from   interaction   between   azoles/erythromycin  and  terfenadine/astemizole     CIMETIDINE   SimD   RANITIDINE,  FAMOTIDINE,  NIZATIDINE   Class   H2-­‐receptor  Antagonists   MOA   Competitive   pharmacologic   block   of   H2   receptors.   Reduction  of  gastric  acid  secretion   Uses   Peptic   ulcer   disease,   Zollinger-­‐Ellison   Syndrome,   Gastro-­‐esophageal  reflux   SE   CYP450   inhibitor   and   anti-­‐androgen   effects   like   gynecomastia  (cimetidine  only)          

            SEROTONERGIC  AGENTS     SEROTONIN  (5-­‐Hydroxytryptamine  or  5-­‐HT)   • Produced  from  the  amino  acid  TRYPTOPHAN   • Metabolized  by  monoamine  oxidase   • Excess   production   in   the   body   is   detected   by   5-­‐ HYDROXYINDOLE  ACETIC  ACID  (5-­‐HIAA)  in  the  Urine   • Physiologic  roles:   o Neurotransmitter   in   CNS   and   enteric   nervous   system   o Local   hormone   that   modulates   gastrointestinal   activity     Serotonin  Receptors  and  Effects   Type  

Distribution  

Mechanism  

5-­‐HT1D  

Brain  

Gi;  ↓  cAMP  

5-­‐HT2  

Smooth  muscle,   Platelets  

Gq;  ↑  IP3,   DAG    

5-­‐HT3  

Area   postrema   (CNS),   sensory   and   enteric   nerves   Pre-­‐synaptic   nerve  terminals   in   enteric   nervous  system  

Ligand-­‐ gated   Ion   channel  

5-­‐HT4  

Gs;  ↑  cAMP    

Prototype   Antagonists     -­‐-­‐-­‐   Ketanserin  

Ondansetron    

Tegaserod     (partial   agonist)  

Effects   Synaptic   inhibition   Vasoconstriction     CNS   excitation,   Smooth   muscle   contraction   or   relaxation,   vasodilation,   diarrhea,  broncho-­‐ constriction   Vomiting    

Intestinal  motility  

  SUMATRIPTAN   SimD   ALMOTRIPTAN,   ELETRIPTAN,   FROVATRIPTAN,   NARATRIPTAN,  RIZATRIPTAN,  ZOLMITRIPTAN   Class   5-­‐HT1D/1B-­‐receptor  Agonists   MOA   5-­‐HT1D/1B  agonists.  Causes  vasoconstriction.  Modulates   neurotransmitter  release.     Uses   Drug  of  choice  for  MIGRAINE,  Cluster  headache   SE   Paresthesias,   Diziness,   Chest   pain,   Coronary   vasospasm,  can  exacerbate  Hypertension     ONDANSETRON   SimD   GRANISETRON,   DOLASETRON,   PALONOSETRON,   ALOSETRON   Class   5-­‐HT3-­‐receptor  Antagonists   MOA   Pharmacologic   antagonists.   Blocks   chemoreceptor   trigger   zone   and   enteric   nervous   system   5-­‐HT3   receptors.   Uses   Chemotherapy   and   post-­‐operative   vomiting,   Irritable   bowel  disease  (alosetron  only)   SE   Diarrhea,   Headache,   QRS   and   QT   prolongation   (dolasetron  only),  Constipation  (alosetron  only)     ERGOT  ALKALOIDS     ERGOT  ALKALOIDS   • Complex   molecules   produced   by   a   fungus   found   in   wet   or   spoiled  grain  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Responsible   for   the   epidemics   of   “St.   Anthony’s   fire”   (ergotism)   described   during   the   Middle   Ages   Most   are   partial   agonists   at   α-­‐adrenoceptors   and   5-­‐HT   receptors   Classification   o VASOSELECTIVE   o UTEROSELECTIVE   o

• •

  ERGOTAMINE   SimD   DIHYDROERGOTAMINE,  METHYSERGIDE   Class   5-­‐HT2-­‐receptor  Antagonists  (vasoselective)   MOA   Mixed   partial   agonist   effects   at   5-­‐HT2   and   α-­‐ adrenoceptors.   Causes   marked   smooth   muscle   contraction  but  blocks    α-­‐agonist  vasoconstriction   Uses   MIGRAINE,  Cluster  headache   SE   Gastrointestinal   upset,   Vasospasm,   Gangrene,   Uterine   spasm,  Retroperitoneal  fibrosis  (methysergide  only)   Notes   Antidote  is  NITROPRUSSIDE       ERGONOVINE   SimD   METHYLERGONOVINE   Class   5-­‐HT2-­‐receptor  Antagonists  (uteroselective)   MOA   Mixed   partial   agonist   effects   at   5-­‐HT2   and   α-­‐ adrenoceptors.   Causes   marked   smooth   muscle   contraction  but  blocks    α-­‐agonist  vasoconstriction   Uses   POST-­‐PARTUM  BLEEDING,  Migraine   SE   Gastrointestinal  upset,  Uterine  spasms,  Abortion      

    KEY  LEARNING  PONTS  –  Biochemistry     Thromboxane  (Tetraeicosanoic  acid)  –  for  Platelet  aggregation     Cyclooxygenase  1    produces  Prostaglandin  (mucus)    GI     Cyclooxygenase   2      produces   Prostacyclin   (pulmonary   circulation);  mediates  pain  and  inflammation       Cyclooxygenase  Isoforms   • CYCLOOXYGENASE-­‐1  (COX-­‐1)   o Found  in  many  tissues   o Important   for   a   variety   of   normal   physiologic   processes   o “Cyloprotective  cyclooxygenase”     • CYCLOOXYGENASE-­‐2  (COX-­‐2)   o Found  primarily  in  inflammatory  cells   o Major  role  in  tissue  injury  (eg,  inflammation)   o Synthesis   of   prostacyclin   in   the   vascular   endothelium   and   of   prostaglandins   important   in   renal  functions         Effects  of  Important  Eicosanoids  

PROSTAGLANDINS  AND  OTHER  EICOSANOIDS    

 

  EICOSANOIDS   • Important   group   of   endogenous   fatty   acid   derivatives   that   are  produced  from  arachidonic  acid   • Major  families  of  eicosanoids  include:   o Straight-­‐chain  derivatives  (leukotrienes)   o Cyclic  derivatives  (prostacyclin,   prostaglandins,   and  thromboxane)   • 20  carbon  atoms,  4  double  bonds    

Eicosanoids   LTB4   LTC4   LTD4   PGE1  

G-­‐Protein   Gq   Gq   Gq  ,  Gi   Gs  ,  Gq  

PGE2  

Gs  ,  Gq  

PGI2  

Gs  

PGF2α  

Gq  

TXA2  

Gq  

Effects     Leukocyte  chemotaxis   Bronchoconstriction,   slow-­‐reacting   substance  of  anaphylaxis   Vascular   smooth   muscle   relaxation,   Protective   effects   on   gastric   mucosa,   Maintains  PDA  (patent  ductus  arteriosus)   Vascular   smooth   muscle   relaxation,   Increases  uterine  tone,     Maintains  PDA  (patent  ductus  arteriosus)   Vascular   smooth   muscle   relaxation   (peripheral,  pulmonary,  coronary)   Increases  uterine  tone,  decreases  IOP   (intraocular  pressure)     Platelet  aggregation  

  MISOPROSTOL   SimD   GEMEPROST   Class   Prostaglandin  E1  Analog   MOA   Activates   EP   receptors.   Causes   increased   HCO3   and   mucus  secretion  in  stomach.  Uterine  contraction.   Uses   Peptic   Ulcer   Disease,   Prevention   of   NSAIDs-­‐induced   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 36 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SE  

gastric  mucosal  injury,  abortifacient   Abdominal   pain,   Diarrhea,   Uterine   cramping,   Miscarriage,  Teratogenic  effect  (Moebius  sequence)  

  ALPROSTADIL   Class   Prostaglandin  E1  Analog   MOA   Activates  EP  receptors,  Causes  vascular  smooth  muscle   relaxation  and  vasodilation   Uses   Maintenance   of   Patent   Ductus   Arteriosus   (PDA),   Erectile  dysfunction   SE   Apnea,   Hypotension,   Arrhythmia,   PRIAPISM,   light-­‐ headedness     MNEMONICS  –  Alprostadil   Prostaglandin  E1  (Alprostadil)   E1  (iwan)  mong  bukas  ang  Ductus!!   Maintains  patency  (open)  of  Ductus  arteriosus     DINOPROSTONE   SimD   SULPROSTONE   Class   Prostaglandin  E2  Analog   MOA   Low   concentrations   contract,   Higher   concentrations   relax  uterine  and  cervical  smooth  muscle   Uses   INDUCTION   OF   LABOR   (cervical   opening),   Abortifacient   SE   Cramping,  Fetal  trauma     CARBOPROST   SimD   BIMATOPROST,  TRAVOPROST,  UNOPROSTONE   Class   Prostaglandin  E2α  Analog   MOA   Activates  FP  receptors.   Uses   Control  of  post-­‐partum  hemorrhage,  Abortifacient   SE   Vomiting,  Diarrhea,  Transient  bronchoconstriction     EPOPROSTENOL   Class   BERAPROST,  ILOPROST,  TREPROSTINIL   MOA   Prostaglandin  I2  Analog   Uses   Activates   IP   receptors.   Causes   vasodilation,   Reduces   platelet  aggregation   SE   PULMONARY   HYPERTENSION,   Reduces   platelet   aggregation  in  dialysis  machines   Notes   Hypotension,  Flushin,  Headache     LATANOPROST   SimD   BIMATOPROST,  TRAVOPROST,  UNOPROSTONE   Class   Prostaglandin  F2α  Analog   MOA   Activates   FP   receptors.   Increases   outflow   of   aqueous   humor,  reduces  intraocular  pressure   Uses   Drug  of  choice  for  GLAUCOMA   SE   Alters   color   of   the   iris,   causing   permanent   eye   color   change          

BRONCHODILATORS  AND  OTHER  DRUGS  USED  IN   ASTHMA  

                      Pathophysiology  of  Asthma   • Bronchoconstriction  caused  by  release  of  several  mediators   from  IgE-­‐sensitized  mast  cells   • Chemotactic   mediators   attract   inflammatory   cells   to   the   airways,  leading  to  chronic  inflammation   • Results   in   marked   bronchial   hyper-­‐reactivity,   partially   mediated  by  vagal  reflexes     Strategies  of  Asthma  Therapy   • Acute  Attacks  of  Bronchospasms  (relievers)   o Use  bronchodilators  or  relievers   o Short-­‐acting  beta  agonists   o Muscarinic  antagonists   o Methylxanthines   o Intravenous  corticosteroids   • Long-­‐term  prevention  and  prophylaxis  (controllers)   o Use  anti-­‐inflammatory  drugs  or  controllers   o Corticosteroids   o Long-­‐acting  beta  agonists   o Mast  cell  stabilizers   o Anti-­‐IgE  antibodies   o Leukotriene  antagonists                                             ALBUTEROL  /  SALBUTAMOL   SimD   LEVALBUTEROL,   TERBUTALINE,   METAPROTERENOL,   PIRBUTEROL,  PROCATEROL,  FENOTEROL   Class   Beta-­‐2-­‐selective  Agonists  (short-­‐acting)   MOA   Activates  Beta-­‐2  receptors  in  bronchial  smooth  muscle.   Causes  bronchodilation.   Uses   ACUTE  ASTHMA  ATTACKS  (drug  of  choice)   SE   Tachycardia,   Tremors,   Nervousness,   Restlessness,   Arrhythmias   when   used   excessively,   Loss   of   responsiveness  (tolerance,  tachyphylaxis)  

  ASTHMA   • Characterized   by   airway   inflammation   and   episodic,   reversible  bronchospasm   • Major  risk  factor  of  asthma:  INFECTION     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 37 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Notes  

May  precipitate  arrhythmias  in  patient  with  concurrent   COPD  and  Heart  disease  

      SALMETEROL   SimD   FORMOTEROL,  CLENETEROL,  BAMBUTEROL   Class   Beta-­‐2-­‐selective  Agonist  (long-­‐acting)   MOA   Activates  Beta-­‐2  receptors  in  bronchial  smooth  muscle.   Causes   bronchodilation.   Potentiation   of   corticosteroid   action.   Uses   Asthma  prophylaxis  (not  for  acute  relief)   SE   Tachycardia,   Tremors,   Nervousness,   Restlessness,   Arrhythmias   when   used   excessively,   Loss   of   responsiveness  (tolerance,  tachyphylaxis)   Notes   Increase   asthma   mortality   when   used   alone;   May   precipitate  arrhythmias     IPRATROPIUM   SimD   TIOROPIUM   Class   Muscarinic  receptor  Antagonist   MOA   Blocks   muscarinic   receptors   in   bronchial   smooth   muscle.  Prevents  vagal-­‐stimulated  bronchoconstriction.   Uses   Asthma,  COPD   SE   Dry  mouth   Notes   More   effective   and   less   toxic   than   beta-­‐agonists   in   patients  with  COPD     THEOPHYLLINE   SimD   AMINOPHYLLINE,  PENTOXIFYLLINE   Class   Methylxanthine     MOA   Phosphodiesterase   inhibition.   Adenosine   receptor   antagonists.  Causes  bronchodilation   Uses   ASTHMA  (prophylactic  against  nocturnal  attacks)   Intermittent  claudication  (pentoxifylline  only)   SE   Insomnia,  Tremors,  Anorexia,  Seizures,  Arrhythmias   Notes   Antidote  in  overdosage  is  BETA  BLOCKERS!   Higher  clearance  in  adolescents  and  smokers.   Narrow  therapeutic  window.     CROMOLYN   SimD   NEDOCROMIL,  LODOXAMIDE   Class   Mast  cell  Stabilizers   MOA   Prevents   calcium   influx   and   stabilizes   mast   cells,   preventing   degranulation   and   release   of   histamine,   leukotrienes  and  other  mediators.   Uses   ASTHMA   PROPHYLAXIS,   Allergies   (ophthalmic,   nasopharyngeal,  gastrointestinal)   SE   Cough,  Airway  irritation   Notes   NO  BRONCHODILATOR  ACTION!     FLUTICASONE   SimD   BECLOMETHASONE,   BUDESONIDE,   CICLESONIDE,   FLUNISOLIDE,  MOMETASONE,  TRIAMCINOLONE   Class   Corticosteroid   MOA   Inhibitor   of   Phospholipase   A2.   Reduces   expression   of   cyclooxygenase   Uses   ASTHMA   PROPHYLAXIS   (drug   of   choice   for   immunosuppression)  ,  COPD,  Allergic  rhinitis   SE   Oropharyngeal   candidiasis,   Minimal   systemic   steroid   toxicity   (eg,   adrenal   suppression),   Mild   growth   retardation   Notes   IV   HYDROCORTISONE   is   used   in   the   treatment   of  

severe  refractory  asthma  (status  asthmaticus).   CICLESONIDE  has  lowest  systemic  steroid  toxicity.     KEY  LEARNING  POINTS  –  Anti-­‐Platelet  Aggregation    PGI2  –  Prostacyclin    cAMP    PGE1                          

AGENTS  USED  IN  ANEMIAS  &  HEMATOPOIETIC   GROWTH  FACTORS     HEMOCHROMATOSIS   • State   of   chronic   iron   overload   that   damages   the   organs   that   store  excess  iron  (heart,  liver,  pancreas)   • TRIAD:     o Cirrhosis,  DM,  Skin  pigmentation   • OCCURRENCE:   o Persons   with   an   inherited   abnormality   of   iron   absorption   o Persons   who   receive   frequent   transfusion   for   treatment  of  hemolytic  disorders  (eg,  thalassemia   major)   • TREATMENT:   o Phlebotomy   o Chronic   administration   of   DEFEROXAMINE   or   DEFERASIROX     DEFEROXAMINE   SimD   DEFERASIROX   Class   Heavy  metal  Chelator   MOA   Chelates  excess  iron   Uses   Acute   iron   poisoning,   Hemochromatosis   NOT   adequately  treated  by  phlebotomy   SE   Hypotension,   ARDs,   Neurotoxicity,   Increased   susceptibility  to  infections     Role  of  Vitamin  B12  (Cobalamin)   • Cobalt-­‐containing  molecule   • Cofactor  in  the  transfer  of  1-­‐carbon  units,  a  step  necessary   for  the  synthesis  of  DNA   • Deficiency   of   either   vitamin   B12   or   B9   (folic   acid)   usually   manifests  as  megaloblastic  anemia   • Vitamin   B12   deficiency   and   NOT   folic   acid   deficiency   causes  Neurologic  defects!                  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 38 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]           Question:   What   are   the   neurologic   defects   of   vitamin   B12   deficiency?     Answer:    Ataxic  Gait  –  Spinocerebellar  tract    Impaired  position    Vibratory  sense  spasticity       Pharmacokinetics  of  Vitamin  B12  (Cobalamin)   • Produced  ONLY  by  Bacteria   • Absorbed   in   the   Distal   Ileum   in   the   presence   of   intrinsic   factor   • Plasma   transport   is   accomplished   by   binding   to   transcobalamin  II   • Stored  in  the  LIVER  in  large  amounts  (5-­‐year  supply)   • 2  available  forms:     o Cyanocobalamin  and  Hydroxocobalamin    

                    Vitamin  B12  Deficiency   • Folates  accumulate  as  N5methyltetrahydrofolate   • Supply  of  tetrahydrofolate  is  depleted   • Production  of  red  blood  cells  slows   • Administration   of   folic   acid   to   patients   with   vitamin   B12   deficiency   helps   refill   the   tetrahydrofolate     pool   and   partially  or  fully  corrects  the  anemia   • Exogenous  folic  acid  does  not  correct  the  neurologic  defects   of  vitamin  B12  deficiency     CYANOCOBALAMIN   SimD   HYDROXOCOBALAMIN   Class   Hematopoietic  Growth  Factor   MOA   Cofactor  required  for  essential  enzymatic  reactions  that   form   tetrahydrofolate,   convert   homocysteine   to   methionine,  and  metabolize  methylmalonyl-­‐CoA   Uses   Vitamin   B12   deficiency,   Megaloblastic   anemia   (pernicious  anemia,  gatric  resection)   SE   NO  significant  toxicity                                                                   Pharmacokinetics  of  Vitamin  B9  (Folic  Acid)   • Readily  absorbed  by  the  gastrointestinal  tract  (Jejunum)   • Only  modest  amounts  are  stored  in  the  body  

      Pharmacodynamics  of  Vitamin  B12   • Essential  in  2  reactions   o Conversion   of   methylmalonyl-­‐coenzyme   A   (CoA)   to  succinyl-­‐CoA   o Conversion  of  homocysteine  to  methionine   • Linked   to   folic   acid   metabolism   and   synthesis   of   deoxythymidylate   (dTMP),   a   precursor   required   for   DNA   synthesis                   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 39 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] •

Decrease   in   dietary   intake   within   1-­‐6   months   is   followed   by  megaloblastic  anemia  

  FOLIC  ACID   SimD   FOLACIN  (PTEROYLGLUTAMIC  ACID),  FOLINIC  ACID   Class   Hematopoietic  Growth  Factor   MOA   Precursor  of  an  essential  donor  of  methyl  groups  used   for   synthesis   of   amino   acids,   purines,   and   deoxynucleotide.   Uses   Megaloblastic   anemia,   Prevention   of   Neural   Tube   Defects  (spina  bifida),  Prevention  of  Coronary  Artery   Disease   SE   NO  significant  toxicity     Recombinant  Hematopoietic  Growth  Factors   • Glycoprotein   hormones   that   regulate   the   differentiation   and  maturation  of  stem  cells  within  the  bone  marrow   • Approved   for   treatment   of   patients   with   blood   cell   deficiencies     EPOETIN  ALFA   SimD   DARBEPOETIN  ALFA,     METHOXY  POLYETHYLENE  GLYCOL-­‐EPOETIN  BETA   Class   Hematopoietic  Growth  Factor   MOA   Agonist   of   erythropoietin   receptors   expressed   by   red   cell  progenitors   Uses   Anemia   associated   with   chronic   renal   failure,   HIV   infection,  Cancer,  and  Prematurity   SE   Hypertension,  Thrombosis,  Pure  red  cell  aplasia   Notes   Hemoglobin  levels  should  be  maintained  <  12  g/dL   Performance-­‐enhancing  drug  in  athletes     (prohibited  use)     (G-­‐CSF)   SimD   SARGRAMOSTIM  (GM-­‐CSF),  PEGFILGRASTIM   Class   Myeloid  Growth  Factors   MOA   Binds  receptors  on  myeloid  progenitors  and  stimulates   cell  maturation  and  proliferation.     Accelerates  neutrophil  recovery  and  reduces  incidence   of  infection   Uses   Neutropenia   associated   with   Chemotherapy,   Myelodysplasia,  and  aplastic  anemia.   Mobilization   of   peripheral   blood   cells   in   preparation   for  hematopoietic  stem  cell  transplantation   SE   Bone  pain  (arthralgia),  Fever,  Edema               OPRELVEKIN  (IL-­‐11)   SimD   THROMBOPOIETIN   Class   Megakaryocyte  Growth  Factor   MOA   Recombinant   form   of   an   endogenous   cytokine;   Activates  IL-­‐11  receptors   Uses   Secondary  prevention  of  thrombocytopenia  in  patients   undergoing   cytotoxic   chemotherapy   for   non-­‐myeloid   cancers   SE   Fatigue,   Headache,   Dizziness,   Anemia,   Fluid   accumulation  in  the  lungs,  Transient  atrial  arrhythmias      

DRUGS  USED  IN  COAGULATION  DISORDERS  

  Mechanisms  of  Hemostasis:   1. Vasoconstriction   2. Platelet  plug  formation   3. Formation  of  clot  via  blood  coagulation   4. Fibrous  organization                                         1st  STEP:  VASOCONSTRICTION   • Local   autacoid   factors   from   traumatized   tissues   and   platelets   o Thromboxane   A2   (TXA2):   platelet   activator   and   powerful  vasoconstrictor   o Endothelium:   a   potent   endothelium   derived   vasoconstrictor   • Local  myogenic  spasm   • Nervous  reflexes     2nd  STEP:  PLATELET  PLUG  FORMATION  (Primary  Hemostasis)   • Exposed  subendothelial  collagen  is  highly  thrmbogenic   • Platelet  adhesion   o Mediated   by   Gp   IIb,IIIa   and   vWF   (essential   for   binding   subendothelial     collagen   to   platelets)   by   GpIb  receptor  in  the  platelet  surface   • Platelet  release  reaction   o Adenosine   diphosphate   (ADP):   platelet   aggregation   o Thromboxane   A2   (TXA2):   platelet   activator   and   powerful  vasoconstrictor   o Serotonin:   platelet   aggregation   and   vasoconstriction   • Platelet  aggregation    Platelet  plug     3rd  STEP:  FORMATION  OF  CLOT  VIA  COAGULATION   • 2  Coagulation  Pathways:   o INTRINSIC  PATHWAY:  PTT    Factor  V,  VIII,  IX,  X,  XI,  XII,  Prothrombin,   Fibrinogen   o EXTRINSIC  PATHWAY:  PT    Factor  V,  VII,  X,  Prothrombin,  Fibrinogen   • Net   result   of   coagulation   pathways:   PROTHROMBIN   ACTIVATOR   (rate-­‐limiting   factor   causing   blood   coagulation)     4th  STEP:  FIBROUS  ORGANIZATION   • Fibrin  mesh  stabilize  your  platelet  plug    

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 40 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                     Glycoprotein   Ia   Ib   IIb-­‐IIIa  

Function  

Adhesion  to  collagen   Binds  vWF   Def:  Bernard-­‐Soullier  Syndrome  (giant  platelets)   Binds  fibrinogen  &  vWF   Def:  Glanzmann’s  Thrombasthenia   Binds  Thrombospondin   Binds  Thrombin   Associated  with  Ib  complex  

IV   V   IX     KEY  LEARNING  POINTS  –  Phases  of  Platelet  Reaction     1. Platelet  adhesion   • Platelets  stick  to  a  foreign  surface  NOT  familiar  to  them   • Initiated  by  exposure  to  subendothelial  collagen   • Dependent  on:  vWF  &  Gp  Ib     2. Platelet  activation   • Simultaneous  events   • Morphologic  changes  and  functional  changes  in  platelets   • Activated  by  Thromboxan  A2     3. Platelet  secretion   • Alpha  granules   • PF  4   • Beta-­‐thromboglobulin   • Thrombospondin   • Platelet-­‐derived  Growth  Factor  (PDGF)   • “permeability  factor”   • vWF   • Fibrinogen   • Fator  V   • Fibronectin   • Dense  granules   • Magnesium   • Phosphate   • Calcium   • ADP  &  ATP   • Serotonin  /  5-­‐Hydroxytryptamine   • Epinephrine       4. Platelet  aggregation   • Other  platelets  are  stimulated  by  ADP  to  undergo  shape   change   (disk      spherical      pseudopods)   exposing   the   Gp  IIb-­‐IIIa  complex   • Fibrinogen  binding  links  platelets  =  first  &  reversible  

• After  release  reaction,  is  irreversible  aggregation                                                                 ANTI-­‐PLATELET  DRUG   • Arterial   thrombosis   is   the   most   common   cause   of   acute   Myocardial   Infarction   (MI),   ischemic   stroke,   and   limb   gangrene   • Predominance  of  platelets  in  arterial  thrombi       Plaque  Disruption           Tissue  Factor   vWF   Collagen             Platelet  Adhesion  and  Secretion                                                      COX-­‐1    

      TXA2                                  ADP           Thrombin     Platelet  Recruitment  and  Activation         SCH530348   GP  IIb/IIIa  Activation   E5555         Platelet  Aggregation       KEY  LEARNING  POINTS  –  Antiplatelet  Drugs!   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 41 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

 

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 1.

COX  inhibitors    Aspirin       2. ADP  antagonists  (Thienopyridines)    Ticlopidine    Clopidogrel    Prasugrel    Cangrelor    Ticagrelor     3. Gp  IIb/IIIa  inhibitors    Abciximab    Eptifibatide    Tirofiban     4. Thrombin  inhibitors    Dabigatran    Ximelagatran    Vorapaxar       5. Anticoagulants     6. Phosphodiesterase  inhibitors    Dipyridamole    Cilostazol     ASPIRIN  (ACETYLSALICYLIC  ACID,  ASA)   SimD   SALSALATE,  SODIUM  SALICYLATE   Class   Anti-­‐Platelet  Dug,  Anti-­‐inflammatory  Drug   Anti-­‐pyretic,  Analgesic   MOA   Non-­‐selective,  irreversible  COX  1  &  2  inhibitor.  Reduces   platelet   production   of   thromboxane   A2,   a   potent   stimulator  of  platelet  aggregation.   Uses   Prevention   of   arterial   thrombosis   (MI,   TIA,   CVD),   Inflammatory   disorders   (rheumatic   fever,   KAWASAKI   DISEASE,  juvenile  rheumatoid  arthritis)   SE   Gastrointestinal   toxicity,   Nephrotoxicity,   Tinnitus,   Hypersensitivity,  Hyperventilation,  HAGMA   Notes   Toxic  dose  (150  mg/kg),  Lethal  dose  (500  mg/kg)   Uncoupler   of   oxidative   phosphorylation   associated   with  REYE’S  SYNDROME  in  children     KEY  LEARNING  POINTS  –  Aspirin  Toxicity   How   many   500   mg   Aspirin   tablets   must   be   ingested   to   produce   toxicity?  Death?     TOXIC  DOSE  =  150  mg/kg   150mg/kg  x  70  kg/500mg/tab  =  21  tabs     LETHAL  DOSE  =  500  mg/kg   500  mg/kg  x  70  kg/500mg/tab  =  70  tabs     What  is  the  triad  of  Aspirin  hypersensitivity?   SAMTER  TRIAD   1. Asthma   2. Aspirin  sensitivity   3. Nasal  polyps       Aspirin  Intoxication   • Increased   respiratory   drive   leads   to   hyperventilation   and   respiratory  alkalosis  

•

Uncoupling   of   Oxidative   Phosphorylation   leads   to   increased   anaerobic   metabolism   via   lactic   acidosis   and   high-­‐anion  gap  metabolic  acidosis  (HAGMA)  

  KEY  LEARNING  POINTS  –  Aspirin  Intoxication   What   is   the   expected   acid-­‐base   abnormality   in   salicylate   poisoning?    RESPIRATORY  ALKALOSIS  with  HAGMA     What   is   the   difference   between   the   presentation   of   aspirin   intoxication  in  children  and  adults?    ADULTS:   mixed   acid-­‐base   disorder   (Respiratory   Alkalosis  with  HAGMA)    CHILDREN:  pure  acid-­‐base  disorder  (HAGMA)     What   is   the   difference   between   an   inhibitor   and   an   uncoupler   of   oxidative  phosphorylation?    INHIBITORS:  completely  halt  ETC    UNCOUPLERS:   dissipate   proton   gradient   without   interrupting  ETC     ABCIXIMAB   SimD   EPTIFIBATIDE,  TIROFIBAN   Class   Anti-­‐platelet  Drugs   MOA   Inhibits   platelet   aggregation   by   interfering   with   Gp   IIb/IIIa  binding  to  fibrinogen  and  other  ligands   Uses   Used  during  percutaneous  coronary  intervention  (PCI)   to   prevent   thrombosis,   Adjunct   to   thrombolysis,   Acute   coronary  syndromes  (unstable  angina,  NSTEMI)   SE   Bleeding,  Thrombocytopenia   Notes   Prevents  vessel  restenosis,  reinfarction  and  death                           CLOPIDOGREL   SimD   TICLOPIDINE,  PRASUGEL   Class   Anti-­‐platelet  Drugs  (Thienopyridine)   MOA   Irreversibly   inhibits   binding   of   ADP   to   platelet   receptors,  reducing  platelet  aggregation   Uses   Prevention   and   treatment   of   Arterial   Thrombosis   (stroke,   transient   ischemic   attack/TIA,   unstable   angina),   Prevention   of   restenosis   after   PCI,   Acute   coronary  syndromes   SE   Bleeding,   Nausea,   Dyspepsia,   Hematologic   (neutropenia,   leukopenia,   thrombotic   thrombocytopenic  purpura)   Notes   GI   &   Hematologic   SE   are   more   common   with   Ticlopidine   Additive  effects  with  Aspirin!     DIPYRIDAMOLE   SimD   CILOSTAZOL   Class   Anti-­‐platelet  Drug   MOA   Inhibits   phosphodiesterase   III   and   increases   cAMP   in   platelets   and   blood   vessels.   Inhibits   platelet   aggregation  and  causes  vasodilation.  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Uses  

SE   Notes  

Prevention  of  thromboembolic  complications  of  cardiac   valve   replacement,   Secondary   prevention   of   ischemic   stroke   (with   aspirin),   Intermittent   claudication   (cilostazol  only)   Headache  (because  it  is  a  vasodilator),  Palpitations   Dipyridamole,  by  itself,  has  a  little  or  no  benefit.   Cilostazol  is  contraindicated  in  Heart  Failure!  

  ANTICOAGULANTS   • Mainly   for   the   prevention   and   treatment   of   venous   thrombosis  (pulmonary  embolism,  deep  vein  thrombosis)   • Drugs  which  inhibit  the  formation  of  fibrin  clots   • 2  major  types  of  anticoagulants:   o Indirect  thrombin  inhibitors:    HEPARIN    ENOXAPARIN  (LMWH)    LEPIRUDIN   o Direct  thrombin  Inhibitors:    COUMARIN  Derivatives  (warfarin)       Comparison  of  Heparin  and  Warfarin   Property   HEPARIN   WARFARIN   Structure   Route   Site  of  Action   Onset   MOA  

Large  acidic   polysaccharide   Parenteral   Blood   Rapid  (minutes)     Activates  Anti-­‐thrombin  III  

Monitoring   Antidote   Use  

PTT   Protamine   Mostly  acute,  over  days  

Pregnancy  

Yes  

Small  lipid-­‐soluble   molecule   Oral   Liver   Slow  (days)   Impairs  post-­‐translational   modification  of  factors  II,   VII,  IX,  and  X  (vitamin  K-­‐ dependent)     PT   Vitamin  K,  FFP   Chronic,  over  weeks  to   months   No  

  MNEMONICS  –  PT/PTT   What  laboratory  test  will  you  request  to  assess  the  extrinsic  and   intrinsic  coagulation  pathways?     PiTT  =  PTT  for  INTRINSIC  PATHWAY!  (heparin)   PeT  =  PT  for  EXTRINSIC  PATHWAY!(warfarin)     HEPARIN  =  drug  of  choice  for  anticoagulation  during  pregnancy!     HEPARIN   Class   Anticoagulant  (indirect  thrombin  inhibitor)   MOA   Activates   anti-­‐thrombin   III   (inactivates   thrombin   or   factor   IIa,   Factor   IXa   &   Factor   Xa   by   forming   stable   complexes  with  them)   Uses   Deep   venous   thrombosis,   Pulmonary   embolism,   Myocardial   infarction,   Unstable   angina,   Adjuvant   to   percutaneous   coronary   intervention   (PCI)   and   thrombolytics,  Atrial  fibrillation   SE   Bleeding,   Heparin-­‐induced   thrombocytopenia,   Osteoporosis  with  chronice  use   Notes   Monitor  with  aPTT!  Antidote:  PROTAMINE  SULFATE  

 

  ENOXAPARIN   SimD   DALTEPARIN,   TINZAPARIN,   DANAPAROID,   FONDAPARINUX   Class   Anticoagulant  (indirect  thrombin  inhibitor)   MOA   Binds   and   potentiates   effect   of   antithrombin   III   on   factor  Xa  (more  selective).  Less  effect  on  thrombin   Uses   Deep   venous   thrombosis,   Pulmonary   embolism,   Myocardial   infarction,   Unstable   angina,   Adjuvant   to   percutaneous   coronary   intervention   (PCI)   and   thrombolytics,  Atrial  fibrillation   SE   Bleeding,  Less  risk  of  thrombocytopenia   Notes   Does  NOT  require  aPTT  monitoring.   Protamine  sulfate  is  only  partially  effective  in  reversing   effects     LEPIRUDIN   SimD   DESIRUDIN,  BIVALIRUDIN,  ARGATROBAN   Class   Anticoagulant  (direct  thrombin  inhibitor)   MOA   Binds   to   thrombin’s   active   site   and   inhibits   its   enzymatic  action   Uses   Anticoagulation   in   patients   with   heparin-­‐induced   thrombocytopenia   (HIT),   Percutaneous   coronary   angioplasty  (with  aspirin)   SE   Bleeding,   Effect-­‐prolonging   antibodies,   Anaphylactic   reactions   Notes   Monitor  effect  with  aPTT.   No  reversal  agent  exist!   Used  with  caution  for  patients  with  renal  insufficiency     WARFARIN   SimD   DICUMAROL  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Class   MOA   Uses   SE   Notes  

Anticoagulant   Inhibits   vitamin   K   epoxide   reductase   (responsible   for   γ-­‐carboxylation   of   the   vitamin   K-­‐dependent   clotting   factors  –  factors  II,  VII,  IX,  X,  Protein  C  &  Protein  S)   CHRONIC   ANTICOAGULATION   (DVT,   Atrial   fibrillation,  valve  replacement)  EXCEPT  in  Pregnancy!!   Bleeding,  Warfarin-­‐induced  skin  necrosis  (for  patients   with   Protein   C/S   deficiency),   Teratogen   (bone   defects,  hemorrhage)   Monitor  effects  with  PT   Antidote  is  VITAMIN  K  (slow)  or  FFP  (fast)   Narrow  therapeutic  window   Active  ingredient  in  most  Rat  Poisons!  

  KEY  LEARNING  POINTS  –  anticoagulant  Overlap   In  patients  requiring  anticoagulation,  why  is  an  overlap  between   heparin  and  warfarin  usually  done?    Warfarin’s   effect   require   elimination   of   preformed   clotting  factors  (8  –  60  hours)    To   bypass   the   initial   prothrombotic   effect   of   warfarin   (skin  necrosis)                           WARFARIN     Drug  Interactions  of  Warfarin   • Cytochrome   P450-­‐inducers   increase   clearance   and   reduce   the  anticoagulant  effect  of  a  given  dose   • Cytochrome  P450-­‐inhibitors  recude  clearance  and  increase   the  anticoagulant  effect  of  a  given  dose     MNEMONICS  –  P450  INDUCERS  AND  INHIBITORS     CYTOCHROME  P450  INDUCERS   Ethel  Booba  takes  Phen-­‐Phen  and  Refuses  Greasy  Carb  Shakes!!    Ethanol    Barbiturates    Phenytoin    Rifampicin    Griseofulvin    Carbamazepine    St.  John’s  Wort  /  Smoking     CYTOCHROME  P450  INHIBITORS   Inhibtors  Stop  Cyber  Kids  Eating  GRApefruit  Q!!    Isoniazid    Sulfonamides    Cimetidine    Ketoconazole    Erythromycin    Grapefruit  juice    Ritonavir    Amiodarone    Quinidine    

  PROTAMINE  SULFATE   Class   Antidote   MOA   Chemical   agonist   of   Heparin.   Reverses   excessive   anticlotting  activity  of  unfractionated  heparin     Uses   Heparin  overdosage   SE   Hypotension,   Bradycardia,   Flushing,   Hypersensitivity,   Dyspnea   Notes   Partially   reverses   effects   of   LMWHs   (low-­‐molecular   weight  heparins)     FIBRINOLYTIC  DRUGS:   • Mainly   for   the   treatment   of   acute   myocardial   infraction,   ischemic  stroke  and  massive  pulmonary  embolism                                                                   ALTEPLASE   SimD   ANISTREPLASE,   RETEPLASE,   STREPTOKINASE,   TENECTEPLASE,    UROKINASE   Class   Thrombolytics   MOA   Tissue   plasminogen   activator   analog.   Converts   plasminogen  to  plasmin,  which  degrades  the  fibrin  and   fibrinogen,  causing  thrombolysis.   Uses   Acute   myocardial   infarction,   Ischemic   stroke,   Pulmonary  embolism   SE   Bleeding,   Cerebral   hemorrhage,   Reperfusion,   Arrhythmias   Notes   Loss  of  effectiveness  (on  2nd  use)  and  allergic  reactions   may  be  observed  with  streptokinase.   Antidote  is  AMINOCAPROIC  ACID     Contraindications  to  Thrombolysis   • History  of  cerebrovascular  hemorrhage  at  any  time  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 44 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] ANTI-­‐INFLAMMATORY  DRUGS     • 1. Non-­‐Steroidal  Anti-­‐Inflammatory  Drugs     • Classification  of  NSAIDs   • • SALICYLATES     o Aspirin  (attach  to  platelets  –  7  days)   AMINOCAPROIC  ACID   • NON-­‐SELECTIVE  NSAIDs   SimD   TRANEXAMIC  ACID   o Ibuprofen   Class   Antiplasmin  Drug  (procoagulant)   o Indomethacin   o Ketorolac   MOA   Competitively  inhibits  plasminogen  activation   o Piroxicam     Uses   Prevention   and   treatment   of   acute   bleeding   episodes   in   • COX-­‐2  SELECTIVE  NSAIDS   patients   with   high   risk   of   bleeding   (hemophilia,   o Celecoxib   intracranial   aneurysms,   menstrual,   obstetrics,   o Etoricoxib   thrombolytics,  post-­‐operative)   o Parecoxib   SE   Thrombosis,  Hypotension,  Myopathy,  Diarrhea     Notes   Contraindicated   in   Disseminated   Intravascular   Common  NSAIDs  Toxicities   Coagulation  (DIC)  and  Genitourinary  bleeding   • CNS:  Headache,  Tinnitus  Dizziness     • CVS:  Hypertension,  Edema,  Heart  Failure   VITAMIN  K1  (PHYTONADIONE)   • GIT:   Abdominal   pain,   Dysplasia,   Nausea,   Vomiting,   Ulcers,   SimD   VITAMIN  K2  (MENAQUINONE)   Bleeding   VITAMIN  K3  (MENADIONE)   • HEMATOLOGIC:  Thrombocytopenia,  Neutropenia,  Aplastic   Class   Endogenous  Vitamin,  Antidote   anemia   MOA   Increases   supply   of   reduced   vitamin   K,   which   is   • HEPATIC:  Abnormal  liver  function  tests,  Liver  failure   required   for   synthesis   of   functional   vitamin   K-­‐ • PULMONARY:  Asthma   dependent  clotting  and  anti-­‐clotting  factors   • RASHES:  all  types,  Pruritus   Uses   Vitamin  K  deficiency,  Antidote  to  Warfarin,  Prevention   of  hemorrhagic  diatheses  in  newborns   • RENAL:   Renal   insufficiency,   Renal   failure,   Hyperkalemia,   Proteinuria   SE   Severe   infusion   reaction   when   administered   too   fast     (dyspnea,  chest  and  back  pain)   ASPIRIN  (ACETYLSALICYLIC  ACID,  ASA)   Notes   Vitamin   K3   (menadione)   shoulde   NEVER   be   used   in   SimD   SALSALATE,  SODIUM  SALICYLATE   therapeutics  (ineffective)   Class   Anti-­‐Platelet  Dug,  NSAIDs  (salicylate)     DESMOPRESSIN   MOA   Non-­‐selective,  irreversible  COX  1  &  2  inhibitor.     Reduces   platelet   production   of   thromboxane   A2,   a   Class   ADH  Agonist   potent  stimulator  of  platelet  aggregation.   MOA   Vasopressin  V2  receptor  Agonist   Uses   Prevention   of   arterial   thrombosis   (MI,   TIA,   CVD),   Uses   Hemophilia   A,   von   Willebrand’s   Disease,   Central   Inflammatory   disorders   (rheumatic   fever,   KAWASAKI   Diabetes  insipidus   DISEASE,  juvenile  rheumatoid  arthritis)   SE   Headaches,  Flushing,  Nausea,  Hyponatremia,  Seizures   SE   Gastrointestinal   toxicity,   Nephrotoxicity,   Tinnitus,   Notes   Increases   the   Factor   VIII   activity   of   patients   with   mild   Hypersensitivity,   Hyperventilation,   HAGMA,   Hemophilia  A  or  von  Willebrands  Disease   Hyperuricemia     Notes   Uncoupler   of   oxidative   phosphorylation   associated   NSAIDs,  ACETAMINOPHEN,  DMARDS  AND  DRUGS   with  REYE’S  SYNDROME  in  children   USED  IN  GOUT       Prevents  uric  acid  excretion  (don’t  use  in  gout)!!         Dosage  Ranges  of  Aspirin     • LOW  RANGE  (<  300  mg/dL)     o Effective  in  reducing  platelet  aggregation     o Follow  first-­‐order  elimination  kinetics     • INTERMEDIATE  DOSES  (300  –  2400  mg/dL)     o Anti-­‐pyretic  and  analgesic  effects     • HIGH  DOSES  (2400  –  4000  mg/dL)     o Anti-­‐inflammatory  effects   Inflammation   o Follows  zero-­‐order  elimination  kinetics   • Complex  response  to  cell  injury  that  primarily  occurs  in  the   Aspirin  Overdose   vascularized   connective   tissue   and   often   involves   the   • DOSAGE:   immune  response   o Toxic  dose:  150  mg/kg  (21  aspirin  500  mg  tabs)   • Mediators  of  inflammation,  function  to  eliminate  the  cause   o Lethal  dose:  30g  (60  aspirin  500  mg  tabs)   of   cell   injury   and   clear   away   debris,   in   preparation   for   • CLINICAL  PRESENTATION   tissue  repair   o HAGMA   • Causes  pain  and  tissue  damage   o Dehydration     o Hyperthermia   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 45 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected] •

Non-­‐hemorrhagic   stroke   or   other   cerebrovascular   event   within  the  past  year   Marked   hypertension   (>180/110   mmHg)   at   any   time   during  the  acute  presentation   Suspicion  of  AORTIC  DISSECTION   Active  internal  bleeding  (excluding  menses)  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

•

o Collapse   o Coma     TREATMENT   o No  specific  antidote   o Supportive  management   o Activated  charcoal  /  gastric  lavage   o Alkalinize  the  urine  with  BICARBONATE  

          2. Disease-­‐Modifying  Anti-­‐Rheumatic  Drugs  (DMARDS)     RHEUMATOID  ARTHRITIS   • Chronic   inflammatory   disease   of   unknown   etiology   marked   by  a  symmetric,  peripheral  polyarthritis   • It   is   the   most   common   form   of   chronic   inflammatory   arthritis     Disease-­‐Modifying  Anti-­‐Rheumatic  Drugs  (DMARDs)   • Heterogenous   group   of   agents   with   anti-­‐inflammatory   actions  used  in  several  connective  tissue  diseases   • Cause  slowing  or  even  reversal  of  joint  damage   • May  take  6  weeks  to  6  months  for  their  benefits  to  become   apparent     METHOTREXATE   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug,     Cancer  Chemotherapeutic  Drug   MOA   Inhibits   AICAR   transformylase   (phosphoribosylaminoimidazolecarboxamide   formyltransferase)   and   Thymidylate   synthase,   with   secondary  effects  on  polymorphonuclear  chemotaxis   Uses   Rheumatoid   arthritis,   SLE,   Juvenile   rheumatic   (idiopathic)   arthritis/JRA,   Psoriatic   arthritis,   Ankylosing   spondylitis,   Polymyositis   ,   Dermatomyositis,  Wegener’s  granulomatosis,  Giant  cell   arteritis,  Vasculitis   SE   Nausea,   Mucosal   ulcers,   Hepatotoxicity,   Hypersensitivity,  Pseudolymphomatous  reaction   Notes   DMARDs   of   first   choice   to   treat   Rheumatoid   Arthritis!   Rescue  agent  is  LEUCOVERIN  (Folinic  acid)     INFLIXIMAB   SimD   ADALIMUMAB,  ETANERCEPT   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   MOA   Binds   to   TNF-­‐α   and   prevents   it   from   activating   TNF-­‐α   receptor   Uses   CHRON’S   DISEASE,   Rheumatoid   arthritis,   Other   rheumatic  diseases   SE   Bacterial   infections   (URTIs),   Reactivation   of   Latent   Tuberculosis,  Lymphoma,  Demyelination,  Reactivation   of   hepatitis   B,   Autoantibody   formation   (ANA,   Anti-­‐ dsDNA),  Infusion  reactions   Notes   Synergistic  effects  with  Methotrexate     AZATHIOPRINE   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   MOA   Forms   6-­‐Thioguanine,   suppressing   inosinic   acid   synthesis,   B-­‐cell   and   T-­‐cell   function,   Immunoglobulin   production,  and  Interleukin  2  secretion   Uses   Rheumatoid   arthritis,   Psoriatic   arthritis,   Reactive   arthritis,  Polymyositis,  SLE,  Behcet’s  disease   SE   Bone  marrow  suppression,  Increased  risk  of  infections,   Increased   incidence   of   lymphoma,   Fever,   Rash,   Hepatotoxicity,  Allergic  reactions   Notes   Cannot  give  Allopurinol  with  Azathioprine  (allopurinol   reduces  xanthine  oxidase  catabolism  of  purine  analogs,   increasing  6-­‐thioguanine  nucleotides,  leading  to  severe  

  IBUPROFEN   SimD   DICLOFENAC,  DIFLUNISAL,  ETODOLAC,  FENOPROFEN,   FLURBIPROFEN,   KETOPROFEN,   MELOXICAM,   NABUMETONE,    NAPROXEN,  OXAPROZIN,  PIROXICAM,   SULINDAC,  TOLMETIN,  MEFENAMIC  ACID   Class   NSAIDs  (non-­‐selective)   MOA   Non-­‐selective   reversible   COX-­‐1   &   COX-­‐2   inhibitor.   Inhibits  prostaglandin  synthesis.   Uses   Analgesia   (musculoskeletal,   headache,   dysmenorrhea),   Antipyretic,  Anti-­‐inflammatory   SE   Gastrointestinal   bleeding   (less   than   aspirin),   Nephrotoxicity   Notes   Long-­‐term  use  reduces  the  risk  of  colon  cancer.     Misoprostol  prevents  NSAIDs-­‐induced  gastritis!   Meloxicam  &  Piroxicam:  COX-­‐2  >  COX-­‐1     KETOROLAC   Class   NSAIDs  (non-­‐seletive)   MOA   Non-­‐selective   reversible   COX-­‐1   &   COX-­‐2   inhibitor.   Inhibits  prostaglandin  synthesis.   Uses   Post-­‐surgical   analgesic   control   (moderate   to   severe,   short-­‐term)   SE   High   risk   for   gastrointestinal   toxicity   and   nephrotoxicity,  Allergic  reactions   Notes   ONLY  INTRAVENOUS  NSAID.   Used  generally  restricted  to  72  hours  ONLY!     INDOMETHACIN   Class   NSAIDs  (non-­‐selective)   MOA   Non-­‐selective   reversible   COX-­‐1   &   COX-­‐2   inhibitor.   Inhibits  prostaglandin  synthesis.   Uses   Anti-­‐inflammatory   (gout,   arthritis,   ankylosing   spondylitis),   CLOSURE   OF   PATENT   DUCTUS   ARTERIOSUS!   SE   Gastrointestinal   toxicity,   Pancreatitis,   Nephrotoxicity,   Serious   Hematologic   reactions   (aplastic   anemia,   thrombocytopenia)     CELECOXIB   SimD   ETORICOXIB,  PARECOXIB,  ROFECOXIB,  VALDECOXIB   Class   NSAIDs  (COX-­‐2  selective)   MOA   Selective   COX-­‐2   inhibitor.   Inhibits   prostaglandin   synthesis.   Uses   Analgesia,  Antipyretic,  Anti-­‐inflammatory     SE   Gastrointestinal   bleeding   (reduced   risk),   Nephrotoxicity,   Myocardial   infarction   and   stroke   (rofecoxib  and  valdecoxib  only)   Notes   COX-­‐2  produces  prostacyclin!     Celecoxib  is  anti-­‐aggregant               TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 46 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] leukopenia)     CHLOROQUINE   SimD   HYDROXYCHLOROQUINE   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   Anti-­‐malarial  Drug   MOA   Suppression   of   T-­‐lymphocyte   responses   to   mitogens,   Decreased   leukocyte   chemotaxis,   Stabilization   of   lysosomal   enzymes,   Inhibition   of   DNA   and   RNA   synthesis,  Trapping  of  free  radicals   Uses   Rheumatoid   arthritis,   SLE,   Sjogren’s   Syndrome,   MALARIA   SE   Ocular   toxicity,   Dyspepsia,   Nausea,   Vomiting,   Abdominal  pain,  Rashes,  Nightmares   Notes   Safe  for  pregnant  women!             CYCLOPHOSPHAMIDE   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug,   Cancer  Chemotherapeutic  Drug   MOA   Forms   phosphoramide   mustard,   which   cross-­‐links   DNA   to  prevent  cell  replication.   Suppresses  T-­‐cell  and  B-­‐cell  function   Uses   Rheumatoid   arthritis,   SLE,   Vasculitis,   Wegener’s   granulomatosis,  Severe  rheumatic  diseases   SE   HEMORRHAGIC  CYSTITIS   Notes   Rescue  agent  is  MESNA!     CYCLOSPORINE     Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   MOA   Inhibits   interleukin-­‐1   and   interleukin-­‐2   receptor   production  and  secondarily  inhibits  macrophage  T-­‐cell   interaction  and  T-­‐cell  responsiveness   Uses   Rheumatoid   arthritis,   SLE,   Polymyositis,   Dermatomyositis,   Wegener’s   granulomatosis,   Juvenile   rheumatoid  arthritis,  Tissue  transplantation   SE   Nephrotoxicity,   Hypertension,   Hyperkalemia,   Hepatotoxicity,  Gingival  hyperplasia,  Hirsutism     MYCOPHENOLATE  MOFETIL   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   MOA   Active   product   (mycophenolic   acid)   inhibits   inosine   monophosphate   dehydrogenase   (important   enzyme   in   the   guanine   nucleotide   synthesis)   and   inhibits   T-­‐cell   lymphocyte  proliferation   Uses   SLE   nephritis,   Vasculitis,   Wegener’s   granulomatosis,   Rheumatoid  arthritis   SE   Gastrointestinal  disturbances,  Headache,  Hypertension,   Reversible  myelosuppression  (neutropenia)     SULFASALAZINE   Class   Disease-­‐Modifying  Anti-­‐Rheumatic  Drug   MOA   Active   metabolite   (sulfapyridine)   inhibits   the   release   of   inflammatory  cytokines   Uses   Rheumatoid  arthritis,  Inflammatory  bowel  disease,  JRA,   Ankylosing  spondylitis   SE   Nausea,   Vomiting,   Headache,   Rash,   Hemolytic   anemia,   Methemoglobinemia,   Neutropenia,   Thrombocytopenia,   Pulmonary   toxicity,   Autoantibody   formation   (anti-­‐ dsDNA),  Reversible  infertility  in  men    

PARACETAMOL     PARACETAMOL  (ACETAMINOPHEN)   SimD   PHENACETIN   Class   Analgesics  (COX-­‐3  inhibitor)   MOA   Selectively   inhibits   COX-­‐3.   Weak   COX-­‐1   and   COX-­‐2   inhibitor.   Inhibits   prostaglandin   synthesis   (weak   prostaglandin  inhibitor).   Uses   Analgesia  (mild),  Antipyretic   SE   Hepatotoxicity,  Renal  papillary  necrosis  and  interstitial   nephritis   (phenacetin   only),   Methemoglobinemia,   Hemolytic  anemia   Notes   Increased  hepatotoxicity  with  alcohol  use.   Preferred   anti-­‐pyretic   in   children   (DOES   NOT   cause   REYE’s  SYNDROME)   Antidote  is  N-­‐ACETYLCYSTEINE     Mechanism  of  Paracetamol  Overdose   • Oxidation   to   a   cytotoxic   intermediate   calle   N-­‐acetyl-­‐p-­‐ benzoquinoneimine   (NAPQ1)   by   phase   I   cytochrome   P450  enzymes  (CYP2E1)   • Occurs   if   substrates   for   phase   II   conjugation   reactions   (acetate  and  glucuronide)  are  lacking   • Centrilobular   region   (zone   III)   is   preferentially   involved   because  it  is  the  are  of  greatest  concentration  of  CYP2E1   • Antidote  is  N-­‐ACETYLCYSTEINE  (NAC),  a  sulfhydryl  donor                 Stages  of  Paracetamol  Overdose   Stage   I  

Time  Period   0.5  to  24  hours  

II  

24  to  72  hours  

II  

72  to  96  hours  

IV  

4  days  to  2  weeks  

Manifestations   Nausea,   vomiting,   diaphoresis,   pallor,   lethargy,  malaise   Elevated  liver  enzymes,  oliguria,  azotemia,   increased  PT,  hyperbilirubinemia   Jaundice,   hepatic   encephalopathy,   bleeding  diatheses,  acute  tubular  necrosis,   HAGMA,  coma,  death   Recovery  

  Paracetamol  Overdose   • DOSAGE:   o Toxic   Dose:   150   mg/kg   (21   Paracetamol   500   mg   tabs)   o Lethal  Dose:  15g  (30  Paracetamol  500  mg  tabs)   • TREATMENT:   o Antidote:  N-­‐ACETYLCYSTEINE   o Supportive  management   o Gastric  decontamination  with  activated  charcoal     DRUGS  FOR  THE  TREATMENT  OF  GOUT     GOUT   • Increased  serum  concentrations  of  uric  acid   • Acute   attacks   involve   joint   inflammation   initiated   by   precipitation  of  uric  acid  crystals     Treatment  Strategies  for  Gout   • Reducing  inflammation  during  acute  attacks   • Accelerating  renal  excretion  of  uric  acid  uricosuric  drugs  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] •

MOA  

Reducing   the   conversion   of   purines   to   uric   acid   by   xanthine  oxidase  

  COLCHICINE   Class   Anti-­‐gout  Drug  (microtubule  assembly  inhibitor)   MOA   Inhibits   microtubule   assembly,   Decreases   macrophage   migration  and  phagocytosis   Uses   Gout,  Familial  mediterranean  fever   SE   Diarrhea,   Nausea,   Vomiting,   Abdominal   pain,   Hepatic   necrosis,   Acute   renal   failure,   Disseminated   intravascular   coagulation,   Seizures,   Hair   loss,   Bone   marrow   depression   (aplastic   anemia),   Peripheral   neuritis,  Myopathy     NSAIDs  in  Gout   • In   addition   to   inhibiting   prostaglandin   synthase,   indomethacin  and  other  NSAIDs  also  inhibit  urate  crystal   phagocytosis   • Aspirin  is  NOT  used  due  to  its  renal  retention  of  uric  acid   at  low  doses   • Indomethacin   is   commonly   used   in   the   initial   treatment   of   gout  as  the  replacement  for  colchicine     PROBENECID   SimD   SULFINPYRAZONE   Class   Anti-­‐gout  Drug  (uricosuric  agent)   MOA   Compete   with   uric   acid   for   reabsorption   in   the   proximal  tubules,  Increases  uric  acid  excretion   Uses   GOUT   SE   Gastrointestinal   irritation,   Rashes,   Nephrotic   syndrome   (probenecid  only),  Aplastic  anemia   Notes   May   precipitate   acute   gout   during   early   phase   of   drug   action   (prevent   by   co-­‐administering   with   colchicine   or   indomethacin).   Inhibit   secretion   of   other   weak   acids   (eg,   penicillin,   methotrexate)                         ALLOPURINOL   Class   Anti-­‐gout  Drug  (xanthine  oxidase  inhibitor)   MOA   Active   metabolite   (alloxanthine)   irreversibly   inhibits   Xanthine  oxidase  and  lowers  production  of  uric  acid   Uses   1st   line   treatment   of   chronic   gout!   Tumor   lysis   syndrome   SE   Gastrointestinal   upset,   Rash,   Peripheral   neuritis,   Vasculitis,   Bone   marrow   dysfunction,   Aplastic   anemia,   CATARACTS   Notes   Inhibit   metabolism   of   mercaptopurine   and   azathioprine.   Withheld   for   1   –   2   weeks   after   an   acute   episode   of   gouty   arthritis   (co-­‐administered   with   colchicine   or   indomethacin  to  avoid  an  acute  attack)     FEBUXOSTAT   Class   Anti-­‐gout  Drug  (xanthine  oxidase  inhibitor)  

Uses   SE   Notes  

Non-­‐purine  reversible  inhibitor  of  xanthine  oxidase   (more  selective  than  allopurinol).  Lowers  production  of   uric  acid   Chronic   gout,   Tumor   lysis   syndrome,   Allopurinol   intolerance   Liver   function   abnormalities,   Headache,   Gastrointestinal  upset   Withheld   for   1   –   2   weeks   after   an   acute   episode   of   gouty   arthritis   (co-­‐administered   with   colchicine   or   indomethacin  to  avoid  an  acute  attack)    

                                                                                                     

SEDATIVE-­‐HYPNOTIC  DRUGS      

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                     DEFINITION  OF  TERMS   • SEDATIVES  (ANXIOLYTICS)   o Drugs   that   reduce   anxiety   and   exert   a   calming   effect   o Degree  of  CNS  depression  should  be  the  minimum   consistent  with  therapeutic  efficacy   • HYPNOTICS   o Drugs  that  produce  drowsiness  and  encourage  the   onset  and  maintenance  of  a  state  of  sleep   o Involve   more   pronounced   CNS   depression   than   sedation                                                                             MNEMONICS  –  GABA  receptor  effects    BENZODIAZEPINES:  frequency  of  opening    BARBITURATES:  duration  of  opening     Major  Inhibitory  Neurotransmitters:    GABA    nervous  system    GLYCINE    spinal  cord  

  Major  Excitatory  Neurotransmitters:    GLUTAMIC  ACID    ASPARTIC  ACID    N-­‐methyl-­‐D-­‐aspartate  (NMDA)             BENZODIAZEPINES     MIDAZOLAM   SimD   BROTIZOLAM,  TRIAZOLAM,  OXAZEPAM,  ETIZOLAM   Class   Benzodiazepine  (short-­‐acting)   MOA   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of  chloride  channel  opening;     Membrane  hyperpolarization   Uses   Acute  anxiety,  Panic  attacks,  Anesthesia,  Induction,  Pre-­‐ operative  sedation   SE   ANTEROGRADE   AMNESIA,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Tolerance,   Dependence  liability,  Rebound  insomnia/anxiety   Notes   Additive  CNS  depression  with  Ethanol     LORAZEPAM   SimD   ALPRAZOLAM,   ESTAZOLAM,   CLONAZEPAM,   LORMETAZEPAM,  NITRAZEPAM,  TEMAZEPAM   Class   Benzodiazepine  (intermediate-­‐acting)   MOA   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of  chloride  channel  opening;     Membrane  hyperpolarization   Uses   Anxiety   disorders,   Insomnia,   Skeletal   muscle   relaxation,  Seizure  disorders,  Tranquilizer   SE   ANTEROGRADE   AMNESIA,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Respiratory   depression,  Tolerance,  Dependence  liability   Notes   Additive  CNS  depression  with  Ethanol     KET  LEARNING  POINTS  –  Sleep  Disturbance  from  BZDs   What   abnormal   sleep   pattern   results   from   the   use   of   benzodiazepines?      Decreased  REM  sleep    Longer  non-­‐REM  (stage  2)    Retrograde   increase   REM   sleep   in   benzodiazepine   withdrawal       DIAZEPAM   SimD   CHLORAZEPATE,   CHLORDIAZEPOXIDE,   FLURAZEPAM,   QUAZEPAM,  FLUNITRAZEPAM   Class   Benzodiazepine  (long-­‐acting)   MOA   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of  chloride  channel  opening;     Membrane  hyperpolarization   Uses   Anxiety   disorders,   Insomnia,   Skeletal   muscle   relaxation,  Seizure  disorders,  Tranquilizer,     ALCOHOL  WITHDRWAL!   SE   ANTEROGRADE   AMNESIA,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Respiratory   depression,  Tolerance,  Dependence  liability   Notes   Additive  CNS  depression  with  Ethanol     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 49 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] FLUNITRAZEPAM   (Rohypnol)   is   used   to   a   date-­‐rape   drug!!  (colorless,  tasteless)     MNEMONICS  –  Chlordiazepoxide   Which  benzodiazepine  has  the  longest  half-­‐life?     CHLORDIAZEPOXIDE   has   the   longest   half-­‐life   (36-­‐200   hours)   and  the  longest  spelling  (many  letters)     Which  drugs  are  considered  date-­‐rape  drugs?    ALCOHOL  (most  common)    FLUNITRAZEPAM  (rohypnol)    GAMMA-­‐HYDROXYBUTYRATE     Clinical  Uses  of  Benzodiazepines   Clinical  Use   Anticonvulsant  maintenance   Status  epilepticus   Skeletal  muscle  relaxation     (eg,  cerebral  palsy)   Panic  disorders,  Phobias   Insomnia   Anesthesia  induction   Bipolar  disorder   Alcohol  withdrawal  

Preffered  Benzodiazepine   CLONAZEPAM   LORAZEPAM,  DIAZEPAM   DIAZEPAM   ALPRAZOLAM,  CLONAZEPAM   ESTAZOLAM,  FLURAZEPAM,  TRIAZOLAM   MIDAZOLAM,  DIAZEPAM   CLONAZEPAM   CHLORDIAZEPOXIDE,  DIAZEPAM  

  PENTOBARBITAL   SimD   SECOBARBITAL,   AMOBARBITAL,   BUTALBITAL,   BUTABARBITAL,  TALBUTAL,  APROBARBITAL   Class   Barbiturate  (short-­‐  and  intermediate-­‐acting)   MOA   Binds   GABA-­‐A   receptor   sites   (distinct   from   benzodiazepines);   Increase   duration   of   chloride   channel  opening.   Uses   Insomnia,  Pre-­‐operative  sedation   SE   Extension   of   CNS   depressant   actions,   Tolerance,   Dependence   liability   (greater   than   benzodiazepines),   ACUTE  INTERMITTENT  PORPHYRIA   Notes   Additive  to  CNS  depression  with  Ethanol.   Potent  inducer  of  CYP450  enzymes     PHENOBARBITAL   SimD   MEPHOBARBITAL,  PRIMIDONE   Class   Barbiturate  (long-­‐acting)   MOA   Binds   GABA-­‐A   receptor   sites   (distinct   from   benzodiazepines);   Increase   duration   of   chloride   channel  opening.   Uses   Insomnia,   Seizure   disorders,   Status   epilepticus,   Hyperbilirubinemias   (Gilbert’s   syndrome   and   kernicterus)   SE   Extension   of   CNS   depressant   actions,   Tolerance,   Dependence   liability   (greater   than   benzodiazepines),   ACUTE  INTERMITTENT  PORPHYRIA   Notes   Additive  to  CNS  depression  with  Ethanol.   Potent  inducer  of  CYP450  enzymes     MNEMONICS  –  Biochemistry  –  Porphyria   What  enzyme  is  deficient  in  Acute  Intermittent  Porphyria?    HYDROXYMETHYLBILANE  SYNTHASE     What   is   the   most   catastrophic   symptom   of   sedative-­‐hypnotic   withdrawal?    REBOUND  SUICIDE     MISCELLANEOUS  (NEWER)  HYPNOTICS     ZOLPIDEM   SimD   ZALEPLON,  ESZOPICLONE   Class   Imidazopyridine   MOA   Bind   selectively   to   a   subgroup   of   GABA-­‐A   receptors,   acting   like   benzodiazepines   to   enhance   membrane   hyperpolarization   Uses   INSOMNIA  ONLY!   SE   Modest   day-­‐after   psychomotor   depression,   Few   amnestic   effects,   Tolerance,   Dependence   liability   (less   than  benzodiazepines)   Notes   Effects  reversed  with  FLUMAZENIL!   Lack   anti-­‐convulsant,   anti-­‐anxiety   and   muscle   relaxant   effects     MNEMONICS  –  Zolpidem   zZzzZZzzzZZzzzZZz  (sleep)   Zolpidem,  Zaleplon  =  SLEEP  DISORDERS     BUSPIRONE   Class   Anxiolytic  Drug   MOA   Partial  agonist  at  5-­‐HT1A  and  possibly  D2  receptors   Uses   GENERALIZED  ANXIETY  DISORDER   SE   Non-­‐specific   chest   pain,   Tachycardia,   Palpitations,  

Benzodiazepine  Overdose   • DOSAGE:   o Toxic  dose  is  1000x  the  therapeutic  dose   • CLINICAL  PRESENTATION:   o Slurred  speech   o Ataxia   o Altered  (decreased)  mental  status   o Respiratory  depression   • TREATMENT:   o Antidote:   FLUMAZENIL   (a   BZ   receptor   antagonist)   o Activated  charcoal  is  useless     FLUMAZENIL   Class   Antidote  (benzodiazepine  antagonist)   MOA   Antagonist  at  benzodiazepine  sites  on  GABA-­‐A  receptor   Uses   Benzodiazepine  overdose   SE   Agitation,   Confusion,   Precipitates,   BENZODIAZEPINE   WITHDRAWAL  SYNDROME   Notes   Seizures   and   arrhythmias   may   occur   when   administered   in   patient   who   took   both   TCAs   and   Benzodiazepines.   Available  in  IV!     BARBITURATES     THIOPENTAL   SimD   METHOHEXITAL,  THIAMYLAL   Class   Barbiturate  (ultra-­‐short  acting)   MOA   Binds   GABA-­‐A   receptor   sites   (distinct   from   benzodiazepines);   Increase   duration   of   chloride   channel  opening.   Uses   Anesthesia  induction,  Increased  ICP   SE   Extension   of   CNS   depressant   actions,   Tolerance,   Dependence   liability   (greater   than   benzodiazepines),   ACUTE  INTERMITTENT  PORPHYRIA   Notes   Additive  to  CNS  depression  with  Ethanol.   Potent  inducer  of  CYP450  enzymes     MNEMONICS  –  Thiopental   TAYOpental  =  TAYO  agad  (shortest-­‐acting)!!   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 50 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

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Notes  

Diziness,   Nervousness,   Tinnitus,   Gastrointestinal   distress,   Paresthesias,   Dose-­‐dependent   pupillary   constriction   No  anticonvulsant   No  muscle  relaxant  properties   Minimal  CNS  depressant  effects   Minimal  abuse  liability   Minimal  tolerance  and  withdrawal  

  MNEMONICS  –  Buspirone   Buspirone  for  Busy  People  (Always  Anxious)   BuSPirone  like  your  BenzodiaSePine!!     Pineal   Gland   (no   BBB)      ↑   age   =   calcifications   occur   &   ↓   melatonin        

ALCOHOLS                                                                         ALCOHOL  DEHYDROGENASE   • Cytosolic,  NAD+-­‐dependent  enzyme   • Found  mainly  in  the  LIVER  and  GUT   • Accounts   for   the   metabolism   of   low   to   moderate   doses   of   ethanol   • Because   of   the   limited   supply   of   the   co-­‐enzyme   NAD+,   the   reaction  has  zero-­‐order  kinetics   o Fixed  capacity  for  ethanol  metabolism  of  7-­‐10  g/h   • Gastrointestinal   metabolism   of   ethanol   is   lower   in   women   than  in  men    

KEY  LEARNING  POINTS!   Why  is  there  Lactic  acidosis  and  Hypoglycemia?    Increased   metabolism      inc.   NADH:NAD+   ratio      diverts  pyruvate  to  lactate  &  OAA  to  malate    AFTERMATH:   inhibits   gluconeogenesis   and   stimulates   FA  synthesis    CONSEQUENCE:   hypoglycemia   and   hepatic   fatty   change   (hepatocellular  steatosis)    Overproduction  of  lactate    acidosis    Depletion   of   OAA   shuts   down   the   TCA   cycle,   shunts   acetyl-­‐CoA  into  ketone  production    Breakdown  of  excess  malate  increases  NADPH  and  thus   FA  synthesis                           Microsomal  Ethanol  Oxidizing  System  (MEOS)   • Responsible   for   ethanol   metabolism   at   blood   levels   higher   than  100  mg/dL   • Chronic  ethanol  consumption   o Induces  cytochrome  P450  enzymes  synthesis  and   MEOS  activity  (CYP2E1  –  high  affinity  to  ethanol)   o Development  of  tolerance  to  ethanol   • Acetaldehyde   is   rapidly   metabolized   to   acetate   by   aldehyde  dehydrogenase   o Inhibited   by   disulfiram,   metronidazole,   oral   hypoglycemics,  and  some  cephalosporins   o Genetic   deficiency   of   aldehyde   dehydrogenase   in   Asians     Acute  Effects  of  Ethanol   • CNS  EFFECTS:   o Sedation,   loss   of   inhibition,   impaired   judgment,   slurred  speech,  ataxia     • EFFECTS  ON  OTHER  ORGAN  SYSTEMS:   o Slight   cardiac   depression,   vasodilation,   hypothermia,  uterine  muscle  relaxation     Blood  Alcohol  Concentration  (BAC)   BAC  (mg/dL)   50  –  100   60  –  80   100  –  200     200  –  300     300  –  400     >  500    

Effects   Sedation,  Subjective  “high”,  Slower  reaction  times   Impairment  of  driving  ability  (DUI)   Impaired  motor  functions,  Slurred  speech,  Ataxia   Emesis,  Stupor   Coma   Respiratory  depression,  Death  

  Chronic  Effects  of  Ethanol   • TOLERANCE  AND  DEPENDENCE   o Result   of   CNS   adaptation   and   increased   ethanol   metabolism   o Cross-­‐tolerance   to   benzodiazepines   and   barbiturates   o Marked  psychological  and  physical  dependence   • LIVER  DISEASE   o Most   common   complication   of   chronic   alcohol   abuse  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Reduced  gluconeogenesis  leads  to  hypoglycemia   Progressive  loss  of  liver  function  (reversible  fatty   liver   to   irreversible   hepatitis,   cirrhosis,   and   liver   failure)   o Increased   severity   in   females   and   those   with   hepatitis  B  and  C   GASTROINTESTINAL  SYSTEM   o Irritation,   inflammation,   bleeding   and   scarring   of   gut  wall   o Absorption   defects   and   exacerbation   of   nutritional  deficiencies   o Increased  risk  of  PANCREATITIS!   CENTRAL  NERVOUS  SYSTEM   o Peripheral   neuropathy   is   the   most   common   neurologic  abnormality  in  chronic  alcoholics   o WERNICKE-­‐KORSAKOFF   SYNDROME   (ataxia,   confusion,  paralysis  of  the  extraocular  muscles)  

              •             •     MNEMONICS  –  Delirium  Tremens   H  –  A  –  D  48!!    Hallucinations      Autonomic  instability   MNEMONICS  –  Wernicke-­‐Korsakoff  Syndrome    Delirium   Weird  ACO  =  Wernicke-­‐Korsakoff  Syndrome   48  –  72  hours  post-­‐discontinuation    Ataxia        Confusion   ALCOHOL  WITHDRAWAL  SYNDROME    Ophthalmoplegia   What   changes   in   the   brain   are   seen   in   Wernicke-­‐Korsakoff   • TREATMENT   Syndrome?   o Correction  of  electrolyte  imbalance    Hemorrhagic   necrosis   of   the   mammillary   bodies   o Administration  of  thiamine   (recollecive  memory)   o Administration  of  a  sedative  hypnotics    Substituting   a   long-­‐acting   sedative-­‐   hypnotic   drug   for   alcohol   and   then   • ENDOCRINE  SYSTEM   gradually  reducing  (“tapering”)  the  dose   o Gynecomastia,   Testicular   atrophy   and   Salt   of  the  long-­‐acting  drug   retention  due  to  altered  steroid  metabolism  in  the    Drug   of   choice   is   long-­‐acting   cirrhotic  liver   BENZODIAZEPINE   (eg,   diazepam,   • CARDIOVASCULAR  SYSTEM   chlordiazepoxide)   o Increased   incidence   of   hypertension,   anemia   and    Short-­‐acting   benzodiazepine   with   less   dilated  cardiomyopathy   complex   metabolism   (eg,   lorazepam)   is   o Binge  drinking  can  cause  arrhythmias   preferred  in  patients  with  compromised   o Ingestion   of   modest   quantities   of   ethanol   (10-­‐15   liver  function   g/day)  raises  HDL  levels  and  may  protect  against     CAD   Treatment  of  Alcoholism   • FETAL  ALCOHOL  SYNDROME   • Opioid  receptor  antagonists  (NALTREXONE)   o Mental  retardation  (most  common)   o Decrease   CNS   effects   of   endogenous   opioid   o Growth  deficiencies   peptides   o Microcephaly   • NMDA  receptor  antagonists  (ACAMPROSATE)   o Characteristic   underdevelopment   of   midface   • DISULFIRAM  inhibits  aldehyde  dehydrogenase   region   o Acetaldehyde   accumulation   leads   to   nausea,   o Associated   with   heavy   consumption   of   alcohol   headache,  flushing,  and  hypotension     during  the  first  trimester  of  pregnancy   o (+)  punishemnt   • NEOPLASIA     o Increased  incidence  of  neoplastic  diseases  in  GIT   MNEMONICS  –  Disulfiram  Reaction   o Small  increase  in  the  risk  of  breast  cancer   What  drug  can  cause  disulfiram  reaction?   • IMMUNE  SYSTEM   Clara  took  the  Pre-­‐Medical  Test  in  the  PM!!   o Enhances  inflammation  in  the  liver  and  pancreas    CHLORPROPAMIDE   o Inhibits  immune  function  in  other  tissues    CEFOPERAZONE  (3rd)   o Heavy  use  predisposes  to  infectious  pneumonia    CEFOMANDOLE  (2nd)   o Treatment  of  Acute  and  Chronic  Alcoholism    CEFOTETAN  (2nd)   • EXCESSIVE  CNS  DEPRESSION    PROCARBAZINE   (anti-­‐neoplastic   drug,   Hodgkin’s   o Maintenance  of  vital  signs   Lymphoma)   o Prevention  of  aspiration  after  vomiting    METRONIDAZOLE   o Intravenous  dextrose     o Thiamine   administration   to   protect   against   METHANOL   Wernicke-­‐Korsakoff  syndrome   • SOURCES:   o Correction  of  electrolyte  imbalance   o Wood  alcohol     o Windshield  cleaners     o “Canned  heat”   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 52 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected] o o

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

• • •

o Commercial  solvents   o Photocopier  toner   CLINICAL  MANIFESTATIONS:   Visual   dysfunction,   Gastrointestinal   distress,   Shortness   of   breath,  Loss  of  consciousness,  Coma   Accumulation   of   formaldehyde   and   formic   acid   causes   severe  acidosis,  Retinal  damage,  and  Blindness  

  Treatment  of  Methanol  Poisoning   • ETHANOL   o Retards  formation  of  formaldehyde   o Acts   as   preferred   substrate   for   alcohol   dehydrogenase   o Competitively  inhibits  the  oxidation  of  methanol   • FOMEPIZOLE   o Inhibitor  of  alcohol  dehydrogenase                           • ETHYLENE  GLYCOL   o SOURCES    Industrial   exposure   (by   inhalation   or   skin  absorption)    Self-­‐administration   (eg,   by   drinking   antifreeze  products)   o CLINICAL  MANIFESTATION    Severe  acidosis  and  renal  damage    Due  to  accumulation  of  oxalic  acid     Treatment  of  Ethylene  Glycol  Poisoning   • ETHANOL   o Competes   for   oxidation   by   alcohol   dehydrogenase   • FOMEPIZOLE   o Slows  or  prevents  formation  of  oxalic  acid                              

ANTI-­‐SEIZURE  DRUGS            

                  SEIZURES   • Finite   episodes   of   brain   dysfunction   resulting   from   abnormal  discharge  of  cerebral  neurons   • Classification  based  on  seizure  characteristics:   o Simple  or  Complex   o Partial,   Generalized,   or   Partial   with   secondary   generalization     Types  of  Seizures   • SIMPLE  PARTIAL  SEIZURES   o Consciousness  is  preserved   o Manifested   variously   as   convulsive   jerking,   paresthesias,   psychic   symptoms   (altered   sensory   perception,   illusions,   hallucinations,   affect   changes)  and  autonomic  dysfunction   • COMPLEX  PARTIAL  SEIZURES   o Impaired  consciousness   o Preceded,   accompanied,   or   followed   by   psychological  symptoms   • GENERALIZED  TONIC-­‐CLONIC  SEIZURES  (GRAND  MAL)   o Tonic  phase  (less  than  1  min)  involves  abrupt  loss   of   consciousness,   muscle   rigidity   and   respiration   arrest   o Clonic   phase   (2-­‐3   min)   involves   jerking   of   body   muscles,   with   lip   or   tongue   biting,   and   fecal   and   urinary  incontinence   • ABSENCE  SEIZURES  (PETIT  MAL)   o Impaired  consciousness  (often  abrupt  onset  and   brief)   o Automatisms;  loss  of  postural  tone,  or  enuresis   o Begin  in  childhood  and  usually  cease  by  age  20  yrs   • MYOCLONIC  SEIZURES   o Sudden,   brief,   shock-­‐like   contractions   of   musculature  (myoclonic  jerks)   • STATUS  EPILEPTICUS   o Series   of   seizures   (usually   tonic-­‐clonic)   without   recovery  of  consciousness  between  attacks   o Life-­‐threatening  emergency     Antiseizure  Drug   Phenytoin   Carbamazepine   Valproic  acid   Phenobarbital     Oxcarbazepine   Clonazepam     Diazepam   Ethosuximide   Gabapentin   Pregabalin   Vigabatrin   Tiagabine   Lamotrigine   Levetiracetam   Topiramate   Felbamate   Zonisamide    

Na+   •   •   •   •   •                 •     •     •  

Ca2+       •     •       •   •   •       •   •   •     •  

K+           •                          

GABA       •   •     •   •     •   •   •   •     •   •   •    

    TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 53 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

Glutamate     •     •           •   •       •   •   •      

Others       NMDA                        

Carbonic  anhydrase  

NMDA  

Carbonic  anhydrase  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] TRADITIONAL  ANTISEIZURE  DRUGS     PHENYTOIN   SimD   FOSYPHENYTOIN,  MEPHENYTOIN,  ETHOTOIN   Class   Anticonvulsant  Drugs  (hydantoin)   MOA   Blocks  voltage-­‐gated  Na  channels   Uses   Drug   of   choice   for   Generalized   tonic-­‐clonic   seizures   and   Partial   seizures!   Status   epilepticus,   Arrhythmias   (group  1B  action)   SE   Nystagmus,   Diplopia,   Sedation,   Gingival   hyperplasia,   Hirsutism,   Anemias,   Peripheral   neuropathy,   Osteoporosis,  Teratogen  (fetal  hydantoin  syndrome)   Notes   Potent  inducer  of  CYP450  enzymes.   Follows  zero-­‐order  kinetics  at  high  doses     FETAL  HYDANTOIN  SYNDROME   • Upturned  nose   • Mild  midfacial  hypoplasia   • Long  upper  lip  with  thin  vermillion  border   • Lower  distal  digital  hypoplasia       CARBAMAZEPINE   Class   Anticonvulsant  Drug  (tricyclic)   MOA   Blocks   voltage-­‐gated   Na   channels   and   decrease   glutamate  release   Uses   Drug  of  choice  for  Generalized  tonic-­‐clonic  seizures,   Partial   seizures   and   Trigeminal   neuralgia!   Bipolar   disorders   SE   Diplopia,   Cognitive   dysfunction,   Drowsiness,   Ataxia,   Blood   dyscrasias,   Stevens-­‐Johnson   syndrome,   Teratogenic  potential   Notes   Potent  inducer  of  CYP450  enzymes     VALPROIC  ACID   SimD   SODIUM  VALPROATE   Class   Anticonvulsant  drug  (branched-­‐chain  fatty  acids)   MOA   Blocks  high-­‐frequency  firing  of  neurons  modifies  amino   acid  metabolism   Uses   Generalized   tonic-­‐clonic   seizures,   Partial   seizures,   Myoclonic  seizures,  Bipolar  disorders  (acute  mania)   SE   Drowsiness,   Nausea,   Tremor,   Alopecia,   Weight   gain,   Hepatotoxicity   (infants),   Teratogen   (neural   tube   defect,   SPINA  BIFIDA)   Notes   Inhibitor  of  CYP450  enzymes     KEY  LEARNING  POINTS  –  Valproic  Acid   Valproate  ate  the  Folate!  (spina  bifida)                 PHENOBARBITAL   SimD   PRIMIDONE   Class   Anticonvulsant  Drug  (barbiturates)   MOA   Bind   to   GABA-­‐A   receptor   sites   (distinct   from   benzodiazepines);   Increases   duration   of   chloride   channel  opening   Uses   Generalized   tonic-­‐clonic   seizures,   Partial   seizures,   Status  epilepticus,  Insomnia,  Hyperbilirubinemia    

SE   Notes  

Extension   of   CNS   depressant   actions,   Tolerance,   Dependence   liability   (greater   than   benzodiazepines),   Acute  intermittent  Porphyria   Potent  inducer  of  CYP450  enzymes.   Preferred   antiseizure   drug   in   children   and   pregnant   women!  

  ETHOSUXIMIDE   SimD   PHENSUXIMIDE,  METHSUXIMIDE   Class   Anticonvulsant  Drug  (cyclic  ureide)   MOA   Decrease  Ca2+  currents  (T-­‐type)  in  thalamus   Uses   Drug  of  choice  for  ABSENCE  SEIZURES   SE   Gastrointestinal   distress,   Lethargy,   Headache,   Behavioral  changes     DIAZEPAM   SimD   Anticonvulsant  Drug  (benzodiazepine)   Class   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of   chloride   channel   opening;   Membrane   hyperpolarization   MOA   STATUS  EPILEPTICUS   Uses   Anterograde   amnesia,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Respiratory   depression,   Tolerance,  Dependence  liability     CLONAZEPAM   Class   Anticonvulsant  Drug  (benzodiazepine)   MOA   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of   chloride   channel   opening;   Membrane   hyperpolarization   Uses   Absence  seizures,  Myoclonic  seizures,  Infantile  spasms   SE   Anterograde   amnesia,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Respiratory   depression,   Tolerance,  Dependence  liability     GABAPENTIN   SimD   PREGABALIN   Class   Anticonvulsant  Drug  (GABA  derivative)   MOA   Blocks  Ca2+  cahnnels.  Increases  GABA  release.  Inhibits   neuranl  discharge  from  seizure  foci.   Uses   Partial   seizures,   Neurpathic   pain   (postherpetic   neuralgia),  Migraine   SE   Dizziness,  Sedation,  Ataxia,  Nystagmus,  Tremor     LAMOTRIGINE   Class   Anticonvulsant  Drug  (phenyltriazine)   MOA   Blocks  Na  and  Ca  channels,  decreases  glutamate   Uses   Generalized   tonic-­‐clonic   seizures,   Partial   seizures,   Myoclonic  seizures,  Absence  seizures,  Bipolar  disorders   SE   Diziness,   Ataxia,   Nausea,   Rash,   Stevens-­‐Johnson   Syndrome     LEVETIRACETAM   Class   Anticonvulsant  Drug  (piracetam)   MOA   Selectively  binds  synaptic  vesicular  protein  SV2A.   Modifies  synaptic  release  of  glutamate  and  GABA.   Uses   Generalized   tonic-­‐clonic   seizures,   Partial   seizures,   Juvenille  myoclonic  epilepsy   SE   Dizziness,   Sedation,   Weakness,   Irritability,   Hallucinations,  Psychosis   Notes   Drug   interactions   are   minimal;   Levetiracetam   is   NOT   metabolized  by  cytochrome  P450!    

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 54 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]             TOPIRAMATE   Class   Anticonvulsant  Drug  (monosaccharide  derivative)   MOA   Multiple   actions   on   synaptic   function,   probably   via   actions   of   phosphorylation   (Na,   Ca,   GABA,   AMPA-­‐ glutamate,  carbonic  anhydrase)   Uses   Generalized   tonic-­‐clonic   seizures,   Absence   seizures,   Partial   seizures,   LENNOX-­‐GASTAUT   SYNDROME,   WEST  SYNDROME,  Migraine   SE   Drowsiness,   Dizziness,   Ataxia,   Psychomotor   slowing,   Memory   impairment,   Paresthesias,   Weight   loss,   Acute   myopia,  Glaucoma,  Urolithiasis   Notes   Antiseizure  drug  with  most  number  of  mechanism  of   action!     Clinical  Uses  of  Antiseizure  Drugs   Seizure  Type   Generalized   tonic-­‐clonic   Seizures   Partial  Seizures  

Drugs  of  Choice   VALPROIC  ACID   PHENYTOIN   CARBAMAZEPINE   CARBAMAZEPINE   LAMOTRIGINE   PHENYTOIN  

Absence  Seizures  

ETHOSUXIMIDE   VALPROIC  ACID  

Myoclonic   and   Atypical   Absence   Syndromes  

VALPROIC  ACID   (not  in  pregnancy)  

Status   Epilepticus  

LORAZEPAM   DIAZEPAM   PHENYTOIN   PHENOBARBITAL  

Alternative  Drugs   Phenobarbital,   Lamotrigine,   Topiramate   Felbamate,   Phenobarbital,   Topiramate,     Valproic  acid   Lamotrigine,   Levetiracetam,   Zonisamide,   Clonazepam   Clonazepam,   Levetiracetam,   Topiramate,   Zonisamide,   Felbamate    

  Other  Clinical  Uses  of  Antiseizure  Drugs!   • BIPOLAR  AFFECTIVE  DISORDERS   o Valproic  acid  (first-­‐line  for  mania)   o Carbamazepine   o Lamotrigine   • TRIGEMINAL  NEURALGIA   o Carbamazepine  (drug  of  choice)   o Oxcarbazepine     • NEUROPATHIC  PAIN  (POSTHERPETIC  NEURALGIA)   o Gabapentin   o Pregabalin     • MIGRAINE   o Gabapentin   o Phenytoin   o Topiramate      

GENERAL  ANESTHETICS     GENERAL  ANESTHESIA   • State   characterized   by   unconsciousness,   analgesia,   amnesia,  skeletal  muscle  relaxations,  and  loss  of  reflexes  

•

General   anesthetics   are   CNS   depressants   with   actions   that   can  be  induced  and  terminated  more  rapidly  than  those  of   conventional  sedative-­‐hypnotics  

                                    Stages  of  Anesthesia   STAGE   1  

NAME   Analgesia  

2  

Disinhibition  

3  

Surgical  Anesthesia  

4  

Medullary  Depression  

EVENTS    Decreased  awareness  of  pain,   sometimes  with  amnesia    Consciousness   is   impaired,   NOT  loss    Patient  is  delirious  or  excited    Amnesia   occurs,   reflexes   are   enhanced,   and   respiration   is   typically  irregular    Retching   and   incontinence   may  occur    Patient  is  unconscious    No  pain  reflexes,  regular   respiration,  and  maintained   blood  pressure    Severe  respiratory  and   cardiovascular  depression   that  requires  mechanical  and   pharmacologic  support  

  INHALATIONAL  ANESTHETICS     INHALATIONAL  ANESTHETICS   • Include   Nitrous   oxide,   Halothane,   Desflurane,   Enflurane,  Isoflurane,  Sevoflurane,  and  Methoxyflurane   • Partial   pressire   of   “tension”   is   a   measure   of   concentration   of  inhaled  anesthetics   o Standard   pressure   of   the   total   inhaled   mixture   is   atmospheric  pressure  (760  mmHg  at  sea  level)   o 50%   nitrous   oxide   in   the   inhaled   air   would   have   a   partial  pressure  of  380  mmHf     Minimum  Alveolar  Anesthetic  Concentration  (MAC)   • Best  measure  of  potency  of  inhaled  anesthetics   • Defined  as  the  alveolar  concentration  required  to  eliminate   the   response   to   a   standardized   painful   stimulus   in   50%   of   patients   • When   several   anesthetic   agents   are   used   simultaneously,   their  MAC  values  are  additive     Properties  of  Inhaled  Anesthetics   Anesthetic   Nitrous  oxide  

Partition   Coefficient   0.47  

MAC  

Metabolism  

Comments  

>100  

None  

Incomplete   anesthetic;   rapid  onset  and  recovery  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Desflurane  

0.42  

6  –  7    

<  0.05  %  

Sevoflurane  

0.69  

2.0  

Isoflurane  

1.40  

1.40  

2  –  5  %   (fluoride)   <  2%  

Enflurane  

1.80  

1.7  

8%  

Halothane  

2.30  

0.75  

>  40%  

Methoxy-­‐ flurane  

12  

0.16  

>70%   (fluoride)  

Low  volatility;  poor   induction  agent   (pungent);  rapid  recovery   Rapid   onset   and   recovery;   unstable  in  soda-­‐lime   Medium  rate  of  onset  and   recovery   Medium  rate  of  onset  and   recovery   Medium  rate  of  onset  and   recovery   Very   slow   onset   and   recovery  

  Effects  of  Inhaled  Anesthetics   • CNS  EFFECTS   o Decrease  brain  metabolic  rate   o Reduce   vascular   resistance,   increase   cerebral   blood  flow  and  increase  intracranial  pressure   • CARDIOVASCULAR  EFFECTS   o Decrease  arterial  blood  pressure  moderately   o Decrease  blood  flow  to  the  liver  and  kidneys   • RESPIRATORY  EFFECTS   o Increased  rate  of  respiration   o Dose-­‐dependent   decrease   in   tidal   volume   and   minute   ventilation,   leading   to   increase   in   arterial   CO2  tension   o Decrease   ventilator   response   to   hypoxia   even   at   subanesthetic   concentrations   (eg,   during   recovery)   o Most  inhaled  anesthetics  are  bronchodilators     KEY  LEARNING  POINTS!   Fick’s  Law  =  anesthetic  moves  ACROSS  a  concentration  gradient     ↑MAC  =  ↓  potency  of  the  drug     NITROUS  OXIDE       Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   Anesthesias   for   minor   surgery   and   dental   procedures,  Balanced  anesthesia  for  major  surgery   SE   Megaloblastic   anemia   on   prolonged   exposure,   EUPHORIA  (laughing  gas)     Notes   Lowest  potency  (highest  MAC)  and  least  cardiotoxicity   among  inhalational  anesthetics   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics     DESFLURANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia   SE   Bronchospasm   (pulmonary   irritant),   Peripheral   vasodilation   Notes   Contraindicated  in  Asthmatic  patients!   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics     SEVOFLURANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia  

SE   Notes  

Peripheral  vasodilation,  Renal  insufficiency   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics  

  ISOFLURANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia   SE   Catecholamine-­‐induced   arrhythmias,   Peripheral   vasodilation   Notes   Cardiotoxic   –   can   cause   CORONARY   STEAL   SYNDROME   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics     ENFLURANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia   SE   Spike-­‐and-­‐wave   activity,   Muscle   twitching,   Breath-­‐ holding,  Myocardial  depression,  Renal  insufficiency   Notes   Can  cause  seizures!     Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics     HALOTHANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia   SE   Catecholamine-­‐induced   arrhythmias,   Myocardial   depression,  Post-­‐operative  hepatitis   Notes   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics     METHOXYFLURANE   Class   General  Anesthetic  (inhalational)   MOA   Facilitate   GABA-­‐mediated   inhibition;   Block   brain   NMDA  and  ACh-­‐N  receptors   Uses   General  Anesthesia   SE   Renal  insufficiency   Notes   Highest   potency   and   lowest   MAC   among   inhalational   anesthetics  (very  slow  onset  and  recovery).   Additive   to   CNS   depression   with   many   agents,   especially  opioids  and  sedative-­‐hypnotics       INTRAVENOUS  ANESTHETICS     THIOPENTAL   SimD   METHOHEXITAL,  THIAMYLAL   Class   General  Anesthetic  (intravenous)   Barbiturate  (ultrashort-­‐acting)   MOA   Binds   to   GABA-­‐A   receptor   sites   (distinct   from   benzodiazepines);   Increases   duration   of   chloride   channel  opening   Uses   Anesthesia  induction,  Increased  ICP   SE   Extension   of   CNS   depressant   actions,   Tolerance,   Dependence   liability   (greater   than   benzodiazepines),   Acute  intermittent  porphyria   Notes   Additive  to  CNS  depression  with  Ethanol.  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Potent  inducer  of  CYP450  enzymes.     MIDAZOLAM   SimD   BROTIZOLAM,  TRIAZOLAM,  OXAZEPAM,  ETIZOLAM   Class   General  Anesthetic  (intravenous)   Benzodiazepine  (short-­‐acting)   MOA   Binds  GABA-­‐A  receptor  subunits  to  increase  frequency   of   chloride   channel   opening;   Membrane   hyperpolarization   Uses   Acute   anxiety,   Panic   attacks,   Anesthesia   induction,   Preoperative  sedation   SE   Anterograde   amnesia,   Decreased   psychomotor   skills,   Unwanted   daytime   sedation,   Dependence   liability,   Post-­‐operative  respiratory  depression   Notes   Additive  to  CNS  depression  with  Ethanol.   Antidote  is  FLUMAZENIL!     KETAMINE   Class   General  Anesthetic  (intravenous)   MOA   Blocks  excitation  by  glutamate  at  NMDA  receptors   Uses   DISSOCIATIVE   ANESTHESIA   (analgesia,   amnesia,   and   catatonia   but   with   retained   consciousness);   patients   are  awake  but  anesthesized!   SE   Cardiovascular   stimulation,   Hypertension,   Increased   ICP,  Emergence  delirium   Notes   Reduce   emergence   delirium   by   pretreatment   with   benzodiazepines!     ETOMIDATE   Class   General  Anesthetic  (intravenous)   MOA   Modulates  GABA-­‐A  receptors  containing  β3  subunits   Uses   General  anesthesia  (specially  in  patients  with  limited   cardiac  or  respiratory  reserve)   SE   Pain   on   injection,   Myoclonus,   Post-­‐operative   nausea   and  vomiting,  Adrenocortical  suppression   Notes   Minimal   effects   on   cardiovascular   and   respiratory   functions.  Preferred  for  pediatric  patients!   No  analgesic  properties!     FENTANYL   SimD   MORPHINE,  ALFENTANIL,  REMIFENTANIL   Class   General  Anesthetic  (intravenous)   Opioid  Analgesic   MOA   Interact   with   μ,   δ,   and   κ   receptors   for   endogenous   opioid  peptides   Uses   General  anesthesia   SE   Respiratory   depression,   Chest   wall   rigidity,   Constipation   Notes   Antidote  is  NALOXONE!   Neuroleptanesthesia   achieved   by   combining   fentanyl,   droperidol,  and  nitrous  oxide     PROPOFOL   SimD   FOSPROPOFOL   Class   General  Anesthetic  (intravenous)   MOA   Potentiates  GABA-­‐A  receptors,  Blocks  Na  channels   Uses   General  anesthesia,  Prolonged  sedation   SE   Bradycardia,   Hypotension,   Pain   at   injection   site,   Anterograde  amnesia,  Dystonia,  Priapism   Notes   Called  “milk  of  amnesia”!!   Used  during  bronchoscopy/endoscopy   Additive  effects  with  sedative-­‐hypnotic  drugs    

TRIVIA  –  Death  of  Michael  Jackson!   MICHAEL  JACKSON  (1958  –  2009)   Immediate  COD:  acute  propofol  intoxication!   Contributory   factors:   drug   interactions   (lorazepam,   midazolam,   diazepam)    

LOCAL  ANESTHETICS     LOCAL  ANESTHETICS   • Results  when  sensory  transmission  from  a  local  area  of  the   body  to  the  CNS  is  blocked   • Local   anesthetics   can   be   administered   locally   by   injection   or  topical  application  to  the  target  area                     MNEMONICS  –  Local  Anesthetics   How   will   you   distinguish   whether   local   anesthetics   are   esters   or   amides?   ESTERS  have  only  1  “I”  in  their  names!    Tetracaine,  Procaine,  Benzocaine   AMIDES  have  2  “I’s”  in  their  names!      Bupivacaine,  Ropivacaine,  Lidocaine     MNEMONICS  –  Half-­‐life  of  Local  Anesthetics   Which  local  anesthetics  have  the  shortest  and  longest  half-­‐lives?   A  PRO  finisihes  the  race  fastest!    PROCAINE  =  shortest  half-­‐life  (1-­‐2  mins)   At  the  END  of  the  long  ROPe!    ROPIVACAINE  =longest  half-­‐life  (4.2  hours)     MOA  of  Local  Anesthetics   • Block   voltage-­‐dependent   Na+   channels,   reducing   influx   of   Na+,  thereby  preventing  depolarization   • Most  are  weak  bases  that  undergo  dissociation   o More  lipid-­‐soluble  (non-­‐ionized,  uncharged)  form   reaches   effective   intracellular   concentrations   more  rapidly   o Once   inside   the   axon,   the   ionized   (charged)   form   of  the  drug  is  the  more  effective  blocking  entity     KEY  LEARNING  POINTS  –  Abscesses   Why   should   you   NOT   inject   local   anesthetics   into   an   abscess   during  incision  and  drainage?    It  WONT  work  due  to  acidic  environment    Low  pKa  =  charged  form  will  predominate    Will   not   be   able   to   cross   the   membrane   and   exert   its   action     MOA  of  Local  Anesthetics   • Blockade  of  Na+  channels  is  both  state-­‐dependent  and  use-­‐ dependent   o State-­‐dependent:  activated  >  inactivated  >  resting   o Use-­‐dependent:   rapidly   firing   fibers   are   usually   blocked  before  slowly  firing  fibers   • Relationship  of  local  anesthesia  with  electrolytes   o Hyperkalemia  enhances  local  anesthetic  activity  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 57 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] o

Hypercalcemia   antagonizes   local   anesthetic   activity  (main  goal:  block  depolarization)  

  LIDOCAINE   Class   Local  Anesthetics  (amide)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local   anesthesia,   Anti-­‐arrhythmic   (group   1B   activity);  Used  post-­‐MI  and  for  digitalis  toxicity   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,  Respiratory  and  cardiovascular  depression     KEY  LEARNING  POINTS  –  Toxic  Dose  of  Lidocaine   What  is  the  toxic  dose  of  LIDOCAINE?    Toxic  dose  =  5mg/kg    For  any  drug  or  solution,  1%  =  10mg/mL   For  a  70kg  patient:    70kg  x  5  mg/kg  =  350  mg  toxic  dose    If  1%  solution  is  used:  350  mg/10mg/mL  =  35  mL                       PRILOCAINE   Class   Local  Anesthetics  (amide)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local  anesthesia,  Dental  anesthesia   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   METHEMOGLOBINEMIA   Notes   Administer   methylene   blue   if   patient   develops   methemoglobinemia     BUPIVACAINE   Class   Local  Anesthetics  (amide)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local   anesthesia,   Epidural   anesthesia,   Intrathecal   anesthesia   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Severe   cardiovascular   toxicity,   Hypotension,   Arrhythmias  (idioventricular  rhythm  –  240  bpm)   Notes   Use  with  caution  in  pregnant  women!   Contraindicated  in  intravenous  regional  anesthesia.   Treat   cardiotoxicity   with   INTRALIPID   (fat   emulsion   used  in  Total  Parenteral  Nutrition)     ROPIVACAINE   Class   Local  Anesthetics  (amide)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local  anesthesia,  Epidural  anesthesia   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Cardiotoxicity   Notes   Longest  half-­‐life  among  local  anesthetics   Contraindicated  in  intravenous  regional  anesthesia.   Treat   cardiotoxicity   with   INTRALIPID   (fat   emulsion  

  Toxicity  of  Local  Anesthetics   • CNS  EFFECTS   o Lighe-­‐headedness   or   sedation,   restlessness,   nystagmus,   generalized   tonic-­‐clonic   seizures,   respiratory  and  cardiovascular  depression   • CARDIOVASCULAR  EFFECTS   o All   local   anesthetics   are   vasodilators   EXCEPT!   COCAINE  (prevents  reuptake  of  norepinephrine)   o Use   with   caution   in   patients   with   pre-­‐exisiting   cardiovascular  disease  because  they  may  develop   heart  block  and  arrhythmias   ESTER  LOCAL  ANESTHETICS     PROCAINE   SimD   NOVOCAINE   Class   Local  Anesthetics  (ester)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local   anesthesia,   Extravasation   complications   from   venipuncture,  Inadvertent  intra-­‐arterial  injections   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Antibody  formation   Notes   Shortest  half-­‐life  among  local  anesthetics     BENZOCAINE   SimD   BUTAMBEN   Class   Local  Anesthetics  (ester)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local  anesthesia,  Topical  anesthesia  (Oral  spray)   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Skin  irritation,  Antibody  formation   Notes   Use  cautiously  when  treating  sunburns  or  large  areas  of   skin!     COCAINE   Class   Local  Anesthetics  (ester),   Drugs  of  Abuse   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local  anesthesia,  Topical  anesthesia   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Antibody   formation,   Abuse   liability,   Severe   hypertension,   Cerebral   hemorrhage,   Cardiac   arrhythmias,  Myocardial  infarction     TETRACAINE   Class   Local  Anesthetics  (ester)   MOA   Blockade   of   Na   channels   slows,   then   prevents   axon   potential  propagation   Uses   Local   anesthesia,   Spinal   anesthesia,   Epidural   anesthesia,  Topical  ophthalmic  anesthesia   SE   Light-­‐headedness,   Sedation,   Restlessness,   Nystagmus,   Seizures,   Respiratory   and   cardiovascular   depression,   Antibody  formation       AMIDE  LOCAL  ANESTHETICS   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 58 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] used  in  Total  Parenteral  Nutrition)      

• •

ROCURONIUM  has  the  most  rapid  onset  time  (60-­‐120  sec)   Diaphragm  is  resistant  to  blockage  

  TUBOCURARINE   Class   Non-­‐depolarizing  Neuromuscular  Blocker       (long-­‐acting)   SKELETAL  MUSCLE  RELAXANTS   MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic   • Neuromuscular  blocking  drugs  are  used  to  produce  muscle   acetylcholine  receptors   paralysis  to  facilitate  surgery  or  assisted  ventilation   Uses   Skeletal   muscle   relaxation   during   intubation   and   • Spasmolytic  drugs  are  used  to  reduce  abnormally  elevated   General  anesthesia   tone  caused  by  neurologic  or  muscle  end  plate  disease   SE   Respiratory   paralysis,   Apnea,   Ganglion   block     (hypotension),   Histamine   release   (moderate),     Recurarization  (part  of  the  drug,  hides  in  fat  tissue)     Notes   Relatively  contraindicated  in  myocardial  ischemia     Reverse  effects  with  NEOSTIGMINE!             MIVACURIUM     Class   Non-­‐depolarizing  Neuromuscular  Blocker       (short-­‐acting)     MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic     acetylcholine  receptors     Uses   Skeletal   muscle   relaxation   during   intubation   and     General  anesthesia     SE   Respiratory   paralysis,   Apnea,   Histamine   release   Types  of  Neuromuscular  Blockade   (moderate)   • DEPOLARIZING  BLOCKADE   Notes   Reverse  effects  with  NEOSTIGMINE!   o Neuromuscular   paralysis   that   results   from   Metabolized  by  pseudocholinesterase.   persistent   depolarization   of   the   end   plate   (eg,   by   succinylcholine)       ATRACURIUM   • NON-­‐DEPOLARIZING  OR  STABILIZING  BLOCKADE   SimD   CISATRACURIUM   o Neuromuscular   paralysis   that   results   from   Class   Non-­‐depolarizing  Neuromuscular  Blocker     pharmacologic   antagonism   at   the   acetylcholine   (intermediate-­‐acting)   receptor  of  the  end  plate  (eg,  by  tubocurarine)   MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic     acetylcholine  receptors     Uses   Skeletal   muscle   relaxation   during   intubation   and     General  anesthesia     SE   Respiratory   paralysis,   Apnea,   Seizures,   Histamine     release,  Bronchospasms     Notes   Reverse  effects  with  NEOSTIGMINE!     Undergoes   HOFFMANN   Elimination   (rapid     spontaneous  breakdown)     Less  adverse  effects  with  Cisatracurium!                                             VECURONIUM     Class   Non-­‐depolarizing  Neuromuscular  Blocker       (intermediate-­‐acting)   NON-­‐DEPOLARIZING  NEUROMUSCULAR  BLOCKERS   MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic     acetylcholine  receptors   MOA  of  Non-­‐Depolarizing  Neuromuscular  Blockers   Uses   Skeletal   muscle   relaxation   during   intubation   and   • Surmountable   blockers   that   prevent   the   action   of   ACh   at   General  anesthesia   the  skeletal  muscle  end-­‐plate   SE   Respiratory  paralysis,  Apnea   • Effects  reversed  by  cholinesterase  inhibitors   Notes   Reverse  effects  with  NEOSTIGMINE!   • Larger   muscles   are   more   resistant   to   neuromuscular   Undergoes  HOFFMANN  Elimination  in  bile.   blockade,  but  recover  more  rapidly   Muscle   relaxation   is   potentiated   by   inhaled   anesthetics,   TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 59 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

SKELETAL  MUSCLE  RELAXANTS  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] aminoglycosides  and  quinidine     ROCURONIUM   Class   Non-­‐depolarizing  Neuromuscular  Blocker     (intermediate-­‐acting)   MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic   acetylcholine  receptors   Uses   Skeletal   muscle   relaxation   during   intubation   and   General  anesthesia   SE   Respiratory  paralysis,  Apnea,  Hypersensitivity   Notes   Reverse  effects  with  NEOSTIGMINE!   SUGAMMADEX   is   a   novel   reversal   agent   for   Rocuronium     PANCURONIUM   Class   Non-­‐depolarizing  Neuromuscular  Blocker     (long-­‐acting)   MOA   Competitive   antagonists   at   skeletal   muscle   nicotinic   acetylcholine   receptors.   Moderate   block   on   cardiac   muscarinic  receptors.   Uses   Skeletal   muscle   relaxation   during   intubation   and   General   anesthesia,   Euthanasia,   Lethal   injection,   STRYCHNINE  POISONING!     SE   Respiratory   paralysis,   Apnea,   Tachycardia,   Hypertension,  Recurarization   Notes   Reverse  effects  with  NEOSTIGMINE!     APPLICATIONS  –  Lethal  injections   What  are  the  drugs  used  in  lethal  injections?    THIOPENTAL  (5g)    PANCURONIUM  (100mg)    POTASSIUM  CHLORIDE  (100  mEq)     DEPOLARIZING  NEUROMUSCULAR  BLOCKERS     Phases  of  Depolarizing  Blockade   • PHASE  I  (DEPOLARIZATION)   o Membrane   depolarizes   with   initial   electric   discharge   o Transient   fasciculations   followed   by   flaccid   paralysis   • PHASE  II  (DESENSITIZATION)   o Membrane   repolarizes   BUT   receptor   is   desensitized  to  the  effects  of  acetylcholine     SUCCINYLCHOLINE   Class   Depolarizing  Neuromuscular  Blocker   MOA   Agonist   at   ACh-­‐N   receptors   causing   initial   twitch   then   persistent  depolarization   Uses   Skeletal   muscle   relaxation   during   intubation   and   general  anesthesia   SE   Muscle   pain,   Hyperkalemia,   Increased   intragastric   pressure   (aspiration),   Increased   intraocular   pressure,   Malignant  hyperthermia   Notes   Metabolized  by  pseudocholinesterase     MALIGNANT  HYPERTHERMIA   • Rare   interaction   of   succinylcholine   (and   possibly   tubocurarine)    with  inhaled  anesthetics  (halothane)   • Potentially   life-­‐threatening   condition   characterized   by   massive  calcium  release  from  the  sarcoplasmic  reticulum  of   skeletal  muscles   • Early  sign:  contraction  of  the  jaw  muscles  (TRISMUS)  

•

Treated   by   rapidly   cooling   the   patient   and   by   administration   of   DANTROLENE   (prevents   the   release   of   Ca2+  from  the  sarcoplasmic  reticulum)  

 

DRUGS  USED  IN  PARKINSONISM                     PARKINSON’S  DISEASE   • Also  known  as  Paralysis  agitans   • Neurodegenerative   disease   caused   by   degeneration   of   dopaminergic   neurons   in   the   substantia   nigra   (loss   of   60%  of  dopamine-­‐producing  neurons)   • Progressive   neurologic   diseases   characterized   by   shuffling   gait,   stoop   posture,   resting   tremor,   speech   impediments,   movement   difficulties   and   an   eventual   slowing   of   mental   processes  and  dementia     MNEMONICS  –  Parkinson’s  Disease   What  are  the  primary  signs  of  Parkinson’s  Disease?   PARKINSON’S  DISEASE!    It’s  a  TRAP!!    Tremor    Rigidity    Akinesia    Postural  instability     Drug-­‐Induced  Parkinsonism   • Occurrence   of   reversible   Parkinsonian   symptoms   in   patients  taking  the  following  drugs:   o Anti-­‐psychotic  drugs:  (typical  anti-­‐psychotics)   o Reserpine   o MPTP  (methylphenyltetrahydropyridine)                                                     LEVODOPA  –  CARBIDOPA  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SELEGILINE   SimD   RASAGILINE   Class   Anti-­‐parkinsonism  Drug  (MAO  Type  B  inhibitor)   Uses   MOA   Selective   inhibitor   of   monoamine   oxidase   type   B,   leading  to  decreased  degradation  of  dopamine.   SE   Increases  response  to  levodopa/carbidopa.   Uses   Parkinson’s  disease   SE   Insomnia,   Mood   changes,   Dyskinesias,   Gastrointestinal   Notes   distress,  Hypotension   Notes   Combination   with   meperidine   causes   agitation,   delirium,  and  death  (fatal  reaction)     Serotonin  Syndrome  occurs  when  used  with  SSRIs   KEY  LEARNING  POINTS!     Parkinson’s  Disease  =  doPamine  Decrease   ENTACAPONE   Alzheimer’s  Disease  =  Acetylcholine  Decrease   SimD   TOLCAPONE     Class   Anti-­‐parkinsonism  Drug  (COMT  inhibitor)   Dopaine  CANNOT  cross  the  BBB!   MOA   Blocks   L-­‐dopa   metabolism   by   inhibiting   catechol-­‐O-­‐   methyltransferase   in   periphery   (both)   and   CNS   Parkinsonian  Phenomena   (tolcapone).  Prolongs  response  to  levodopa.   • ON  –  OFF  PHENOMENA   Uses   Parkinson’s  disease  (wearing-­‐off  phenomena)   o Alternating   periods   of   improved   mobility   and   SE   Dyskinesias,   Gastrointestinal   distress,   Postural   akinesia,     occurring   over   a   few   hours   to   days   hypotension,   Sleep   disturbance,   Orange   urine,   during  treatment   Hepatotoxicity   (tolcapone   only),   Neuroleptic       malignant  syndrome,  Rhabdomyolysis   • WEARING  –  OFF  PHENOMENA     o Deterioration   of   drug   effect   in   between     medication  doses     o Due   to   progressive   destruction   of   nigrostriatal     neurons  that  occurs  with  disease  progression         BROMOCRIPTINE     SimD   PERGOLIDE   AMANTADINE   Class   Anti-­‐parkinsonism  Drug  (dopamine  agonist)   Class   Anti-­‐parkinsonism  Drug  (anti-­‐viral)   MOA   Partial  agonist  at  dopamine  D2  receptors  in  the  brain   MOA   Potentiate   dopaminergic   function   by   influencing   the   Uses   Parkinson’s   disease,   Levodopa   intolerance,   synthesis,  release,  or  reuptake  of  dopamine.   Hyperprolactinemia   Antagonizes   the   effects   of   adenosine   at   adenosine   A2A   SE   Anorexia,   Nausea,   Vomiting,   Dyskinesias,   Postural   receptors   hypotension,   Behavioral   changes,   Erythromelalgia,   Uses   Parkinson’s  disease,  Influenza   Pulmonary  fibrosis   SE   Behavioral   changes   (acute   toxic   psychosis),   LIVEDO     RETICULARIS   (swelling   of   medium-­‐sized   blood   vessel   PRAMIPEXOLE   in   lower   extremeties),   Gastrointestinal   disturbances,   SimD   ROPINIROLE   Urinary   retention,   Postural   hypotension,   Peripheral   edema     Class   Anti-­‐parkinsonism  Drug  (dopamine  agonist)   Notes   May  improve  bradykinesia,  rigidity  and  tremor   MOA   Partial  agonist  at  dopamine  D3  receptors  in  the  brain     Uses   Parkinson’s  disease,  Restless  Legs  Syndrome   MNEMONICS  –  Livedo  Reticularis!   SE   Anorexia,   Nausea,   Vomiting,   Dyskinesias,   Postural   What  drugs  can  cause  livedo  reticularis?   hypotension,   Behavioral   changes,   COMPULSIVE   A  man  reads  FHM  and  GQ!!   GAMBLING,   Hypersexuality,   Over-­‐eating,    Amantadine   Uncontrollable  tendency  to  fall  asleep    Hydroxyurea  –  chronic  myelogenous  leukemia   Notes   Contraindicated   in   patients   with   active   peptic   ulcer    Minocycline   disease,   psychotic   illness,   or   recent   myocardial    Gemcitabine  –  chemotherapeutic  agent   infarction      Quinidine         APOMORPHINE   BENZTROPINE   Class   Anti-­‐parkinsonism  Drug  (dopamine  agonist)   SimD   BIPERIDEN,  TRIHEXYPHENIDYL,  ORPHENADRINE   MOA   Partial   agonist   at   dopamine   D3   receptors   in   the   brain.   Class   Anti-­‐parkinsonism  Drug  (anti-­‐cholinergic)   Antagonist  at  5-­‐HT  and  alpha  receptors.   MOA   Decreases  the  excitatory  actions  of  cholinergic  neurons   Uses   Off-­‐periods   of   Parkinson’s   disease,   Alcoholism,   Opiate   on   cells   in   the   striatum   by   blocking   muscarinic   addiction,  Erectile  dysfunction,  Alzheimer’s  disease   receptors.   SE   Severe   nausea,   Dyskinesias,   Hypotension,   Drowsiness,   Uses   Parkinson’s   disease,   Extrapyramidal   symptoms   caused   Sweating   by  anti-­‐psychotics   Notes   Premedicate   with   TRIMETHOBENZAMIDE   to   prevent   SE   Drowsiness,   Inattention,   Confusion,   Delusions,   severe  nausea   Hallucinations,  Atropine-­‐like  effects     TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 61 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected] Class   MOA  

Anti-­‐parkinsonism  Drug  (dopamine  precursor)   Levodopa   is   a   dopamine   precursor.   Carbidopa   inhibits   peripheral  metabolism  via  dopa  decarboxylase.   PARKINSON’S  DISEASE  (primary  drug)   Gastrointestinal   upset   (emesis),   Dyskinesia   (choreoathetosis),   Behavioral   changes,   On-­‐Off   phenomena,   Wearing-­‐off   phenomena,   Postural   hypotension   Contraindicated  in  patients  with  history  of  PSYCHOSIS!   Hypertensive   crisis   occurs   when   used   with   monoamine   oxidase  inhibitors  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Notes  

Improve   tremor   and   rigidity,   with   ittle   effect   on   bradykinesia.   Exacerbate   tardive   dyskinesias   that   result   from   prolonged  use  of  anti-­‐psychotic  drugs  

 

ANTIPSYCHOTIC  AGENTS  AND  LITHIUM  

•

Not  fully  satisfactory  because  antipsychotic  drugs  are  only   partly  effective  in  most  patients  

  Dopamine  Receptors   • Five  different  dopamine  receptors  (D1-­‐D5)   • D2   receptors   in   caudate   putamen,   nucleus   accumbens   (ventral  tegmental  area),  cerebral  cortex  and  hypothalamus   o Target  of  action  of  older  anti-­‐psychotics   o Strong   correlation   between   blockade   of   D2   receptors  and  extrapyramidal  dysfunction     Dopaminergic  Tracts   • MESOCORTICAL  –  MESOLIMBIC   o Regulating  mentation  and  mood   • NIGROSTRIATAL   o Extrapyramidal  function   • TUBERO-­‐INFUNDIBULAR   o Control  of  prolactin  release   • MEDULLARY-­‐PERIVENTRICULAR   o Eating  behavior   • INCERTOHYPOTHALAMIC   o Anticipatory   motivational   phase   of   copulatory   behavior     Treatment  of  Schizophrenia   • All   antipsychotics   reduce   some   of   the   positive   symptoms   of   schizophrenia   • Clozapine   is   effective   in   some   schizophrenic   patients   resistant  to  treatment  with  other  antipsychotic  drugs   • None   of   the   typical   antipsychotics   has   much   effect   on   negative  symptoms  of  schizophrenia   • Atypical   drugs   are   reported   to   improve   some   of   the   negative  symptoms  of  schizophrenia     Toxicities  of  Antipsychotics  

    Classification  of  Anti-­‐psychotics   • TYPICAL   (CLASSICAL)   ANTIPSYCHOTICS   (first   general   anesthesia  with  greater  extrapyramidal  symptoms)   o PHENOTHIAZINES    Chlorpromazine    Thioridazine    fluphenazine   o THIOXANTHENES    thiothixene   o BUTYROPHENONES    Haloperidol     • ATYPICAL   ANTIPSYCHOTICS   (metabolic   side   effects:   obesity,  DM,  agranulocytosis)   o HETEROCYCLICS    Clozapine   Type   Manifestations   Mechanism      Loxapine   Autonomic   Loss   of   accommodation,   dry   Muscarinic    Olanzapine   Nervous  System   mouth,   difficulty   urinating,   cholinoceptor    Risperidone   constipation   blockade    Quetiapine   Orthostatic   hypotension,   Α-­‐adrenoceptor   impotence,   failure   to   blockade    Ziprasidone   ejaculate    Aripiprazole     Central   Nervous   Parkinson’s   syndrome,   Dopamine-­‐receptor     System   akathisia,  dystonias   blockade     Tardive   dyskinesia   Supersensitivity   of     (uncontrollable   movement   of   dopamine  receptors   Potency  of  Typical  Antipsychotics   muscles  of  the  foot)   • LOW  POTENCY   Toxic-­‐confusional  state   Muscarinic  blockade   o Fewer  extrapyramidal  effects  but  more  H1,  α1,  and   Endocrine   Amenorrhea-­‐galactorrhea,   Dopamine-­‐receptor   muscarinic  blocking  effects   System   infertility,  impotence   blockade   resulting   in   hyperprolactinemia   o EXAMPLES:   chlorpromazine,   thioridazine,   Other   Weight  gain   Possible   combined   H1   mesoridazine   and  5-­‐HT2  blockade   • HIGH  POTENCY     o More   extrapyramidal   effects   and   less   H1,   α1,   and   KEY  LEARNING  POINTS!   muscarinic  blocking  effects    Schizophrenia  –  increase  in  dopamine!   o EXAMPLES:  haloperidol,  fluphenazine,  droperidol    EPS   –   drug-­‐induced   parkinsonism   (bind   tightly   to     dopamine-­‐2  receptors)!   Dopamine  Hypotheis    2nd  General  anesthesia  –  binds  tightly  to  serotonin   • Schizophrenia   is   caused   by   a   relative   excess   dopamine   in   Neuroleptic-­‐Induced  Movement  Disorders   specific  neuronal  tracts  in  the  brain   Disorder   Timing   Characteristics   Treatment   o Many   antipsychotic   drugs   block   brain   dopamine   Acute   4hrs  –  4  dys   Retrocollis,   Diphenhydramine   receptors  (especially  D2  receptors)   Dystonia   Opisthotonos,   o Dopamine   agonist   drugs   (eg,   amphetamine,   Oculogyric  crisis   levodopa)  exacerbate  schizophrenia   Parkinsonism   4  dys  –  4  mos   Tremor,  Rigidity,   Benztropine   o Increased  density  of  dopamine  receptors  has  been   Akinesia,  Postural   detected  in  certain  brain  regions       TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM Page 62 of 97 For inquiries visit www.topnotchboardprep.com.ph or mail us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Rabbit   Syndrome   Tardive   Dyskinesia  

4  mos  –  4  yrs   4  mos  –  4  yrs  

Akathisia  

Any  time  

Neuroleptic   Malignant   Syndrome    

Any  time  

instability   Perioral  tremor   Repetitive   involuntary   movement  (tongue   protrusion,  lip   smacking/pursing)   Restlessness,   pacing,  sitting  up   and  down   Fever,   encephalopathy,   vitals  unstable,   elevated  CPK,   Rigidity  

Benztropine   None  

Decrease  dose,   diphenhydramine   Withdraw  drug,   dantrolene,   diazepam,   dopamine  agonist  

  TYPICAL  ANTIPSYCHOTICS     CHLORPROMAZINE   Class   Typical  anti-­‐psychotic  (Phenothiazine)   MOA   Block  of  D2  receptors  >>  5-­‐HT2  receptors   Uses   Schizophrenia  and  other  psychotic  disorders   SE   Extrapyramidal   dysfunction,   Tardive   dyskinesia,   Hyperprolactinemia,   Atropine-­‐like   effects,   Faliure   of   ejaculation,   Postural   hypotension,   Marked   sedation,   CORNEAL   and   LENS   DEPOSITS,   Neuroleptic   malignant   syndrome,  Contact  dermatitis     THIORIDAZINE   SimD   FLUPHENAZINE,  PERPHENAZINE,   PROCHLORPERAZINE,  TRIFLUOPERAZINE   Class   Typical  anti-­‐psychotic  (Phenothiazine)   MOA   Block  of  D2  receptors  >>  5-­‐HT2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Antiemesis  (prochlorperazine)   SE   Extrapyramidal   dysfunction,   Tardive   dyskinesia,   Hyperprolactinemia,   Atropine-­‐like   effects,   Faliure   of   ejaculation,   Postural   hypotension,   RETINAL   DEPOSITS,  Cardiotoxicity  (arrhythmias)   Notes   Strongest  autonomic  effects!   Only  antipsychotic  with  fatal  overdose!     HALOPERIDOL  (Haldoe)   SimD   DROPERIDOL   Class   Typical  anti-­‐psychotic  (Butyrophenone)   MOA   Block  of  D2  receptors  >>  5-­‐HT2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   HUNTINGTON’S  DISEASE,  TOURETTE’S  SYNDROME     SE   Extrapyramidal   dysfunction   (major),   Tardive   dyskinesia,   Hyperprolactinemia,   NEUROLEPTIC   MALIGNANT  SYNDROME   Notes   Weakest  autonomic  effects!   Least  sedating  among  typical  antipsychotics!     ATYPICAL  ANTIPSYCHOTICS     CLOZAPINE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors     Uses   Schizophrenia   (refractory,   suicidal)   and   other   psychotic  disorders   SE   Extrapyramidal  dysfunction  (less),  Hyperprolactinemia   (less),   Postural   hypotension,   Weight   gain,   Hyperglycemia   (diabetes   mellitus),   Hyperlipidemia,  

Myocarditis,   Agranulocytosis,   Seizures,   Ileus,   Hypersalivation  (sialorrhea)   Only  anti-­‐psychotic  that  reduces  the  risk  of  SUICIDE!  

Notes           OLANZAPINE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Bipolar   disorder,  Anorexia  nervosa,  Depression   SE   Extrapyramidal  dysfunction  (less),  Hyperprolactinemia   (less),   Postural   hypotension,   Weight   gain,   Hyperglycemia  (diabetes  mellitus),  Hyperlipidemia     QUETIAPINE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Bipolar   disorder  (manic  episodes)   SE   Extrapyramidal  dysfunction  (less),  Hyperprolactinemia   (less),   Postural   hypotension,   Weight   gain   (less),   Somnolence,   Fatigue,   Sleep   paralysis,   Hypnagogic   hallucinations,  Cataracts,  Priapism   Notes   QUIET-­‐time!  Sleep!     RISPERIDONE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Bipolar   disorder,   Depression,   Intractable   hiccups,   Tourette   syndrome   SE   Extrapyramidal   dysfunction   (less),   Weight   gain   (less),   Insomnia,   Hyperprolactinemia   (marked),   Photosensitivity   Notes   Only  antipsychotic  approve  for  schizophrenias  in  the   youth!   Rise  and  shine!!  –  less  sedating     ZIPRASIDONE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Bipolar   disorder  (acute  mania)   SE   Extrapyramidal   dysfunction   (less),   Postural   hypotension,  QT  prolongation  (torsades)   Notes   No  atropine-­‐like  effects.   Little  or  no  tendency  to  cause  hyperglycemia.   Hyperprolactinemia  or  weight  gain!   Increased   mortality   in   elderly   patients   witn   dementia-­‐related  psychosis!     ARIPIPRAZOLE   Class   Atypical  anti-­‐psychotic   MOA   Block  of  5-­‐HT2  receptors  >>  D2  receptors   Uses   Schizophrenia   and   other   psychotic   disorders,   Bipolar   disorder,  Depression,  Autism,  Cocaine  dependence   SE   Extrapyramidal   dysfunction   (less),   Gastrointestinal   upset,  Tremor,  Hypersensitivity  (rare)   Notes   Least  sedating  atypical  antipsychotic!   No  atropine-­‐like  effects   Little  or  no  tendency  to  cause  hyperglycemia.  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Hyperprolactinemia  or  weight  gain!     MNEMONICS  –  Neuroleptic  Malignant  Syndrome   What  are  the  features  of  neuroleptic  malignant  syndrome?   NEUROLEPTIC  MALIGNANT  SYNDROME!!    Fever    Encephalopathy    Vitals  unstable    Elevated  CPK    Rigidity                           LITHIUM     Clinical  Use  of  Lithium     • Treatment  of  Bipolar  Disorders    (manic–depressive)   o Decreases   manic   behavior   and   reduces   both   the   frequency  and  the  magnitude  of  mood  swings   o Protective  effects  against  suicide  and  self-­‐harm   • Used   concurrently   with   antidepressants   during   maintenance  therapy   o Monotherapy   with   antidepressants   can   precipitate  mania  in  bipolar  patients   • Antipsychotic   agents   and/or   benzodiazepines   are   commonly   required   at   initiation   of   treatment   because   of   slow  onset  of  action     LITHIUM   Class   Mood  Stabilizer   MOA   Uncertain.   Decreases   cAMP,   Inhibits   inositol-­‐1-­‐ phosphatase,   causing   depletion   of   inositol   and   inositol   triphosphate   Uses   Bipolar  disorder,  Recurrent  depression,  Schizoaffective   disorder   SE   Tremor,   Sedation,   Ataxia,   Aphasia,   Thyroid   enlargement,   Nephrogenic   diabetes   insipidus,   Edema,   Acneiform   skin   eruptions,   Leukocytosis,   Teratogen   (EBSTEIN  ANOMALY),  Bradycardia   Notes   Contraindicated  in  Sick  Sinus  Syndrome!   Treat  overdose  with  hemodialysis.     Lithium  Overdose   • Threshold  for  toxicity  is  2  mEq/L   • Therapeutic   overdoses   are   more   common   than   deliberate   or  accidental  ingestion   o Due   to   change   in   the   patient’s   status   (diminished   serum  sodium,  use  of  diuretics  of  fluctuating  renal   function)   • CLINICAL  MANIFESTATIONS   o Neuromuscular   excitability,   tremors,   twitching,   agitation,   weakness,   ataxia,   leukocytosis,   bradycardia,  hypotension   • TREATMENT   o Hemodialysis  is  preferred  over  peritoneal  dialysis    

                    SimD   Class   MOA   Uses   SE   Notes  

           

Class   MOA   Uses   SE   Notes  

         

     

                                                                               

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                                                                           ACKNOWLEDGEMENTS:   This  Anatomy  Supplement  Handout  was  lovingly  made  by  Mei  Ann   Ty-­‐Arias,  MD.    Her  sources  are:   1.  Hi-­‐Yield  Anatomy   2.  USMLE  1st  Aid   3.  Kaplan  Anatomy   4.  Personal  Notes     Addiitonal  Tables  on  Muscles  of  the  Upper  &  Lower  Extremities  were   provided  by  one  of  our  previous  students,  Miguel  Ramos,  MD.     Thank  you  very  much  Mei  Ann!    &  Migs  =)                  

                                                                                                                            saasdasdasdasds   asdas    

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] asdddddd\                                                                                                                                  

                                                                                                                                 

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]                                                                                                                                  

                                                                                       

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