Mechanism Of Drug Action

NURSING PHARMACOLOGY HAND-OUTS MECHANISMS OF DRUG ACTION A. To produce optimal desired or therapeutic effects, a drug must reach appropriate concentration at its site of action. B. Molecules of the chemical compound must proceed from point of entry into the body to the tissues with which they react C. The magnitude of the response depends on the dosage and the time course of the drug in the body D. Concentration of the drug at its site of action is influenced by various processes, which are divided into three phases of drug activity/action for it to elicit a response 1. Pharmaceutic Phase (for P.O) A. Disintegration of dosage form - breakdown of solid drugs into smaller particles Rate limiting​-time it takes for the drug to disintegrate & become available for the body to absorb it. B. Dissolution of drug - dissolving of smaller particles in G-I fluid ready for absorption. Concepts: *In GIT, drugs need to be in solution form to be absorbed *Solid oral drugs (disintegrate-dissolve-absorption), liquid drugs are rapidly absorbed than solid drugs *drugs disintegrate & absorbed faster in acidic fluids (pH 1-2) than in alkaline fluids *food in GIT can interfere with dilution & absorption of certain drugs *EC drugs resist disintegration in stomach, but sensitive in alkaline env’t (S.Int.) so drug effect may be delayed 2. Pharmacokinetic Phase (SC, IM, IV) 4 sub processes: A. Absorption process by w/c a drug passes from its ​site of admin into body fluids/bloodstream B. Distribution- transformation of a drug from its ​site of absorption to its site of action C. Metabolism/Biotransformation- sequence of chemical events that change a drug into a less active form after it enters the body (detoxification process) D. Excretion- process by w/c drugs are eliminated from the body. 3. Pharmacodynamic Phase (biologic, physiologic response results)- refers to the drug effect on cellular level’s physiology biochemistry & MoA A. Drug-receptor interaction PHARMACOKINETICS A. Active transport - requires energy/carrier (CHON or enzyme) to cross the drug into the cell membrane (move against concentrated gradient) B. Passive transport - no need for energy/carrier, works by diffusion (High-Low concentration) C. Pinocytosis - engulfs the drug to carry it across the membrane D. Absorption 1. Variables/Factors that effect drug absorption A. Nature of the absorbing surface *In GIT ADEK vitamins are absorbed better than B & C vitamins. *GIT (esoph- stomach) is acidic env’t, lipid covered, & CHON based. *CHON- based drugs (Insulin &GH) - destroyed in S.Int by digestive enzymes *S.Int is alkaline env’t

*Penicillins have additives such as K+/Na- for better absorption in gastric mucosa, because they are poorly absorbed in acidic env’t (caution for babies/elderly) *some drugs are irritating to stomach mucosa (gastric irritants), give food & fluids to dilute drug concentration. *​HEPATIC FIRST PASS/FIRST PASS EFFECT​- some drug are not absorbed directly into systematic circulation. Some oral drugs→absorbed in the lumen of S.Int by mucosal villi surface (removal of S.Int will ↓ absorption) → goes to portal venous system via the portal vein → molecules goes to the liver w/c break downs by liver enzymes. B. Blood flow to the site of administration *rich blood supply enhances absorption (IM than SC) *shock state, vasoconstriction impedes drug absorption C. Solubility of the drug (physical state of the drug) *H₂o soluble drugs (vit B&C) needs carrier (Enzyme/CHON) to pass GI membrane *G-I membrane is made up of lipid (fat) & CHON, so lipid-soluble drugs pass easily through G-I membrane (ADEK vit) D. Ph *drugs absorb/disintegrate best in acidic fluid (pH of 1-2) *young & old (↓gastric acidity)- alkaline env’t (drug absorption is slower) E.Drug concentration *drugs in given in High concentration (pure) is rapidly absorbed, than drugs w/ low concentration (concentrated vs. diluted) F.Dosage form-liquid forms are absorbed faster than solid forms *oral Pen-G is usually given in large doses bec. HCL acid tries is destroyed by gastric juices G. Routes of drug administration- parenteral route are absorbed faster than oral route. (IV- IM- SC- inhalation- topical- oral) H. Bioavailability (BA)- refers to fraction of an administered dose of unchanged drug that reaches the systemic circulation (e.g when given as IV the BA is 100%, but if its other route e.g oral the BA ↓ bec. of First-pass effect or incomplete absorption) I. Exercise-affects blood flow, more blood goes to muscles than GIT J. Pain, Stress, Food (solid, fatty)- slows gastric emptying time, drug remains longer in stomach 2. Mechanism involved in absorption A. Diffussion B. Osmosis C. Filtration E. ​Distribution 1. Factors influencing drug distribution: A. Blood Flow *blood carries drugs, impairment in blood circulation/amt. of blood can interfere drug distribution (eg. Antibiotics is not well absorbed in sites w/ abscesses, exudates & tumors) *Body wt. (obese)→ greater fat content, the slower the drug is release (blood crosses the fat slowly) B.

Affinity to Body Tissue or Receptor sites RECEPTOR​- an area on cell membrane, where drug attaches itself & response takes place. (eg. CHON, nucleic acid, enzyme, lipids, CHO residue). Drug acts through receptors, by its ability to bind/affinity to a specific receptor.

Lock & Key principle (the right key would fit the lock, the better the drug fits @ the receptor site, the more biologically active the drug is” Agonist​→ will connect itself to “R” site & ​produce/initiate a pharmacological response Antagonist​→ will attempt to attach, but since its uneven to “R’ site, no drug response or ​block/px ​a response *Competition on “R” site occurs when 2 or more drug tries to occupy it. C. Specificity & Selectivity- almost ALL drugs lack specificity (non-specific) & lack specificity (non-selective) *​Non-specific drugs =affect 1 receptor @various sites (but widely distributed throughout the body) *​Non-selective drugs​ = affects various receptors ClinSit: Non-Specific drug Bethanecol (Urecholine) - ​used for tx of p-op urinary retention by ↑ bladder contraction. How it works: Urecholine will stimulate cholinergic receptors in the bladder (↑urination by contracting the bladder & relaxation of sphincters), BUT other cholinergic receptors in the body are affected w/ corresponding responses like: Heart/bv ​= ↓HR/↓BP Eyes​= pupillary constriction (miosis) GI​= ↑ gastric acid secretion (HCL) Lungs​= bronchoconstriction ClinSit: Non-Selective drug Epinephrine/Adrenaline- ​Emergency drug How it works: Epinephrine will stimulate & act on various receptors in the body producing various responses like: A​₁ = BV (↑BP) B₁​ = Heart (↑HR) B₂​ = Lungs (constricts bronchioles) D. Plasma protein (CHON) binding effect-once drug is distributed in plasma/vascular system→ many are bounded (attached) w/ CHON (albumin) CHON-bound Unbound (Free-active (inactive drug) ID drug) FAD Diazepam (valium) 98% 2% Aspirin

49%

51%

*FAD-active drugs, floating drugs & can cause pharmacologic response. *As FAD in tissues ↓, CHON- bound ID are released from their attachment→ to maintain the balance of free drug *when 2 highly CHON- bound drugs are given concurrently, they complete for CHON- binding sites→ causing more free drug in the circulation (drug accumulation→ drug overdose→ drug toxicity)

ClinSit: ​Pt’s w/ Kidney (RF) & Liver dse (Hepa/LC)= has ↓plasma CHON level (albumin), precaution is needed, problem with drug excretion may occur because kidneys can’t filtered-out CHON-bound drugs. Lab Exam (TPA/G) to check for S. CHON levels. E.

Volume Distribution (fluid volume in body) *Edema= has enlarged area, may need to ↑ or larger dose *Dehydration= smaller doses is needed for even drug distribution

2.

Barriers to drug distribution (px some drugs to enter certain body organs) A. Blood-brain barrier- to pass through this barrier, ​drug must be lipid/fat soluble & non-CHON bound B. Placental barrier- highly ionized drugs (+/-) experience difficulty in crossing the placental membrane F.

Metabolism/Biotransformation Liver- principal site of drug metabolism. (First Pass effect)- liver enzymes breaks down/converts/inactivated drug molecules into metabolites (active/inactive) or H₂O soluble substances (either for excretion or systemic absorption) 1. Active metabolites - causes an effect in the body 2. Inactive metabolites - these are deactivated drug molecules after effect of liver enzymes and readily excreted by the body HALF-LIFE (t½) - ​time it takes for ½ of the drug concentration to be eliminated/excreted by the body. This is the determining factor for calculating drug dosage intervals/frequency (OD- BID- TID- QID- RTC) *​short t½- ​4-8​°​or less (furo- 1.5​°​/ rifam- 2​°​) *​long t½- ​24​°​or more (lanoxin- 36​°​) Concepts on t½: *drugs with short t½ can be given more than 1x a day *drugs with long t½ if given more than 2x a day→ causes drug accumulation→ leading to toxicity *pt’s w/ liver & kidney dses., should have cautioned of ↑ng doses & ↑ng drug frequency. FACTORS AFFECTING DRUG METABOLISM: *Age-infants &elderly have reduced ability to metabolize some drugs *Nutrition-liver enzymes involved in metabolism rely on adequate amounts of amino acids, lipids, vitamins & CHO *Insufficient amt. Drug of body hormones- less Insulin/Adrenal corticosteriods can reduce metabolism of drugs in liver G.

Excretion/Elimination 1. Organs of excretion A. Kidneys- principal site drug elimination, carried out by GFR & tubular secretions via urine *Unbound drugs & H₂O soluble drugs are filtered by kidney *CHON-bound drugs ca’t filtered-out by kidney (it has to be converted to free/unbound→ to be excreted via urine) *urine pH influence drug elimination acid←4.5 to 8→ alka *acidic urine→ promotes elimination of weak-base drugs *alkaline urine→ promotes elimination of weak-acid drugs

ClinSit: *​Aspirin (weak acid)- if given overdose→ turns to a strong acid→ produces an acidic urine→ w/c can’t be eliminated in the body because Its not a alkaline drug→ doctor will give NaHCO₃→ to change acid urine to alkaline urine so that it can be excreted by the kidney. *large quantities of CPP diet (cranberry juice, prune, plums) can produce acidic urine (↓urine pH) *Aging process (Geria)- ↓renal fxn→ resulting in slower elimination of drugs→ causing higher drug concentration in blood stream B. Intestines- through feces C. Lungs D. Sweat & salivary glands E. Mammary glands- through breast milk F. Bile PHARMACODYNAMICS A. Theories of drug action- most drugs produce their effects by one of the following ways 1. Drug-receptor interaction A. Agonists B. Antagonists C. Affinity D. Efficacy E.Types of receptors 1. Beta₁​- Heart (1) - heart muscle contraction/↑HR 2. Beta₂​- Lungs (2) - smooth muscle relaxation/ bronchodilation 3. Alpha₁- ​BV - smooth muscle contraction/↑BP 4. Alpha₂​- smoothe muscle contraction & neurotransmitter inhibition/ bronchoconstriction 5. Other receptors (Histamine, Acetylcholine, Neropinephrine, Epinephrine/Adrenaline, Cholinergic, Dopaminergic) 2. Drug-enzyme interaction 3. Nonspecific drug interaction B. Drug-response relationship 1. Plasma level profile of a drug 2. Biologic half-life 3. Therapeutic threshold or minimum effective concentration (MEC)/Time Response Curve Goal: ​to maintain drug availability w/in plasma level TRC is Affected by: ​Drug Dosing/ Frequency/ Time-Interval *some drugs produce effects in minutes, other takes hours/days *if drug serum/plasma drops below MEC, adequate drug dosing is not achieved; while too high drug serum/plasma above MEC results to toxicity 3 Parameters of Time-Response Curve 1. Onset of Action- ​begins when drug enters plasma & lasts until it reaches MEC (minimum effective concentration) 2. Peak of Action- ​drug reaches its highest serum/plasma concentration 3. Duration of Action- ​refers to length of time drug has a pharmacologic effect

4. Therapeutic index​- “safety of patient/drug is our major concern”. It estimates the margin of safety of a drug in plasma/serum level. T.I = LD50 / ED50 (the closer the ratio is to 1, the > the danger of toxicity) *↓T.I - drug levels in blood should be monitored, narrow margin of safety, dose need adjustment *↑T.I- wide margin of safety less danger & toxic effects, no need to monitor. 5. Loading Dose​- used when immediate drug response is desired, large initial dose is given to achieve a rapid MEC is plasma level. *after LD, prescribed dosage per day is ordered. ClinSit: *Digoxin (for A/Fib.) - 1 - 1.25mg IV or 0.25mg ½ tab OD *Heparin (for M.I) - 5,000 U IV bolus, then start Heparin drip (D₅W200CC = Heparin 10,000 U @ 14 mgtts/min (700 U/hr) C. Factors altering drug responses 1. Age 2. Body Mass 3. Sex 4. Environmental milieu 5. Time of administration 6. Pathologic state 7. Genetic factors 8. Psychologic factors D. Predictable responses- drug responses can have a 1​°​or 2​° physiologic effect/ both. *1​°​effect - is usually desireable 1. Desired action- the 1​°​effects intended, the reason the drug is prescribed. 2. Side effects- effect of a drug that is unintended, can be ​desirable ​or undesirable​ (also called 2​°​effects) ClinSit: A. Diphenhydramine (Benadryl) - antihistamine 1​°​- Tx Sx of Allergy 2​°​- CNS depression causing drowsiness Desirable effect=​ if given @HS (sedation) Undesirable= ​can’t drive a car or any activity B. Aspirin (ASA)- antiplatelet aggregator 1​°- ​Px & delays clotting formation 2​°- G​astric irritant E. Iatrogenic responses (adverse effects produced unintentionally) F. Unpredictable adverse responses 1. Drug allergy (medications frequently implicated in allergic reactions)immunologic reaction to a drug 2. Anaphylactic reaction- severe allergic reaction w/c usually occurs immediately following administration of a drug 3. Delayed reaction (“serum sickness”)- a reaction similar to allergy from an anti-serum drug derived from non-human animal source

4. Hypersensitivity- used synonymously with allergy. But they are not the same 5. Idiosyncratic effect- an unexpected peculiar response to a drug, either over response, under response, unpredictable or unexplained of an individual 6. Tolerance- a decreased physiologic response to the repeated administration of a drug or chemically r/t substance. 7. Cross Tolerance- a phenomenon that occurs when someone who is tolerant to the effects of a certain drug also develops a tolerance to another drug. It happens between 2 drugs w/ similar function/effects. (amphetamine & caffeine; alcohol & cannabis sativa) 8. Tachyphylaxis- an acute rapid decrease in response to a drug after its administration. Can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response. 9. Cumulative effect- it is the increasing response to the repeated doses of a drug that occurs when the rate of administration exceeds the rate of metabolism/excretion. 10. Drug dependence- it is a reliance or a need to take a drug or substance. Intense physical emotional disturbance is produced if the drug is withdrawn. 11. Drug antagonism- the interaction of 2 drugs to inhibit or cancel each others effect 12. Summation (addition or additive effect)- similar to agonist 13. Synergism- drug interaction in w/c the effect of 2 drugs in combination is greater than the effect of each drug given separately. 14. Potentiation- 2 drugs administered at the same time wherein 1 drug ↑ the effect of the other DRUG INTERACTIONS: A. Variable influencing drug interaction include 1. Intestinal absorption 2. Competition for plasma protein binding 3. Drug metabolism or biotransformation 4. Action at the receptor site 5. Renal excretion 6. Alteration of electrolyte balance B. Drug-to-Drug Interactions- occur when the action of one drug is altered by the action of another drug. Some interactions are beneficial. 1. Additive Effect- 2 drugs when taken together produces double effect. Eg. Propoxyphene (Analgesic) = Aspirin (Analgesia effect) = added analgesic effort 2. Synergistic Effect- combined effect of 2 drugs is > than the sum of the effect of each drug if given alone. E.g Codeine + Aspirin = much greater analgesic effect (more than doubled) 3. Antagonistic Effect- 1 drug interferes w/ the action of another drug. E.g. Tetracycline + Antacid = ↓absorption of tetracycline 4. Interference/ Displacement- one drug inhibits the metabolism/excretion nd of a 2​ drug, causing ↑ activity of the 2​nd drug. E.g Probenecid (uricosuric) + Spectinomycin (Anti-infective)= prolonged antibacterial activity from spectinomycin due to blocking renal excretion by probenecid. Probenecid is excreted while spectinomycin is retained in the body. 5. Drug Incompatibility- 1 drug is chemically incompatible w/ another drug (causing drug deterioration) when 2 drugs are mixed. Should not be co-administered/mixed. 6. E.g Ampicilin + Gentamicin = ampicilin inactivates gentamicin (Signs of incompatibility; haziness, precipitation, color changes during drug preparation)

C. Drug-to-Food Interaction Drugs

Foods to Avoid

Antacid (CaCO₃) Tums

Bran, Whole grain breads Citrus fruits, Colas

Erythromycin Penicilins Tetracycline Anticoagulants

MAOIs

Ca-rich foods Vit. K rich food (green leafy veggies) avocado Tyramine- containing foods (chocolates, wine, cheese, pasteurized, femented)

D. Drug-to-Lab Interaction (a drug is prescribed to correct abnormal laboratory values) K+ = 3.5 - 5.5 mEq/LDrug Na= 135 - 145 mEq/L E. Drug-induced Photosensitivity (produces glaring to the eyes Phenytoin (Dilantin) - anticonvulsant

DRUG STORAGE A. Drug potency can be affected by: a. Temperature- proper storage of drugs, use room thermometer b. Light - antineoplastic meds, use cover c. Moisture - tablets in bottles w/ preservatives & cotton d. Shelf-life - expiration dates, can still be used after 1-month after, but the drug is not anymore potent.