Pharmdrugchart2

Drug ANTIFUNGAL

Mechanism Amphotericin B

Flucytosine

Nystatin (topical)

IMIDAZOLES

Ketaconazole (itraconazole )

Fluconazole

Clotrimazole

Clincal Use

-Binds ergosterol – DOC -Systemic mycoses (animals sterol) -Pores in membrane Broad spectrum Antifungals (increases permeability) -Low therapeutic index -IV (intrathecal in meningitis) -Pro-Drug -Deaminate  5fluorouracil -Fxnal/strxral instability -Inhibits thymidine synthetase -Enters CSF -Structurally similar to Ampho B -Same mechanism -Not well-absorbed -All work by blocking fungi cyt P450 -Inhibits ergosterol production -Disrupts membrane -Increased permeability -Also inhibits -gonadal/adrenal steroid synthesis Oral -Similar to ketaconazole -Enters CSF -Slow metabolism -No endocrine side effects Topical only

Econazole

Water-soluble cream

Miconazole (monistat)

Dermatological & vaginal cream

Combo w/ Ampho B to decrease toxic effects of Ampho B -Synergistic b/c also increases flucytosine penetrance -Meningitis – crypto or candida UTI- candida Torulopsis glabrata Candidiasis -Vaginal -Skin -Oral for topical tx of GI fungi (thrush) DOC – non-meningeal blastomycosis, paracoccidiomycosis, coccidiomycosis -Mucocutaneous candidiasis -Vaginal candida -Cushings Syndrome Testicular Ca (anti-androgenic effect) -Esophageal candidiasis -Prevents relapse of cryptococcal meningitis -DOC – cryptococcal meningitis, candidemia, coccidiomycosis - Enters CNS readily -DOC – oral thrush -Tinea -Otomycosis -Cutaneous/vulvar candida -Versicolor -Candida -Dermatophytes Tenia pedis (athletes foot), cruris, versicolor

Side Effects Neurologic imbalance Anemia – decreases erythropoietin Electrolyte imbalance Nephrotoxic Fever, chills, pain, N/V – pre-tx w/ steroid/NSAID BM depression

Rare – lack of absorption N/V Topical b/c too toxic

-N/V, anorexia -Allergic rash -Inhibits steroid synthesis -Decreased libido, gynecomastia -Liver dysfxn -Teratogenic -Increases cycloserine/warfarin levels (x-rxn w/ human Cyt P450) -Nephrotoxic Steven’s-Johnson’s syndrome – bullous erythema formae -Thrombocytopenia in AIDS pt. -Co-administration w/ phenytoin, sulfonylurea, warfarin cyclosporin increases plasma concentration

Local erythema Burning/itching

Vulvovaginal candidiasis

Griseofulvin

-Microtubule interxn -Disrupts mitotic spindles -Keratin-containing tissues & may take months -Can be given IV to tx Candidas if allergic to ampho B -Must given w/ fatty meal

Trichophyton Dermatophytes - Superficial -Microsporum -Epidermophyton -Trichophyton

-Barbituataes decrease absorption -Hepatotoxic – increase metabolism of warfarin, contraceptives (BC) -H/a post-discontinuation -Peripheral neuritis -Teratogenic /carcinogenic

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Drug ANTIVIRALS Bockage of adsorption, penetration, & uncoating Nucleic acid synthesis

Mechanism

Clincal Use

Side Effects

Amantadine Rimantidine

-increase endosomal pH (blockage of uncoating) -enters CNS -oral

Acyclovir

-activiated by VIRAL thymidine kinase -premature chain termination -disseminated throughout body – oral, topical, IV -irreversibly binds template primer to viral DNA polymerase -competes w/ deoxyguanosine -only viral infected cells affected -acyclovir analog -inhibits Viral DNA Pol

Prophylactic for Reswpiratory viruses Antivirals -Influenza A -Rubella -Parkinson’s disease (amantidine) -HSV-1,2 -VZV -DOC – HSV encephalitis -prophylaxis immunocompromised seropositive -CMV resistant – no thymidine kinase

-CNS affects -teratogenic -contraindicated in psychiatric disorders, epilepsy, CAD -renal failure  toxicity -local irritation (topical) -h/a, diarrhea, n/v (oral) -renal dysfxn(crystallization), seizure, delirium hypotension (hi IV dose)

DOC – CMV (disseminated /retinitis) -prophylaxis in BM suppression

-reversible neutropenia -thrombocytpenia -renal dysfxn -seizures Ocular irritation Edema Photophobia Pain

Gancyclovir

Trifluoridine idoxuridine cytarabine

Vidarabine

-phosphorylated by HOST kinases -incorporated to host & infected cells -inhibit DNA to disrupt fxn

-adenosine analog -inhibits DNA pol -topical or systemic

Azidothymidi ne (AZT)

-Phosphorylated inhibits RT -terminates DNA synth/replication

Interferons

-induce protein kinase --oligoadenylate kinase, protein kinase, phosphodiesterase (blocks peptide chain) -inhibitory on DNA/RNA synth -glycoprotein -inorganic phosphate analog -inhibits DNA pol w/o being phosphorylated

Foscarnet

Ribavirin

-synthetic guanosine analog -inhibits viral coded RNA Pol (inhibits viral mRNA synth)

Topical only -HSV keratitis DOC – keratoconjunctivitis w/ respect to HSV -acyclovir resistance (2nd line) -AML -HSV keratitis/encephalitis -in immunocompromised DOC -neonatal herpes -VZV, HSV-1,2 HIV

-Herpes zoster -HBV -Kaposi’s sarcoma -Hairy cell leukemia -HPV – (genital warts) –gamma-INF -acyclovir – resistant strains -CMV 2nd to gancyclovir – CMV retinitis-in immunosuppressed DOC – RSV – children – aerosol -Influenza A, B Lassa/hemorrhagic fever

Systemically -Bone marrow suppression -renal damage

GI irritation Hepatic dysfxn Convulsions

-BM toxicity -CNS – h/a, insomnia, agitation, seizure -toxicity – precipitated by acetaminophen, lorazepam, indomethacin, sulfa’s, probenecid, cimetidine -FLU-like (h/a, fever, muscle aches) -CV – dysfxn -neurotoxic -BM suppression -GI irritation

Renal impairment Tremors & seizures Hypocalcemia Anemia Interferes w/ AZT Anemia in Lassa fever Elevates bilirubin Electrolyte dysfxn Contraindicated in pregnancy

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LATE PROTEIN/ VIRAL ASSEMBLY

Methisazone

PROTEASE INHIBITORS

-late structural protein synthesis inhibition -

DDC (dideoxycytosine ) Saquinovir indinovir ritinovir

-small pox (eradicated)

-Converted to ddCTP -Alters DNA synth

AZT-resistant HIV

-Blocks aspartate proteinase to prevent cleavage of gag-pol precursor protein -Blocks packaging & assembly

-Given in high dose to completely stop replication of virus -too low or monotherapy  resistance

Peripheral neuritis

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o Gaseous Anesthetics Drug type

Drug

Inhaled anesthetics

Nitrous oxide

Desflurane

Isoflurane

Mechanism MAC 100 -Weak; used w/ others -Rapid onset, rapid recovery -< CV & resp. depression MAC 8.0 Irritating Not very soluble Rapid onset & recovery -Less potent MAC 1.4

Enflurane

MAC 1.68 -Rapid onset & recovery

Halothane

MAC .75 -Resp. & CV depression -Vasodilation  relaxing SM (uterine) -Increase intracranial pressure MAC.16 -Excellent skeletal muscle relaxation -Slow onset & awakening

Methoxymethane

Clinical Use

Side Effects

Potent analgesic!!!! No anesthetic Give w/ 20% O2

-Safest -Diffusional hypoxia -Vit B12 def. -2nd gas effect (enhance solubility of 2nd) -Little muscle relaxant

Ambulatory surgery

Bronchial irritation

-No arrhythmias -No problems w/ catecholes -More potent muscle relaxant

Irritating

Pediatric anesthetic – not hepatotoxic to kids

SEIZURE (assoc. w/ hypercarbia) Malignant hyperthermia Renal toxicity (fluoride ion)
-Reserved for OB -Most potent inhalant

-Metabolism releases fluoride (RENAL DAMAGE)

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Neuromuscular Blockers: Two Types: Non-depolarizing-Competitively inhibits the NMJ receptors by binding without activation of pre and postsynaptic sites. These cannot enter CNS due the charge of thei ammonium ions. Presynaptic inhibition- Release of Ach diminishes and contraction “fades” Postsynaptic inhibition- Blocks Ach at receptor. This is a competitive block therefore increased Ach can reverse this. Depolarizing-Competitive agonist that binds to and activates the NMJ receptor but inactivates it by keeping the ion channel open (IE the receptor is prevented from cycling back to it’s closed state). Drug

Duration Long

Tubocurarie A Gallamine c Pancuronium t i n g

Mechanism

Clinical Use

Adverse Effects

Nondepolarizing Nondepolarizing Nondepolarizing

Muscle parplysis Muscle parplysis Muscle parplysis

Histamine release Vagal Blockade Indirect sympathomimetic effect

Nondepolarizing

Short surgical procedure

Safe for organ failure due to nonenzymantic metabolism Toxic metabolite will build up with long-term infusion in pts with organ failure.

( 1 . 5 h r s ) Medium

Atracurium A c t Vecurium i n g

Vent patients (long term)

( 3 0 m i n ) Very

Succinylcholine S h o r t

Depolarizing

Intubations

Muscle soreness Malignant Hyperthermia

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Mivacurium

Nondepolarizing

Not used due to favor of succinylcholine

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Nitrosurias Drug CANCER THERAPY Alkalating Agents Methane sulfona tes Other

Carmustine Lomustine Mechlorethamine

Busulfam

Cisplatin Cyclophosphamide Chlorambucil

Carboplatin

ANTI-

METAB OLITE INHIB ITORS S-phase specific

Methotrexate (W/ leukovorin)

Liphophilic Mechanism (BBB-CNS tumors) Non-phase specific -Penetrates CNS -Alkylation of N7 -Alkylate DNA Guanine in DNA inhibiting replication -Cross-linkage between Methane sulfate chains & depurination -NO DNA duplication IV or IA Alkylating-like Pro-Drug -Complexes w/ guanine -Activated via in DNA hydroxylation via Cyt -Binds to proteins – P450 cross-linkage -Covalent x-link -Cytotoxic to all cell guanine stages -Oral; Newer form of cisplatin Slow-acting -No protein binding (chlorambucil)

-Malignant Cancer therapy glioma Brain cancers Hodgkin’s disease Solid tumors

-Dihydrofolate reductase inhibition -Decrease THF -Inhibit conversion of dUMP to TMP -Hi doeses 7-OH  crystaluria -CSF only Hi doses

ALL-children Choriocarcinoma – w/ dactinomycin Burkitt’s -BRCA -Head/neck ca -Long-term use in psoriasis/RA  hepatic fibrosis/cirrhosis -Abortion when used w/ misoprostol in 3rd term

Leucovorin Rescue 5-fluorauracil

-Pyrimidine analog that interferes w/ conversion of deoxuyurdylic acid  thymic acid -F-dUMP competes w/ dUMP (thymidilate synthetase) Arabinosyl Pyrimidine antagonist -Decreases TMP & MITOTIC Vincristine -Microtubule assembly Cytidine ara-CTPDNA – competitive inhibits synthesis INHI (oncovin) inhibitor (Cytarabine/ARAinhibitor for DNA Pol 6-mercaptopurine Purine analog – BITO vinblastin -Blocks mitosis C) -Chain termination upon activated by RS e M-phase specific incorporation HGPRT (Vinca alkaloids) ANTIBIOTICS Adriamycin Broadest antitumor -Inhibits (doxorubic amidotransferase spectrum Paclitaxel (Taxol) M-phase spec. in) -Competitive -Blocks Hyperstablizes substrate/DNA pol IMPAMP/GMP microtubule inhibitor – allopurinol -CAREFUL -INTERCALATION— —(xanthine oxidase) topoisomerse inhibits drug II interference metabolismtoxic OTHER Epipidophyllotoxin Topoisomerase II -Superoxide/ (via levels) (Etoposid inhibitor quinone moiety) free e) – VP16 -Strand breakage radicals fragmenting Effecfts in S & G2 DNA -Now used in combo w/ -Preference for bleomycin & cisplatin Sphase (not specific) Daunorubicin Same

Bleomycin

Actinomycin D (dactinomy cin)

Intercalates w/ GC or GT -Free radicals -Splits DNA G2-phase specific -Complexes w/ Fe++ -Intercalates in small groove -Interferes w/ DNAdep RNA pol

Clincal Use

-CML

-Testicular ca -Burkitt’s lymphoma --Combo -- vinblastine, bleomycin, -BRCA cisplatin, etoposide -Nephrotic syndrome -Ovarian ca -RA (intractable -Bladder ca

Same as platin

Slow growing solid tumors (colon, breast, ovarian, pancreatic, gastric) Superficial basal cell

AML-myelogenous -Vincristine – (childhood tumors) –some Combo w/ t-TG+daumorubicin adult leukemias & solid tumors ALL—maintain remissions Vinblastine – testicular ca((now etoposide preferred), (bleomycin & cisplatin), lymphomas, Kaposi’s, breast Solid tumors Resistance: export (P-glycoprotein) ALL & granulocytic leukemias Breast ca Hodgkins Ovarian ca, Kaposi’s sarcoma (liposomal prep decreasescardiac toxicity)

Small cell ca Hodgkins CNS malignancies Testicular ca Leukemia Acute lymphocytic & agranulocytic leukemias -Not as effective against solid tumors Small cell lung ca Testicular ca (w/ vinblastine & cisplastin) Lymphomas

Childhood tumors

Delayed hematopoietic Side Effects dep. Aplastic marrow Severe vomiting Renal toxicity Bone marrow suppression CNS toxicity Latent viral infxn Extravasation is serious BMSAdrenal suppression Pulmonary fibrosis (Ondestron) -Hemorrhagic cystitis w/ fibrosis of Limiting: Nephrotoxic bladder due to acrolein (active (mannitol/hydration) metabolite) Acoustic nerve damage -Tx w/ MESNA, hydration & mannitol) Lo Ca++/Mg++ BMS Neurotoxic -oral/liver metabolism w/ toxicity @ all Sterility dose levels Less toxic/nauseating than cis-platin Limiting – myelosuppression (thrombocytopenia) Bone marrow toxicity GI disturbances Urticaria Alopecia Renal damage-Hi dose - 90%unchanged in urine Lo—50%--liver can only detoxify so much @ a time – measure blood/renal fxn Hepatic fibrosis – in low doses (mostly long-term for immunosuppression)- also recirculates in biliary stasis GI toxicity Ulceration of oral & GI mucosa BMS Anorexia N/V/D Hand/foot syndrome

N/V/D Neurotoxic (axonal transport) Myelosuppression Hepatic dysfxn N/V Vincristine: neurotoxic Thrombocytopenia Vinblastine: BM suppression (blasts Myelotoxicity marrow) Cardiotoxic – ECG changes – cumulative dose dependent (unique)(give Fe++ Neutropenia chelator) Hypersens. Rxn (dyspnea, urticaria, BMS hypotension) Alopecia --Good to give w/ dexamethosone, diphenhydramine, & H2 blocker Cardiac toxicity Leukopenia – limiting

Pulmonary fibrosis – low levels of deactivating enzyme in this tissue -Tachypnea/dyspnea -Rash-hypertrophic skin change -Anaphylactoid rxn No BMS 36 BMS

STEROIDS

Prednisone (Also immunosupp ressive)

Asparaginase

IMMUNOSUPPRESSIVES

Azothioprine

Pro-drug -Precursor for mercaptopurine -Actively dividing cells -Amidotransferase inhibition (IMPAMP/GMP) -Incorporated into DNA Particularly active against lymphoid cells -See cancer chemotherapy

Autoimmune disease Renal transplants **Caution allopurinol toxicity

Cyclophosphamide

-2nd line to azothioprine -Hi dose  tolerance to new antigen

Cyclosporin A

Interferes w/ early antigen response -Inhibits T-helper cells -Inhibits calmodulin, Il2, -Cyt P450

Autoimmune -RBC hemolysis, Ab RBC dyscrasia, BM suppression BM transplant @ hi doses Organ transplants G vs H disease RA Glomerulonephritis RBC dysplasia Inflammatory bowel disease Psoriasis

FK509 (tacrolimus)

Similar to Cyclosporin A -Higher potency & fewer side effects -P450 metabolism

Liver transplant -Rescue in other organ transplants

Antilymphocyte Globin

Rxn against T-cell (poly or monoclonal)

Anti-OKT-3 (Muromonab-CD3)

Monoclonal, mature T-celldirected Ab -Blocks killer T-cells Converted to mycophenolic acid (MPA)

G vs. H disease Organ transplants -Serological immunity not impaired Renal transplant/allograft crisis

Methotrexate

-Antibodies

Immunosuppression CANCER: Lymphomas General anti-lymphocytic DOC for: effect -ITP -Triggers apoptosis -Autoimmune hemolytic anemia IMMUNOSUPPRESSION: -Acute glomerulonephritis Toxic to some T-cell G vs. H disease lines -Suppress immunity & inhibits production of mediators -Ameliorate drug toxicity/inflammation Decreases rapidly-growing ALL – esp. childhood leukemias that show nutritional requirement for asparagines

Mycophenotate

Prophylaxis against G vs. H in BMT Severe RA Psoriasis

Adrenal suppression Growth inhibition Decreased muscle tone Osteoporosis Cushing’s syndrome Immune suppression

Hypersensitivity rxn Decreases clotting factors Hepatotoxic Pancreatitis Seizures, coma BMS Gi irritation Skin rash Hypersensitivity rxn

Hepatic fibrosis/cirrhosis (not BM suppression) Abortion in combo w/ misoprostol (PGE1 analog) Leucovorin rescue -doesn’t cause side effects of steroids/anti ca drugs

Nephrotoxicity is limiting factor Neurotoxic – hi in liver transplant Infxn Lymphomas Hirsutism Gingival hyperplasia Hypertension

NO gingival hyperplasia, less hypertension -Otherwise similar to Cyclosporin A -avoid use w/ NSAID – interferes w/ renal blood flow Hypersensitivity rxn/serum sickness

Hypersensitivity rxn

Kidney transplant

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Mechanism Isoniazid (INH)

-inhibits synthesis of mycolic acid -intracellular/ extracellular organisms -acetylated -affects synth. Of lipids/ nucleic acids

-bacteriostatic/ -cidal

-inhibits DNA-dep RNA pol -decreaase RNA synth -CNS penetration -prokaryocytes -red/orange urine, sweat, tears etc. Mechanism u/k

Bacteriocidal -TB -atypical mycobacteria -M. Leprae – in combo -meningitis – prophylactic (h. influenza, N. Meningitidis)

Pyrazinamide

Mech u/k

Bacteriocidal TB

Streptomycin

30s inhibitor

TB (advanced & military) Tularemia, plague, meningitis -

Rifampin

Ethambutol

Second line drugs

Ethionamide

LEPROSY

Clincal Use

Para-amino salicylic acid (PAS) Cycloserine

Dapsone

Clofazimine

Amithiozone

-Structurally similar to isoniazid -diff mechanism -large doses required -competitive inhibitor for PABA in Folate synth Inhibits cell wall synthesis by competitively inhibiting conversion of L-ala to D-ala, then linking Dform Bacteriostatic agent inhibiting folate – (PABA-antagonist) dihydropterate synthase (similar to sulfonamides) -acetylation -excreted via kidneys

TB- resistance if used alone M. Kanasii Prophylactically – given alone

Bacteriostatic -TB, M. kansasii -atypical mycobacteria

2nd line for TB/atypical mycobacteria -nocardia infection if sulfa’s fail -renal TB – 70% excreted in urine

Side Effects Peripheral neuritis (inhibits pyridoxal phosphate kinase) --given w/ pyridoxine (Vit. B6) -hepatotoxic (hydrazine metabolite) -allergic rash/drug fever -potentiates effects of phenytoin & warfarin -hemolysis in G6PD deficiency -GI irritation -Hepatotoxic -Thrombocytopenia -induces P450 (increase metabolism of steroids & oral contraceptives) -Flu-like syndrome Decreased visual acuity/optic neuritis (reversible) -peripheral neuritis -h/a, confusion GI irritation Hepatitis  death Hyperuricemia  gout Photosensitivity Optic nerve dysfxn GI irritation – due to dose Impotence Mental disturbance GI irritation Hemolysis in G6PD def Hypersensitivity Exacerbate epileptic seizures CNS disturbance Peripheral neuropathies

Leprosy Alternate tx for P. carinii in AIDS pt. --recommended therapy = dapsone +clofazimine + rifampin

Phenazine dye binds to DNA to inhibit template fxn

-dapsone resistant leprosy bacteriocidal to M. leprae anti-inflammatory effect tx lepra rxn of dapsone

Alternate drug to dapsone Thiosemicarbazone

Dapsone-resistant replacement

Allergic rxn Peripheral neuritis Hemolysis in G6PD def Lepra rxn (erythema Nodosum; similar to jarisch herxheimer rxn w/ penicillin & syphilis) Discoloration of skin Eosinophilic enteritis GI irritation Hepatotoxicity GI irritation

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Primaquine

Tissue schozont icide Drug

Blood schizonticide

Cloroquine

Amiodaquine

Pyrimethamine

Quinine mefloquine

8-aminoquinolone 1. Liver stage 1. GI irritation -liver phase of Antimalarials infxn (exoerythrocytic) 2. H/A -“Tissue shizonticide” 2. Primary Falciparum, 3. Agranulocytosis -extensive metabolism Malariae 4. Pruritis 5. Methemaglobinemia Mechanism (oxidation/ Clincal Use3. Secondary Vivax, Ovale Side Effects demethylation) 6. Hemolysis in G6PD def. (latent hypnozoite) – only -DOC for all types -DOC – prophylaxis of all types 1. Short term – GI disturbance agent to cure b/c they except falciparum (except resistant falciparum) remain in liver 2. Long-term – SIGHT, HEARING -blocks enzymatic synth -persistent liver stage (w/ 4. Gametocidal for all 4 DAMAGE – of RNA & DNA primaquine) interrupted transmission -buffers cellular pH to -amebiasis (cemetine) amebic liver decrease cellular abcess invasion -collagen disorders/autoimmune like -concentration: liver, lupus & RA b/c anti-inflammatory idney, lung, blood, brain effect -RBC – bindsw/ -gametocide ferriprotopphorphyrin IX  damages membrane  lysis of parasite/RBC - erythrocytic phase Similar to cloroquine 1. Agranulocytosis 2. Photosensitivity 3. Dermatitis 4. GI disturbances 5. H/A Inhibits dihydrofolate Prophylaxis of resistant falciparum 1. Megaloblastic anemia reductase of parasite (w/ cloroquine & pyrimethamine) 2. Sulfa-skin rashes Decreases P. Malariae & toxoplasma (w/ 3. GI distress purin/pyrimidine synth sulfadiazine) 4. Hemolysis Works @ lower -synergistic w/sulfadoxine in folate 5. Kidney damage concentration than pthway 6. Steven-Johnson syndrome required for mammalian enzyme Fansidar: pyrimethamine + sulfadoxine Inhibits DNA Gyrase P. falciparum infxn resistant to 1. Cinchonism (h/a, tinnitus, blurred - prevent DNA strand chloroquine vision) separation Relieve leg cramps 2. Cardiac conduction disturbances Blocks DNA replication Myotonia congenital 3. Black water fever, (intravascular & RNA transcription Sclerosing agent hemolysis) -20% excreted 4. GI distresss unchanged 5. Hemolysis in G6PD def

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Aminoglycosides Drug AMINOGLYCOSIDES

Mechanism Gentamycin Amikacin Tobramycin

Streptomycin

-Inhibits 30s -enters microbe via O2-dep active transport -interferes w/ assembly of fxnal ribosome -misreading of mRNA -No CNS action Amikacin: resistant to aminoglycoside inactivity enzyme produced by Gram (-) Not effective in Gram (-) rods

Clincal Use

Side Effects

AEROBIC ONLY Gram – E. Coli Proteus Klebsiella Serratia Pseudomonase Enterobacteriaceae TB (streptomycin)

Ototoxic (vestibular & cochlear) Nephrotoxic

TB – advanced & military

Optic nerve dysfxn

NM blockade Hypersensitivity rxns Superinfxn

Tularemia

Spectinomyci n

Netilmycin

Neomycin (topical) (paramomycin ) (kanamycin)

POLYMYXINS

Polymixin B, E (Colistin)

Very limited spectrum

-Similar to amikacin -Slight resistant to -aminoglycoside inactivating enzymes -too toxic for systemic use -only used topically & sometimes orally -kanamycin/Paramycin is antiamebic -interacts w/ phospholipids -penetrates -disrupts cell membranes -lyses cell TOPICAL only

Y. Pestis – plague Meningitis Penicillin-resistant gonococcal Allergic penicillin gonococcal (not effective against syphilis) Good for gentamycin-resistant organisms (as is amikacin)

Not ototoxic or nephrototoxic

Less ototoxic & nephrotoxoc

GI infxn Sterilization for bowel surgery Hepatic coma to reduce ammonia intoxication

Cochlear toxicity Nephrotoxic Hypersensitivity Allergic rxn Pottentiates action of NM blockers

Ophthalmic Skin Ear Mucous membranes

Nephrotoxicity severely limits use Neurotoxic – parasthesia, dizziness, ataxia Acute renal tubular necrosis

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Drug AMEBIASIS

Mechanism metronidazole

-undergoes reductive bioactivation -cytotoxic products binds protein/DNA - cell death via pyrvate, ferridoxin oxodoreductase in anaerobic infxn

Clincal Use -severe intestinal & extraintestinal amebiasis -UG trichomonas Pseudomembranous colitis Amebiasis Giardiasis Gardnerella vaginalis Anaerobic infxn – esp B. fragilis Acute ulcerative gingivitis Cancrum oris Cutaneous leishmania

Side Effects Teratogenic /carcinogenic Seizures Ataxia Disulfiram- like N/V/D Dry mouth/stomatitis Insomnia Weakness Urethral burning

Decubitis ulcers

Emetine Dehydroemetine

Diloxanide furoate

Iodoquinol

-Blocks Ribosome (prot. synth) -IM injection Narrow therapeutic range Only given in hospital Concentration: liver, spleen, kidney heart --cumulative effect

Mechanism u/k Oral Hydrolyzed in gut diloxanide -oral, - 90% absorbedconjugated inliver, urine excretion Mechanism u/k Oral

Anaerobic infxns – esp. B. Fragilis Intestinal & extra-intestinal amebiasis Balantidium coli Fasciiola hepatica Pargonimus westermani

Mebendazole

Thiabendazole

Pyrantel pamoate Oxantel pamoate

-inhibits microtubule synth -depletes helminth energy stores by decreasing glucose uptake -hi therapeutic index

Congener of mebendazole Larvicidal & ovicidal Inactivated by liver hydroxylation -excreted urine/liver

Depolarizing NM blockage block of nicotinic receptors  paralyze worm expelled from GI tract

Pain/abcess @ injxn site Urticaria/ pruritic eruption N/V/D Weakness & fatigue Disulfiram-like rxn w/ alcohol

DOC - asymptomatic carriers of cysts Moderate/severe intestinal amebiasis Alternate in asymptomatic carriers Mild-severe intestinal amebiasis

ANTIHELMINTHS Nematodes

Heart: cloudy swelling & necrosis, hypotension, CHF , arrhythmia

DOC: Nematodes

1.

Whip worm (trichuris trichuria); prolapsed rectum

2.

Pin worm (enterobius vermicularis) Eichonococcus granulosis

3. Also: Ascaris hookworm DOC: Threadworm (strongyloides) Trichinosis Larva migrans; ancylostoma (creeping eruptions; cutaneous)

DOC: Ascaris (Oxantel doesn’t work) Hookworm Enterobius infection

Potentiate coumadin Mild N/V Abd cramps Esophagitis Dry mouth urticaria Proteinuria Nephrotoxicity – high doses Optic atrophy Peripheral neuropathy N/V Thyroid enlargement Agranulocytosis GI irritation Contraindicated in pregnancy Rapid metabolization

Vertigo Crystalluria/hematuria Hypotension Note: killed parasites  fever, chills, rigors, skin rash & lymphadenopathy (like StevenJohnson syndrome) Rash & fever GI irritation H/A 42 Dizziness Weakness

Ivermectin

Other

Diethyl carbamazine

Albendazole

Piperazine Citrate Cestodes

-enhanced GABAmediated neurotransmission in nematodes (paralysis) -facilitates removal by RES -doesn’t cross BBB

DOC – onchocerciasis (river blindness) Filiarisis Strongyloidiasis Scabies

Mech u/k Violent allergic rxn (dying parasite proteins) Kills microfiliriae & adult

DOC: filiariasis (w. Bancrofti) Onchocerciasis (river blindness) – alternate drug

-Blocks glucose uptake  decreased ATP production -inhibits microtubular assembly (similar to mebendazole )

Alternate -Neurocystercosis -Echinococcus Also: Hookworm, enterobius, strongyloides, trichuris

-paralysis of worm via non-depol blockade

Alternate: -Ascaris -Enterobius DOC: T. Solium (followed by purge) t. saginata (tapeworm) Diphyllobothrium (fish tape worm, B12 def)

Niclosamide

-Inhibits oxidative phosphorylation in mitochondria -ineffective against ova present in segments -follw by purge Drug Mechanism Trematodes Praziquantel Increased permeability to ANTIHELMINTHS LevamisoleCa++ Depolarizing NM blocker -Muscular spasticity

Clincal Use DOC: schistomiasis Alternate: -Ascaris DOC cystercercosis (larval T. -Hookworm /paralysis) of worm Solium) Restores depressedT-cell fxn of: Improves of T-cell fxn in Tapeworms Vacuolization cells -RA RA death Paragonimus wetermani -Recurrent apthous stomitis Broad spectrum -herpes etc Niridazole Concentrates in the Schistosomiasis - alternate drug worm to cause glycogen depletion Anti-inflammatory effect AMEBIASIS/ANTIHELMINTHS

Metrifonate

Nifurtimox Sodium Stibogluconate (pentavalent antimony)

Organophosphate compound inhibiting actylcholinesterase

Alternate -Schistosoma hematobium -S. mansoni T. cruzi; Chaga’s disease Leishmaniasis

Lymph node nelargement & tenderne Arthralgia Hypotension tachycardia

Mazzoti rxn – acute rash post-tx (tx w/ antihistamines or steroids) -pyrexia -resp. distress -hypotension -prostration Teratogenic BM suppression Hepatitis Alopecia Contraindications: -Hepatic & renal insufficiency -Epilepsy Nausea Abd pain Pruruitis Fever Side Effects Increased rates of abortion Vasculitis Agranulocytosis H/a Proteinuria Sedation N/V Fever/Rash Carcinogenic/ teratogenic Causes hemolysis in G6PD def Psychiatric problems Pulmonary infiltration Eosinophilia Immunosuppression/anti-inflammatory Cholinergic stimulation @ hi dose

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DIABETES: Diabetes Type I (IDDM)

Diabetes Type II (NIDDM)

Mechanism

Insulin is defective or is never formed. Antibodies against pancreatic betacells.

Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed.

Survival

Insulin is absolutely required for survival.

Patient will survive without insulin

Synonyms

Ketosis-Prone Diabetes

Ketosis-Resistant Diabetes

Juvenile-Onset Diabetes

Adult-Onset Diabetes

Onset

Sudden, often discovered by ketoacidosis. Childhood polydipsia, polyphagia, polyuria.

Gradual, insidious. Often discovered incidentally, or when chronic complications arise.

Nutrition

Often thin. Failure of action of insulin.

Usually obese.

Ketoacidosis

Frequent

Seldom or never

Treatment (order of importance)

Insulin always required

Diet and exercise

Diet

Oral hypoglycemics

Never oral hypoglycemics

Insulin

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Diabetes Drug RAPID ACTING

Mechanism CZI crystalline zinc insulin

Semilente insulin

Lyspro

INTERMEDIATE

NPH insulin

Lente Insulin

PROLONGED

Ultralente Insulin

ORAL HYPOGLYCEMICS 1st generation

Tolbutamine Chlopropamide Tolazamide acetohexamide

2nd generation

Biguanidines

Glipizide Glyburide

Phenformin Metformin

Acarbose

Clincal Use

“Regular Insulin” -pork, beef, human recombinant -4 hr. peak -ONLY one IV -suspension of amorphous insulin (portk/beef) -supplement for intermediate or prolonged forms -doesn’t complex w/ zinc -very soluble & rapid acting -delayed absorption -conjugation w/ protamine (less soluble) -16 hour peak Like NPH (similar onset/duration) -Poorly soluble -Delayed onset w/ prolonged duration -peak ~20 hours -enhance pancreatic insulin -close ATP-dep K+ channels -depolarization -decrease serum glucagons concentrations

-subcutaneous -IV (emergency) -lowers blood sugar w/in minutes

-100x more potent -longer duration -shorter life

Type II (NIDDM)

Metformin – new form -NO effect on insulin production or release -enhances peripheral glucose utilization Starch blocker: inhibits alpha glucosidase -decrease starch absorption from the GI

Side Effects -hypoglycemia (poor dosing) -general insulin allergy -local fat atrophy/hypertrophy

-subcutaneous

-sub cutaneous -tx all forms of diabetes (except ketoacidosis or emergency hyperglycemia) -previously untx diabetic who requires insulin Rx

Type II (NIDDM)

Neutropenia Neuronal (tinnitus/h/a) Cutaneous lesions Chlorpropamide -enhanced ADH secretion -disulfiram-like rxn -granulocytopenia -cholestatic jaundice -photosensitivity Hypoglycemic crisis -NO agranulocytpopenia -LESS disulfiram-like rxn -fatal lactic acidosis -contraindication in prior MI or other metabolic problems

-used in fat people

Flatulence Osmotic diarrhea

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Drug STRONG AGONIST

Mechanism morphine

-hyperpolarizes nerve cells (inhibit neuronal firing & presynaptic inhibition of NT release) -Mu receptors in substantia gelatinosa decrease(Sub P release) -inhibits release of excitatory transmitters from neurons carrying pain stimuli -Liver  6-glucuronide  kidney excretion

Heroin

Meperidine (Demero l)

Methadone

Fentanyl

WEAK AGONISTS

-3x more potent than morphine -metabolized to form morphine /acetyl morphine -enters CNS better -more exaggerated euphoria K receptors -enters CNS better than morphine -metabolite (normeperidine) has extremely long t1/2 -kidney/liver dysfxn, clonus twitching & seizures

-Mu -potency = morphine -<euphoria -longer action -oral -80x potency of morphine -rapid onset, short duration -doesn’t release histamine (unlike morphine)

GOLD STANDARD -analgesia Rx’s diarrhea (decrease GI motility) -relieves cough (suppress central cough reflex) -spinal anesthesia MI, Post-op pain Pulmonary edema No medical use

Addiction Respiratory depression Vomiting Dysphoria Decreased blood volume Increases intracranial pressure Urinary retention – in hypertrophic prostate Histamine release (hypotension, sweating, itching) Addiction

Analgesia (post-op)

Less urinary retention than morphine -addictive -doesn’t cause pinpoint pupils (acts more like atropine)

Pulmonary edema -less peripheral effects

Post-op pain Heroin addiction – maintenance therapy Helps w/ heroin w/d -prevents heroin high -long duration of action Anesthetic – decreased amt. Needed -combo w/ droperidol “dissociative/ neuroleptic analgesia” -w/ dropieridol & NO “neuroleptic anesthesia” Anti diarrhetic

-

cerebral vasodilation – increase intracranial pressure (contraindicated in head injury) -stiff man phenom; need to give succinyl Choline

Very insoluble Sometimes combined w/ atropine Decreases addiction even more

Propoxyphene (nalbuphine) (darvon)

-derivative of methadone -similar to morphine/ codeine -only oral -weaker

Analgesia Anti-tussive (cough)

Constipation Respiratory depression Convulsions Hallucinations Confusion -magnified w/ alcohol/CNS depressants -high dose causes psychotic episodes

Methylmorphine

Cough

Itching

less potent than morphine w/ higher oral efficacy

Analgesia

Dextromethorp han Pentazocine

Buprenorphine

OPIOID ANTAGONIST

Diacetyl-morphine

Side Effects

Diphenoxylate Loperamide

Codeine

MIXED ACTION

-opioid receptor in CNS & GI

Clincal Use

Naloxone

Naltrexone

-low abuse potential -less euphoria -replaced cough in cough -most non-prescription cough meds Partial agonist of k receptors -weak agonst to m & d -spinal chord to promote analgesia -preciptate w/d if user is addict -binds PCP site also

-partial agonist @ mu -antagonize morphine -long duration of action Rapidly displaces all receptor bound opioid molecules -enables reversal of heroin overdose -competitive antagonist of mu, k, receptors Similar to naloxone -longer duration of action

Very little addiction b/c lack of solubility

Cough (OTC)

Non-addictive

Analgesia – chronic severe pain -given w/ naloxone – if used orally, then naloxone is destroyed but if injected will induce w/d sx in abuser

Respiratory depression Constipation Nightmares Tachycardia Dizziness

Reverse coma & respiratory depression of opioid overdose -decreases pain tolerance -blocks analgesic effect of placebo -blocks stress-produced analgesia

Precipitates w/d sx in morphine & heroin users

Used in opioid-dependence maintenance programs(not as good as methadone) -now used to reduce alcohol craving (fairly successful)

46

Drug ENDOCRINE Growth Hormones

Prolactin

THYROID

Thioamides

Mechanism Octreotide

Bromocriptine

Iodide

Propylthiouracil (PTU) Methimazole (US) Carbimazole (EUR) -pro-drug for methimazole

Propranolol

Somatostatin analog that modulates neurotrans-more selective for GH over insulin

DA receptor agonist -D1 antagonist, D2 agonist -1st pass

-inhibit Thyroid hormone release -rapid onset, but short duration

Peroxidase inhibitor Iodide ===X==>iodine PTU: -protein bound, used in pregnancy, avoid in lactation -inhibits T4-T3 conversion Methimazole – 10 hr. t ½ , not protein bound, doesn’t affect T4-T3 conversion Beta blocker. -blocks sympathomimetic manifestations -may reduce peripheral T4 T3

Clinical Use 1. Acromegaly 2. TSH/ACTH secreting tumors 3. Islet cell tumors including those secreting: VIP, glucagons 4. Carcinoid 5. GI; variceal bleeding -DOC: M & F Hyperprolactinemia -Parkinson’s Disease -Breast engorgement (after abortion) -Excess GH (octreotide better) Presurgery – firm gland Problems: delay radioiodine tx, action of thioamides PTU-1st drug in emergencies “thydoid storm” Hyperthroidism PTU is highly protein bound vs. methimazole which is not

-Hyperthyroidism – tx’s sx

Side Effects -Nausea, cramps, diarrhea -low glucose tolerance -fat malabsorption -flatulence -gall stones (w/ long term therapy) -Cold induced digital vasospasm(at higher doses) -nausea, constipation -orthostatic hypotension -neuropsychiatric prob’s -angioedema -larynx swelling, hemorrhage serum sickness -Agranulocytosis -Rash -jt. Pain/stiffness -parasthesia -h/a -hair pigment loss

See autonomics

47

Prednisone Has extremely Has low anti-inflammatory action with Samedisease as above Same as above ADRENALlow anti-inflammoatory -Addison’s -Cushing syndrome Intermediate Hydrocortisone Prednisolone and mineralocorticoid extremely low mineralcorticoid action. CORTICO(Cortisol) potentices. -Replacement therapy for -Diabetogenic action TriamcinoloneDuration Duration of is action 12-36 hours. secondary or tertiary STEROIDS of action 8-12 is hours. -Protein catabolism with Triamcinolone is not administered I.V. Orally, i.m. or i.v. Higher excretion of adrenocortical insufficiency sketetal atrophy Long Acting Betamethasone placenta -Relieve inflammation, -masks symptoms Short Acting Ca and -crosses poor intestinal absorption. -Congenital adrenal hyperplasia -Perforation of ulcers Dexamethasone -used for fetal lung maturation (RDS) hypersensitivity (RA, -cushing’s syndrome etc… -Immunosuppression -Osteroporosis (betamethasone) osteroarthritis, skin see cortisol -Cancer -Cardiovascular inflammation) -CNS-psychosis -Diagnosis of Cushing’s syn. -Fluid retention (HPT, CHF) (Dexamethasone Suppression-Cataracts& Glaucoma Test) Beclomethasone -inhalers Asthma - inhalation Budesonide -hi first pass (no adrenal suppression) -large anti-inflammatory w/ no mineralcorticoid action. Steroid synth Aminoglutethimide -Chol-pregnenolone conversion -estrogen-dep breast cancer GI & Neurological side inhibitor blocked (cyt P450) effects -aromatase blocked rash -inhibits all sterid synth Ketokonazole -inhibits P450 -hepatic dysfunction Diethystilbestrol Very potent&effective synthetic Same as above. Associated w/ vaginal (DES) steroid. Has less first pass -Prostatic carcinoma (clear cell) carcinoma in metabolism. -Prevent abortion daughters of mothers who took it during pregnancy ESTROGENS Estrone -excreted as glucuronides -replacement -Nausea, breast tenderness Estriol -pregnancy – made in placenta -contraception -vascular: -puberty, secondary sexual charact., -menopause – hot flash, thrombophlebitis, embolism reproductive cycle, brain development vaginitis -cholestatic jaundice -suppress FSH preventing ovulation -osteoporosis -postmenopausal bleeding -hyperpigmentation -hypertension -depression

ANTI-ESTROGENS

Clomiphene

-antagonist -pituitary/hypothalamus -blocks (-) feedback on GnRH/FSH increased FSH release (follicular stimulation)

Infertility assoc. w/ anovulatory cycles

Cancer: -increased endometrial (prevented by concomitant progestin) -Ovarian enlargement (Reversible))

48

Tamoxifen

-estrogen receptor partial agonist -prevent/treat breast ca

-estrogen-dependent tumor cells

-secretory phase of menstrual cycle -suppress LH & prevent luteal changes

-supposedly better @ prophylaxis in postmenopausal osteoporosis -Contraceptive component -Anovulation/oligoovulation; induces bleeding

Raloxifene

PROGESTINS

CONTRACEPTIVES

Progestin

Ethinyl estradiol Norethindrone

-cause same effect as pregnancy -derivatives of estrogen

-Weight gain -Hair growth -Depression, fatigue -Early or mid-cycle bleeding Long-term: -same effects as pregnancy -increase T4 binding, HT, throbosis Other: -Nausea, breast tenderness, edema -mid-cycle spot bleeding (decrease estr & increase Prog) -wt. gain, hair growth, depression (decrease prog) -excess bleeding in late cycle (increase Prog, decrease Estr)

ANTI-PROGESTINS

CALCIUM REGULATING

Mifeprostone (RU-486)

Calcifediol (25OH) Calcitrol (1,25 OH)

Calcitonin

Glucocorticoids

Estrogens

Binds to (antagonizes) the cytoplasmic progestin receptor-lose support for the conceptus & lose inhibition of uterine contractions; also blocks glucocorticoid actions. Calcifediol -kidney & skeletal muscle. Calcitrol - GI & bone -forms of Vit D. -Calcitriol - most potent - high Ca transport across the brush border membranes - enhance Ca resorption from the kidney -parafollicular -decreases renal Ca++/PO4resorption & bone -decreases serum Ca++ -antagonize Vit D stimulated GI absorption -prevent bone resorption Prevent bone loss after menopause. Probably antagonists of PTH.

-Abortions -Cushing’s disease (NEW therapy b/c of its antiglucocorticoid action)

-Paget’s disease -Osteoporosis -Hypercalcemia

-Uterine bleeding -Possibility of incomplete abortion

No significant effects -Nausea -Hypersensitivity

-Intermediate Rx of hypercalcemia due to sarcoidosis, lymphoma, myeloma, D-hypervitaminosis -Prevent osteoporosis (no enhancement of bone formation)

49

Raloxifene

Diphosphonates (Etidronate & Pamidronate) Mithramycin

Gallium Nitrate

MINERALCORTICOIDS

INHIBITORS OF STEROID BIOSYN

Fluoride Fludrocortisone Deoxycorticosterone

Metyrapone

Ketoconazole

Aminoglutethimide

GONADO-TROPINS & SEX STEROIDS

GnRH (gonadorelin)

FSH/LH Preparations

Menotropin HCG HMG Urofillotropin

-estrogen agonist in bone -antagonist in uterus/breast -Retard the formation and dissolution of hydroxyapatite crystals in bone -Inhibits osteoclastic activity -DNA-binding cytostatic drug (intereferes w/ osteoclasts) -1/10 cytotoxic dose -inhibit bone resorption (decrease hydroxyapatite solubility) -Stablizes hydroxyapatite crystals -Very potent -Act similar to aldosterone in the kidney -Deoxycorticosterone is the precursor to aldosterone Inhibits 11-hydroxylation (final step in cortisol synthesis & the synthesis of corticosterone—the precursor of aldosterone Anti-fungal, strongly inhibits gonadol & adrenal steroid synthesis at high conc. Blocks the first step (cholestrolpregnenolone) of glucocorticoid synthesis. ALL adrenal steroid synthesis is suppressed

Stimulate the pituitary release of & FSH. Must be in given in pulsatile fashion to be therapeutic. If given in constant dosing, you get desensitization FSH & LH like actions. Menotropin is derived from the urine of postmenopausal women; it contains a mixture of FSH & LH.

New -have to see what fracture rate is -Hypercalcemia -Osteroporosis -Paget’s disease -Hypercalcemia due to malignancies -ca (osteoporosis, pagets)

-Osteomalacia -Hypophosphatemia -High Arthralgia Since it’s given in such low doses, no real effects nephrotoxic

Osteroporosis

-Cushing’s Syndrome -Tests adrenal cortex function -Ectopic ACTH syndrome -Adrenal syndrome -Cushing’s -Testicular Cancer, anti-fungal

-Water retention -Hirsutism -Transient citizens -GI disturbances

-Cushing’s -Breast Cancer (low estrogens and androgens) **Must be used in combo w/ dexamethasone -Adrenal Cortex tumors -Hypogonadism or delayed puberty, infertility -Cryptochidism -Endometriosis -Hypothalamic ammenorrhea -Female infertility (IVF); normally given in combo w/ GnRH or Clomiphen -pituitary insufficiency -cryptorchidism

Urofillotropin: -only FSH (from pregnant women)

-Multiple pregnancy -Ovarian Hyperstimmulation Syndrome: Massive ovarian enlargement, vascular fluid into the peritoneum, hypovolemia, ascites, death

HCG: -LH-like

Leuprolide

Estradiol Estriol Estrone

HMG: -postmenopausal urine -slow release -suppress FSH/LH (estrogen & testosterone) Naturally occurring steroids. High first pass metabolism. Given IM.

Prostate Cancer

-Post menopausal therapy (osteroporosis & hot flashes) -Development of secondary characteristics

-Vascular (thrombophlebitis, pulmonary embolism) -Nausea

50

-Breast cancer -Contraception

-Cholestatic jaundice -Depression -Breast tenderness -Post-menopausal bleeding -Hyperpigmentation -Hypertension

51

EPILEPSY DRUGS Drug EPILEPSY Decrease Na+ current

Phenytoin

Carbamazepine

Valproate

Lamotrigine Chloride current increase Barbituates

Phenobarbital

Primidone

Mechanism -alters ionic flux (Na, K, Ca) -membrane stabilizing -prevents spread of discharge -shifts from 1st to 0 order

-related to TCA -antimuscarinic effects -enzyme inducer

Psychomotor, grand mal Trigeminal neuralgia Psychosis (alternative to Li+)

-blocks Na & “T” channel -blocks PTZ seizure better than ECT -plasma protein-bound (inhibits met of phenytoin, phenobarbitone, lamotrigine) -Na+ channel blocker

-petit mal -2nd choice grand mal -akinetic epilepsy

-blocks PTZ (little sedation)

clorazepate Vigabatrin

Tigabine “T” Ca++ blockers

Valproate

Ethosuximide

-structural similar to GABA -irreversible inhibition GABA transaminase -increases GABA concentration -DOES NOT INDUCE MICROSOME -inhibits reuptake of GABA -used in partial seizure -blocks PTZ seizure -potentiates GABA -competes for phenytoin, phenobarb, lamotrigine protein-bindings sites -antagonize PTZ

Side Effects Gingival hyperplasia Hirsutism, coarsening facial feat. Megaloblastic anemia Osteomalia (increased Vit. D metabolism -interfere w/ Ca++ metabolism) Pregnancy – fetal hydantoin (cleft palate, microcephaly, hypoplastic phalanges) -hyponatremia -H2O retention enhancing effect of ADH on DCT -Neurotoxic -Hypersensitivity – photosensitivity, lupus, agranulocytosis -neural tube defect -fulminant hepatitis (<3 yo)

-partial seizures

-too sedative -anticonvulsant -long t ½ (less addictive) -alkalinization of urine -microsomal inducer -prodrug (deoxybarbituate ==> phenobarbitone + phenylethyl malonamide (PEMA))

Benzodiazepine

Clonazepam

Clinical Use Grand-mal Partial Status epilepticus (IV) 2nd choice – trigeminal neuralgia(1st carbamazepine) digitalis-induced arrhythmia

-increased porphyrin synth (genetically susceptible) CI: liver, kidney diseases, pulmonary insufficiency -same as phenobarb

-short-term tx for epilepsy (sedation) -DOC – emergency - convulsion, status epilepticus, tetanus, eclampsia, convulsant poisoning -Petit mal -adjuvant in myoclonic & akinetic epilepsy Partial seizure

Thrombophlebitis Drop in BP Resp. depression

Tolerance – <6 mths

Toxic metabolite: -hepatic biotransformation ==>fulminant hepatitis - absence seizures

GI intolerance Neurological:

52

Excitatory transmittor blocker

Felbamate

-blocks glutamate

-intractable partial seizure

Gabapentin

-GABA analog

-~GABA

Topiramate

-enhance GABA -weak block of glutamate -voltage sensitive Na+ channels

Partial seizures

CA inhibitor -produces acidosis

Absence

-tiredness agitation, mood change drowsiness -aplastic anemia -hepatotoxicity -sedation -behavior change in children -movement disorders -sedation -mental dulling -renal stones -wt. loss parasthesia -rapid tolerance

-useful in refractory cases

Sedation

Acetazolamide Bromide CHOICE OF ANTICONVULSANT

Phenytoin Carbamazepine Valproate

Generalized tonic clonic (grand mal) Absence (petit mal)

Ethosuximide Carbamazepine

Partial-complex

Phenytoin Valproate Vigabatrine Valproate

Akinetic

Primodone Clonazepam Diazepam

Febrile seizure

Phenobarbitone Diazepam Phenytoin phenobarbitone

53

ALCOHOL Drug ALCOHOLS

ETOH

Mechanism -absorbed same as H2O -some metabolization in gut -mostly in liver -minor elimination via lungs -Alcohol dehydrogenase – NAD-dep – ==> acetaldehyde + antabuse + NAD ==> acetic acid -MEOS (microsome ETOH Oxidizing System) – mitochondria in liver -NADH shuttles pyruvate from glucose (hypoglycemia)

Clinical Use -decrease fever -nerve block -antiseptic -solvent -may facilitate GABA Withdrawal: -physical dep . / DT’s -Tx – diazepam w/ tapering -acute – glucose, thiamin -antabuse – induces disulfiram rxn also, metronidazole, fulfas, griseofulvin, cephalosporin, phenylbutazone, phenothiazine -Naltrexone – opioid antagonist – prevents craving

Methanol

Ethylene Glycol

-competes w/ alcohol dehydrogenase for elimination

-also uses alcohol dehydrogenase -oxalic acid is elimination by-product

Substitue for ETOH by alcoholics Toxicity – give ETOH w/ dialysis Toxicity – ETOH

Side Effects -all the good/bad CNS effects -hypoglycemia -hyperuricemia -relaxes uterine SM -vasodilation ==> hypothermia -decreased cardiac contractility -diuresis Chronic Liver – fatty ==> cirrhosis GI – gastritis, nutritional defects CVS/blood – HPT, MI, cardiomyopathy -poor immune response -increase brca P450 induction – testicular feminization gynecomastia, impotence, sterility CNS – polyneuritis, Wernicke’s, Korsakoff’s (Thiamine tx) Fetus – teratogenic, retard, growth def Visual dysfxn GI distress Coma Acidosis - death Renal damage/death

54

• Drug THROMBOLYTIC AGENTS

Streptokinase

Urokinase TPA ANTI-PLATELET

Aspirin

ANTICOAGULANT

Dipyridamole Heparin

Mechanism Bacterial culture Generates plasmin Human kidney cells Generates plasmin Recombinant Generates plasmin Inhibits TXA2 Increases bleeding time Prevent thrombosis on artificial valves Activates antithrombin III Anti-thrombin inactivates IX, X, XI, XII Parenteral Renal excretion Doesn’t cross BBB or placenta Immediate action

Clinical Use DVT PE Coronary throbus Same Same

Can be used in pregnancy Long-acting Antidote: Protamine

A mucopolysaccharide

Warfarin

Vit. K SYNTH. ANALOG Phytonadione Menadione menadiol

Side Effects

Vit. K-dep. Clotting factors – II, VII, IX, X Lipid soluble – oral Secreted in milk Protein-bound

CI in pregnancy Prophylaxis use

Causes synth. of clotting factors

For Warfarin overdose & newborns

Antidote:give fresh plasma / Vit. K

Menadione – H2O soluble

Bleeding  1st sign hematuria Suppress aldosterone Hypersensitivity Osteoporosis Reversible alopecia Thrombocytopenia B SHORT CI: Bleeding disorder Ulcer, hemorrhoid, threatened abortion Surgery Aspirin or antiplatelets -GI Bleed -Petechiae -Adrenal insufficiency -Low Therapeutic index – drug interactions -Pregnancy B PAL CI: Synthetic analogs Hemolysis – G6PD Kernicterus – newborn (hyperbilirubinemia) Deficiency -decrease prothrombin/ clotting factors -ecchymoses, bleeding

PRO-CLOTTING

VIII IX Tranexamic acid Aminocaproic acid

Antihemophilic Globulin

Hemophilia A From dried human plasma Has several Vit. K-dep. factors Inhibit conversion of plasminogen to plasmin

Hemophilia B (Christmas)

Post-tPA , urokinase, streptokinase i.e. bleeding due to fibrinolysis hemophiliacs

55

OTHER

Thrombin

Clots fibrinogen

Protamine

Heparin antagonist From fish sperm

Topical hemostat (capillary bleeding)

56