Drug ANTIFUNGAL Amphotericin B

Mechanism

Clincal Use

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

-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 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 Vulvovaginal candidiasis Trichophyton Dermatophytes - Superficial -Microsporum -Epidermophyton -Trichophyton

Flucytosine

Nystatin (topical)

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

IMIDAZOLES

Ketaconazole (itraconazole )

-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 Stevens-Johnsons syndrome bullous erythema formae -Thrombocytopenia in AIDS pt. -Co-administration w/ phenytoin, sulfonylurea, warfarin cyclosporin increases plasma concentration

Fluconazole

Clotrimazole

Econazole Miconazole (monistat)

Water-soluble cream Dermatological & vaginal cream

Local erythema Burning/itching

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

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

29

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

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

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

Side Effects -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)

Acyclovir

Gancyclovir

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

Trifluoridine idoxuridine cytarabine

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

-reversible neutropenia -thrombocytpenia -renal dysfxn -seizures Ocular irritation Edema Photophobia Pain Systemically -Bone marrow suppression -renal damage

Vidarabine

-adenosine analog -inhibits DNA pol -topical or systemic

GI irritation Hepatic dysfxn Convulsions

Azidothymidi ne (AZT)

-Phosphorylated inhibits RT -terminates DNA synth/replication -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 -synthetic guanosine analog -inhibits viral coded RNA Pol (inhibits viral mRNA synth)

Interferons

-Herpes zoster -HBV -Kaposis 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

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

Foscarnet

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

Ribavirin

30

LATE PROTEIN/ VIRAL ASSEMBLY

Methisazone

-late structural protein synthesis inhibition -

-small pox (eradicated)

PROTEASE INHIBITORS

DDC (dideoxycytosine ) Saquinovir indinovir ritinovir

-Converted to ddCTP -Alters DNA synth -Blocks aspartate proteinase to prevent cleavage of gag-pol precursor protein -Blocks packaging & assembly

AZT-resistant HIV

Peripheral neuritis

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

31

o
Gaseous Anesthetics Drug type Inhaled anesthetics Drug Nitrous oxide 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 MAC 1.68 -Rapid onset & recovery MAC .75 -Resp. & CV depression -Vasodilation relaxing SM (uterine) -Increase intracranial pressure MAC.16 -Excellent skeletal muscle relaxation -Slow onset & awakening Clinical Use Potent analgesic!!!! No anesthetic Give w/ 20% O2 Side Effects -Safest -Diffusional hypoxia -Vit B12 def. -2nd gas effect (enhance solubility of 2nd) -Little muscle relaxant Bronchial irritation

Desflurane

Ambulatory surgery

Isoflurane Enflurane

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

Irritating SEIZURE (assoc. w/ hypercarbia) Malignant hyperthermia Renal toxicity (fluoride ion) <Hepatotoxic Hepatotoxicity Lo threshold for catecholamineinduced arrhythmia MALIGNANT HYPERTHERMIA Carcinogenic Increased risk of miscarriage -Metabolism releases fluoride (RENAL DAMAGE)

Halothane

Pediatric anesthetic not hepatotoxic to kids

Methoxymethane

-Reserved for OB -Most potent inhalant

32

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 its closed state). Drug Tubocurarie A Gallamine c Pancuronium t i n g ( 1 . 5 h r s ) Medium Atracurium A c t Vecurium i n g ( 3 0 m i n ) Very S h o r t Succinylcholine Depolarizing Intubations Muscle soreness Malignant Hyperthermia Nondepolarizing Short surgical procedure Vent patients (long term) Safe for organ failure due to nonenzymantic metabolism Toxic metabolite will build up with long-term infusion in pts with organ failure. Mechanism Nondepolarizing Nondepolarizing Nondepolarizing Clinical Use Muscle parplysis Muscle parplysis Muscle parplysis Adverse Effects Histamine release Vagal Blockade Indirect sympathomimetic effect

Duration Long

33

Mivacurium

Nondepolarizing

Not used due to favor of succinylcholine

34

35

Nitrosurias Drug CANCER THERAPY Alkalating Agents Methane sulfona tes Other

Carmustine Lomustine Mechlorethamine

Busulfam

Cisplatin Cyclophosphamide Chlorambucil

Carboplatin

Liphophilic (BBB-CNS Mechanism 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) -Dihydrofolate reductase inhibition -Decrease THF -Inhibit conversion of dUMP to TMP -Hi doeses 7-OH crystaluria -CSF only Hi doses Leucovorin Rescue

-Malignant glioma Cancer therapy Brain cancers Hodgkins disease Solid tumors -CML

Clincal Use

Delayed hematopoietic dep. Side Effects 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 Lo50%--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

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

Same as platin

ANTI-

METAB OLITE INHIB ITORS S-phase specific

Methotrexate (W/ leukovorin)

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

-Pyrimidine analog that interferes w/ conversion of deoxuyurdylic acid thymic acid -F-dUMP competes w/ dUMP (thymidilate synthetase) Arabinosyl Pyrimidine TMP & -Decreasesantagonist MITOTIC Vincristine -Microtubule assembly Cytidine ara-CTP competitive inhibits DNA synthesis INHI (oncovin) inhibitor (Cytarabine/ARA- Purine analogDNA Pol inhibitor for 6-mercaptopurine BITO vinblastin -Blocks mitosis C) -Chain terminationby activated upon RS e M-phase specific incorporation HGPRT (Vinca alkaloids) ANTIBIOTICS Adriamycin Broadest -Inhibits antitumor (doxorubic amidotransferase spectrum Paclitaxel (Taxol) M-phase spec. in) -Competitive -Blocks Hyperstablizes substrate/DNA IMPAMP/GMP pol microtubule inhibitor -CAREFUL allopurinol -INTERCALATION (xanthine oxidase) topoisomerse inhibits drug II interference metabolismtoxic 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

5-fluorauracil

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 ALLmaintain remissions Vinblastine testicular ca((now etoposide preferred), (bleomycin & cisplatin), lymphomas, Kaposis, breast Solid tumors Resistance: export (P-glycoprotein) ALL & granulocytic leukemias Breast ca Hodgkins Ovarian ca, Kaposis 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

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

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

Childhood tumors

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

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 Pro-drug -Precursor for mercaptopurine -Actively dividing cells -Amidotransferase inhibition (IMPAMP/GMP) -Incorporated into DNA Particularly active against lymphoid cells -See cancer chemotherapy -2nd line to azothioprine -Hi dose tolerance to new antigen Interferes w/ early antigen response -Inhibits T-helper cells -Inhibits calmodulin, Il2, -Cyt P450 Autoimmune disease Renal transplants **Caution allopurinol toxicity

Adrenal suppression Growth inhibition Decreased muscle tone Osteoporosis Cushings syndrome Immune suppression

IMMUNOSUPPRESSIVES

Azothioprine

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

Methotrexate

Prophylaxis against G vs. H in BMT Severe RA Psoriasis 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 Liver transplant -Rescue in other organ transplants

Cyclophosphamide

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

Cyclosporin A

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

FK509 (tacrolimus)

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

-Antibodies

Antilymphocyte Globin

Rxn against T-cell (poly or monoclonal)

Anti-OKT-3 (Muromonab-CD3) Mycophenotate

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

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

37

38

Mechanism Isoniazid (INH) -inhibits synthesis of mycolic acid -intracellular/ extracellular organisms -acetylated -affects synth. Of lipids/ nucleic acids -inhibits DNA-dep RNA pol -decreaase RNA synth -CNS penetration -prokaryocytes -red/orange urine, sweat, tears etc. Mechanism u/k

Clincal Use -bacteriostatic/ -cidal TB- resistance if used alone M. Kanasii Prophylactically given alone Bacteriocidal -TB -atypical mycobacteria -M. Leprae in combo -meningitis prophylactic (h. influenza, N. Meningitidis) Bacteriostatic -TB, M. kansasii -atypical mycobacteria Bacteriocidal TB

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

Rifampin

Ethambutol

Second line drugs

Pyrazinamide

Mech u/k

Streptomycin Ethionamide

30s inhibitor -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 Phenazine dye binds to DNA to inhibit template fxn

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

LEPROSY

Para-amino salicylic acid (PAS) Cycloserine

2nd line for TB/atypical mycobacteria -nocardia infection if sulfas fail -renal TB 70% excreted in urine

Dapsone

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

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

Clofazimine

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

Amithiozone

Alternate drug to dapsone Thiosemicarbazone

39

Tissue schozont icide

Drug Blood schizonticide

Primaquine

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 3. Secondary Vivax, Ovale Mechanism (oxidation/ Clincal Use 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

40

Aminoglycosides Drug AMINOGLYCOSIDES Gentamycin Amikacin Tobramycin Mechanism -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 AEROBIC ONLY Gram E. Coli Proteus Klebsiella Serratia Pseudomonase Enterobacteriaceae TB (streptomycin) Side Effects Ototoxic (vestibular & cochlear) Nephrotoxic NM blockade Hypersensitivity rxns Superinfxn

Streptomycin

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

Optic nerve dysfxn

Spectinomyci n

Very limited spectrum

Not ototoxic or nephrototoxic

Netilmycin

Neomycin (topical) (paramomycin ) (kanamycin)

POLYMYXINS

Polymixin B, E (Colistin)

-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

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

Ophthalmic Skin Ear Mucous membranes

41

Drug AMEBIASIS metronidazole

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

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

Emetine Dehydroemetine

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

Heart: cloudy swelling & necrosis, hypotension, CHF , arrhythmia Pain/abcess @ injxn site Urticaria/ pruritic eruption N/V/D Weakness & fatigue Disulfiram-like rxn w/ alcohol 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

Diloxanide furoate

Iodoquinol

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

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

ANTIHELMINTHS Nematodes

Mebendazole

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

DOC: Nematodes

1. 2.

Whip worm (trichuris trichuria); prolapsed rectum Pin worm (enterobius vermicularis) Eichonococcus granulosis

Thiabendazole

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

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

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

Pyrantel pamoate Oxantel pamoate

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

DOC: Ascaris (Oxantel doesnt work) Hookworm Enterobius infection

Ivermectin

-enhanced GABAmediated neurotransmission in nematodes (paralysis) -facilitates removal by RES -doesnt cross BBB

DOC onchocerciasis (river blindness) Filiarisis Strongyloidiasis Scabies

Lymph node nelargement & tenderne Arthralgia Hypotension tachycardia

Other

Diethyl carbamazine

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

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

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

Albendazole

-Blocks glucose uptake decreased ATP production -inhibits microtubular assembly (similar to mebendazole ) -paralysis of worm via non-depol blockade

Alternate -Neurocystercosis -Echinococcus Also: Hookworm, enterobius, strongyloides, trichuris Alternate: -Ascaris -Enterobius DOC: T. Solium (followed by purge) t. saginata (tapeworm) Diphyllobothrium (fish tape worm, B12 def)

Piperazine Citrate Cestodes Niclosamide

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

Clincal Use DOC: schistomiasis Alternate: -Ascaris DOC cystercercosis (larval T. -Hookworm /paralysis) of worm Solium) Restores Improves T-cell fxn Vacuolization of cells in Tapeworms depressedT-cell fxn of: -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

Organophosphate compound inhibiting actylcholinesterase

Nifurtimox Sodium Stibogluconate (pentavalent antimony)

Alternate -Schistosoma hematobium -S. mansoni T. cruzi; Chagas disease Leishmaniasis

43

DIABETES: Diabetes Type I (IDDM) Mechanism Insulin is defective or is never formed. Antibodies against pancreatic betacells. Insulin is absolutely required for survival. Ketosis-Prone Diabetes Juvenile-Onset Diabetes Onset Sudden, often discovered by ketoacidosis. Childhood polydipsia, polyphagia, polyuria. Often thin. Failure of action of insulin. Frequent Insulin always required Diet Never oral hypoglycemics Diabetes Type II (NIDDM) Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed. Patient will survive without insulin Ketosis-Resistant Diabetes Adult-Onset Diabetes Gradual, insidious. Often discovered incidentally, or when chronic complications arise. Usually obese. Seldom or never Diet and exercise Oral hypoglycemics Insulin

Survival Synonyms

Nutrition Ketoacidosis Treatment (order of importance)

44

Diabetes
Drug RAPID ACTING CZI crystalline zinc insulin Mechanism Regular Insulin -pork, beef, human recombinant -4 hr. peak -ONLY one IV -suspension of amorphous insulin (portk/beef) -supplement for intermediate or prolonged forms -doesnt 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 Clincal Use -subcutaneous -IV (emergency) -lowers blood sugar w/in minutes Side Effects -hypoglycemia (poor dosing) -general insulin allergy -local fat atrophy/hypertrophy

Semilente insulin

-subcutaneous

Lyspro

INTERMEDIATE

NPH insulin

Lente Insulin

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

PROLONGED

Ultralente Insulin

ORAL HYPOGLYCEMICS 1st generation

Tolbutamine Chlopropamide Tolazamide acetohexamide

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

2nd generation

Glipizide Glyburide

-100x more potent -longer duration -shorter life 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

Type II (NIDDM)

Biguanidines

Phenformin Metformin

Acarbose

-used in fat people

Flatulence Osmotic diarrhea

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Drug STRONG AGONIST morphine

Mechanism -opioid receptor in CNS & GI

-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

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

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

Heroin

Diacetyl-morphine -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

Meperidine (Demero l)

Analgesia (post-op) Pulmonary edema -less peripheral effects

Less urinary retention than morphine -addictive -doesnt cause pinpoint pupils (acts more like atropine)

Methadone

-Mu -potency = morphine -<euphoria -longer action -oral -80x potency of morphine -rapid onset, short duration -doesnt release histamine (unlike morphine)
Very insoluble Sometimes combined w/ atropine Decreases addiction even more

Fentanyl

Diphenoxylate Loperamide WEAK AGONISTS Propoxyphene (nalbuphine) (darvon)

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 Analgesia Anti-tussive (cough)

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

Very little addiction b/c lack of solubility

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

-derivative of methadone -similar to morphine/ codeine -only oral -weaker Methylmorphine less potent than morphine w/ higher oral efficacy -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

Codeine

Cough Analgesia

Itching

Dextromethorp han MIXED ACTION Pentazocine

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

Buprenorphine

OPIOID ANTAGONIST

Naloxone

Naltrexone

-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

Reverse coma & respiratory depression of opioid overdose -decreases pain tolerance -blocks analgesic effect of placebo -blocks stress-produced analgesia Used in opioid-dependence maintenance programs(not as good as methadone) -now used to reduce alcohol craving (fairly successful)

Precipitates w/d sx in morphine & heroin users

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Drug ENDOCRINE Growth Hormones Octreotide

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

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 -Parkinsons 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

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 probs -angioedema -larynx swelling, hemorrhage serum sickness -Agranulocytosis -Rash -jt. Pain/stiffness -parasthesia -h/a -hair pigment loss

Prolactin

Bromocriptine

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

THYROID

Iodide

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

Thioamides

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

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

Propranolol

-Hyperthyroidism txs sx

See autonomics

47

Prednisone Has low low anti-inflammoatory Same as above ADRENAL-Addisons as above -Cushing syndrome Intermediate Hydrocortisone Has extremely anti-inflammatory action with Samedisease Prednisolone and mineralocorticoid mineralcorticoid action. extremely low potentices. CORTICO(Cortisol) -Replacement therapy for -Diabetogenic action Triamcinolone Duration of action hours. STEROIDS Duration of action is 8-12 is 12-36 hours. secondary or tertiary -Protein catabolism with Orally, Triamcinolone is not administered I.V. i.m. or i.v. Higher excretion of adrenocortical insufficiency sketetal atrophy Long Acting Betamethasone and -crosses placenta -Relieve inflammation, -masks of ulcers Short Acting Ca poor intestinal absorption. -Congenital adrenal hyperplasia -Perforation symptoms Dexamethasone -used for fetal lung maturation (RDS) hypersensitivity (RA, -cushings -Immunosuppression -Osteroporosis syndrome etc (betamethasone) osteroarthritis, skin see cortisol -Cancer -Cardiovascular inflammation) -CNS-psychosis -Diagnosis of Cushings 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 Cancer: -increased endometrial (prevented by concomitant progestin) -Ovarian enlargement (Reversible))

ANTI-ESTROGENS

Clomiphene

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

Infertility assoc. w/ anovulatory cycles

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Tamoxifen

-estrogen receptor partial agonist -prevent/treat breast ca

-estrogen-dependent tumor cells

Raloxifene

PROGESTINS

Progestin

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

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

CONTRACEPTIVES

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) -Uterine bleeding -Possibility of incomplete abortion

ANTI-PROGESTINS

Mifeprostone (RU-486)

CALCIUM REGULATING

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

Calcitonin

Glucocorticoids

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 -Cushings disease (NEW therapy b/c of its antiglucocorticoid action)

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

No significant effects -Nausea -Hypersensitivity

Estrogens

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Raloxifene

-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 corticosteronethe 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

Diphosphonates (Etidronate & Pamidronate) Mithramycin

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

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

Gallium Nitrate Fluoride Fludrocortisone Deoxycorticosterone

MINERALCORTICOIDS

INHIBITORS OF STEROID BIOSYN

Metyrapone

Ketoconazole

-Cushings Syndrome -Tests adrenal cortex function -Ectopic ACTH syndrome -Adrenal syndrome -Cushings -Testicular Cancer, anti-fungal -Cushings -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

-Water retention -Hirsutism -Transient citizens -GI disturbances

Aminoglutethimide

GONADO-TROPINS & SEX STEROIDS

GnRH (gonadorelin)

FSH/LH Preparations

Menotropin HCG HMG Urofillotropin

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. Urofillotropin: -only FSH (from pregnant women) HCG: -LH-like HMG: -postmenopausal urine -slow release -suppress FSH/LH (estrogen & testosterone) Naturally occurring steroids. High first pass metabolism. Given IM.

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

Leuprolide

Prostate Cancer

Estradiol Estriol Estrone

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

-Vascular (thrombophlebitis, pulmonary embolism) -Nausea

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-Breast cancer -Contraception

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

51

EPILEPSY DRUGS Drug EPILEPSY Decrease Na+ current Phenytoin Mechanism -alters ionic flux (Na, K, Ca) -membrane stabilizing -prevents spread of discharge -shifts from 1st to 0 order Clinical Use Grand-mal Partial Status epilepticus (IV) 2nd choice trigeminal neuralgia(1st carbamazepine) digitalis-induced arrhythmia 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)

Carbamazepine

-related to TCA -antimuscarinic effects -enzyme inducer

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

Valproate

Lamotrigine Chloride current increase Barbituates Phenobarbital

-blocks Na & T channel -blocks PTZ seizure better than ECT -plasma protein-bound (inhibits met of phenytoin, phenobarbitone, lamotrigine) -Na+ channel blocker -too sedative -anticonvulsant -long t (less addictive) -alkalinization of urine -microsomal inducer -prodrug (deoxybarbituate ==> phenobarbitone + phenylethyl malonamide (PEMA))

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

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

Primidone

Benzodiazepine

Clonazepam clorazepate Vigabatrin

-blocks PTZ (little sedation)

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

-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:

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Excitatory transmittor blocker

Felbamate Gabapentin

-blocks glutamate -GABA analog

-intractable partial seizure -~GABA

Topiramate

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

Partial seizures

Acetazolamide Bromide CHOICE OF ANTICONVULSANT Phenytoin Carbamazepine Valproate Ethosuximide Carbamazepine Phenytoin Valproate Vigabatrine Valproate Primodone Clonazepam Diazepam Phenobarbitone Diazepam Phenytoin phenobarbitone

CA inhibitor -produces acidosis

Absence -useful in refractory cases Generalized tonic clonic (grand mal) Absence (petit mal) Partial-complex

-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 Sedation

Akinetic

Febrile seizure

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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 . / DTs -Tx diazepam w/ tapering -acute glucose, thiamin -antabuse induces disulfiram rxn also, metronidazole, fulfas, griseofulvin, cephalosporin, phenylbutazone, phenothiazine -Naltrexone opioid antagonist prevents craving 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, Wernickes, Korsakoffs (Thiamine tx) Fetus teratogenic, retard, growth def Visual dysfxn GI distress Coma Acidosis - death Renal damage/death

Methanol

-competes w/ alcohol dehydrogenase for elimination

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

Ethylene Glycol

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

54


Drug THROMBOLYTIC AGENTS Streptokinase 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 Doesnt cross BBB or placenta Immediate action A mucopolysaccharide Clinical Use DVT PE Coronary throbus Same Same Side Effects

Urokinase TPA ANTI-PLATELET Aspirin

ANTICOAGULANT

Dipyridamole Heparin

Can be used in pregnancy Long-acting Antidote: Protamine

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

Warfarin

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

CI in pregnancy Prophylaxis use Antidote:give fresh plasma / Vit. K

Vit. K SYNTH. ANALOG Phytonadione Menadione menadiol

Causes synth. of clotting factors Menadione H2O soluble

For Warfarin overdose & newborns

PRO-CLOTTING

VIII IX Tranexamic acid Aminocaproic acid

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

Hemophilia B (Christmas)

Antihemophilic Globulin

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

55

Thrombin OTHER Protamine

Clots fibrinogen Heparin antagonist From fish sperm

Topical hemostat (capillary bleeding)

56