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24 Cards in this Set
- Front
- Back
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Describe M2 inhibitors MOA(anti-influenza) and resistance
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MOA:
a) Inhibits influenza A uncoating by blocking M2, a proton ion channel (inhibits acidification) b) alter hemagglutinin processing Resistance-develops rapidly 30%; assocated w/ mutation in transmembrane domain of M2 protein Drugs (end in 'antadine': 1. Amantadine 2. Rimantadine |
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Describe the uses and side effects of M2 inhibitors (anti-influenza)
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Uses-treatment of influenza A virus infections (H1N1, H2N2 and H3N2) and prophylaxis as alternative to influenza vaccine in high-risk patients
Side effects: 1. CNS-nervousness, light-headedness, difficulty concentrating, insomnia 2. GI-loss of appetite, nausea 3. neurotoxic effects of amantadine increased by ingestion of antihistamines and psychotropic or anticholinergic drugs (especially in elderly) 4. High amantadine plasma concentrations (1.0-5.0 g/mL) associated w/ serious neurotoxic reactions (delirium, hallucinosis, seizures, coma)and cardiac arrhythmias |
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Differentiate between amantadine and rimantadine
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Amantadine-peaks sooner and has shorter half life; most excreted unchanged in urine; excreted in breast milk
Rimantadine-<25% drug excreted unchanged in urine (dosage adjustment not essestial in altered renal functon); remainder eliminated as hydroxylated or conjugated metabolites |
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Describe the MOA of neuraminidase inhibitors
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MOA:
bind to active binding pockets of viral neuraminidase enzyme, causing conformational change in active site of viral enzyme; altered viral enzyme is rendered incapable to release budding virions on cell surface and slows down viral spread Drugs: 1. Oseltamivir 2. Zanamivir |
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describe oseltamivir
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A. pharmacokinetics
ethyl ester pro-drug that lacks antiviral activity; cleaved by esterases in gut and liver to active oseltamivir carboxylate Both pro-drug and active metabolite excreted unchanged in urine B. resistance resistant strains contain hemagglutinin and/or neuraminidase mutations (H1N1 100% resistant) C. uses prevention or treatment of influenza A and B infections (speeds functional recovery 1-2 days if initiated w/in 48h); can give to young children (<1) D. Side effects GI intolerance-nausea, vomiting, emesis (result of local irritation) |
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Describe zanamivir
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A. pharmacokinetics
given via inhalation of dry powder in lactose carrier (low oral bioavailability); eliminated in urine (90%) as parent drug B. resistance hemagglutinin and/or neuraminidase mutations C. uses prevention and treatment of influenza A and B (shorten recovery time 1-3 days); reduces risk of lower respiratory tract complications in adults (40%) D. side effects 1. wheezing 2. bronchospasm note-NOT recommended w/ underlying airway disease |
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describe the MOA and side effects of polyene macrolides (anti-fungal)
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Drug: amphotericin B
MOA: Binds to ergosterol in fungal cell membrane, creating pores-->depolarization and cell leakage Side effects: 1. Immediate systemic effects-TNF-α and IL-1 cause fever, chills, rigor and hypotension (cytokine storm) (b) Renal toxicity-vasoconstriction of renal afferent arterioles-->renal ischemia (c) Hematologic toxicity-anemia 2° to decreased production of EPO |
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Describe the pharmacokinetics of polyene macrolides
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commercial formulations differ in their kinetics:
1. C-AMB-complexed w/ bile salt deoxycholate to form a colloidal solution (don't add electrolytes to infusion-will cause colloid to aggregate) 2. L-AMB – unilamellar vesicle formulation in which highest systemic levels can be achieved (particularly liver and spleen); produces least infusion-related reactions (fever, chills, hypoxia) 3. ABLC-complex w/ lipids; low blood levels; approved for salvage therapy of deep mycoses 4. ABCD-complexed w/ cholesteryl sulfate to form colloidal solution; less nephrotoxic than C-AMB produce more chills and hypoxia compared to C-AMB (infuse over 3-4 hours and pre-medicate pts w/ antipyretics to reduce chills and fever) |
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describe the MOA, side effects and drug interactions of azole antifungals
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MOA:
1. inhibition of 14-α-sterol demethylase-->impair biosynthesis of ergosterol and accumulation of 14-α-methysterols (disrupts close packing of acyl chains of phospholipids)-->impair functions of membrane-bound enzyme systems-->inhibiting growth of fungi (ii) blockade of respiratory-chain electron transport Side effects: 1. Epigastric distress (common) 2. Headache 3. allergic rash 4. increases in aminotransferase activity (monitor liver enzymes) 5. Teratogenic Drug interactions inhibits CYP-450 enzymes Drugs (end in 'conazole'): 1. fluconazole 2. itraconazole 3. voriconazole 4. posaconazole |
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differentiate between the azole antifungals
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1. fluconazole-penetrates well into CSF, sputum, urine & saliva; excreted unchanged in urine (↓ dose in renal impairment)
2. itraconazole-widely distributed in tissues (exception-CNS and urine) metabolized in liver to hydroxy-itraconazole (active metabolite) substrate and potent inhibitor of CYP3A4; highly bound to plasma proteins (99%) BBW-should NOT be given w/ quinidine, dofetilide or pimozide; increases risk for serious CV events (torsades de pointes) 3. voriconazole-good CNS penetration (high Vd); metabolized in liver Less inhibition of CYP3A4 enzymes (predominantly via CYP2C19) nonlinear metabolism; higher doses cause >linear ↑ in systemic drug exposure Dosage adjusted during hepatic insufficiency; no adjustment required in renal insufficiency Side Effects-Visual disturbances (blurring & changes in color vision) 4. posaconazole-rapid distribution to tissues resulting in high tissue levels w/ low blood levels; long T1/2 |
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Describe echinocandins
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MOA
Blocks synthesis of β-(1,3)-D-glucan (polysaccharide component of cell wall in many pathogenic fungi)→disrupts cell wall structure (osmotic instability)-->Fungal cell DEATH Pharmacological properties: 1. lack of oral bioavailability 2. protein binding (>97%) 3. can't penetrate into CSF 4. lack of renal clearance 5. slight-modest effect of hepatic insufficiency Drug names: (end in 'fungin') 1. Caspofungin 2. Micafungin 3. Anidulafungin |
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differentiate the echinocandins
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1. Caspofungin (IV)-water soluble; synthesized from fermentation product of Glarea lozoyensis
metabolized by peptide hydrolysis and N-acetylation in liver (decrease dose in liver impairment) shortest T1/2; smallest Vd Side effects: (a) NVD, headache, facial flushing. (b) Cyclosporine-increase plasma [caspofungin] & ↑ liver enzymes (don't give) 2. Micafungin-linear pharmacokinetics over large range of doses and ages (premature infants to elderly) Clearance is more rapid in premature infants compared to older children or adults 3. Anidulafungin-water insoluble; extracted from fungus Aspergillus nidulans cleared from body by slow chemical degradation; No DDI reported longest T1/2, largest Vd |
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describe isoniazid (INH)
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most active drug against TB; used in all regimens (unless resistance); effective against intracellular and extracellular infections
prodrug activated by catalase-peroxidase KatG; deletions or mutations in this gene account for resistance MOA-inhibits enoyl acyl carrier protein reductase and β-ketoacyl-ACP synthase-->disruption of cell wall synthesis cidal against actively growing bacilli, but static against resting organisms partly metabolized by acetylation; N-acetyl-transferase type 2 (NAT2) is genetically determined (half of population are fast acetylators, other half slow) Drug levels in fast acetylators are 1/3-1/2 levels found in slow acetylators; for slow acetylators, decrease in renal or hepatic function-->drug accumulation and increased risk of side effects Side effects: 1. drug-induced hepatitis (symptoms are present in absence of virus); risk increases with age (can be fatal), during pregnancy and post-partum period, and in undernourished states (alcoholism) 2. lupus-like syndrome (rare) 3. convulsions (pts w/ seizure disorders) 4. peripheral neuritis-causes paresthesia of feet and hands; due to deficiency in pyridoxine 5. INH secreted in breast milk-->pyridoxine deficiency in neonates (add vitamin B6) 6. inhibit cytochrome P450-->increase levels of drugs (phenytoin and warfarin) |
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Describe rifampin
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effective against mycobacteria, most Gram-positive and many gram negative bacteria (lacks the selectivity of INH)
MOA (cidal)-inhibition of DNA-dependent RNA polymerase-->inhibition of synthesis of RNA kills intracellular and extracellular organisms (including those in abscesses and lung cavities) should be administered on empty stomach (food dimishes concentration) excreted in bile; subject to enterohepatic recirculation (dose adjusted for liver function) administered >2X/week to avoid flu-like syndrome Side effects (well-tolerated): 1. red-orange color to the urine, feces, saliva, sweat and tears (stain contact lenses) 2. rash 3. fever 4. nausea and vomiting 5. hepatitis and death from liver failure (rare); increases risk w/ preexisting liver disease or other hepatotoxic drugs) 6. induces several P450 isoforms-->decreases activity of many drugs (HIV protease inhibitors, digoxin, anticoagulants, contraceptives) |
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Describe rifabutin and rifapentine
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rifabutin-derivative of rifampin; less potent inducer of CYP450
unique side effects-polymyalgia, pseudojaundice, anterior uveitis rifapentine-longer half-life; moderate inducer of CYP450 parent compound and its metabolite are both active |
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Describe pyrazinamide
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analog of nicotinamide; pro-drug metabolized by mycobacteria to pyrazinoic acid (PZA)
cidal against mycobacteria only in acidic environment; acidic conditions for activation at edges of necrotic TB cavities where inflammatory cells produce lactic acid M. TB nicotinamidase or pyrazinaminidase deaminates pyrazinamide to pyrazinoic acid (POA−); transported to extracellular milieu by efflux pump In an acidic extracellular milieu, POA– is protonated to POAH (more lipid-soluble), then enters the bacillus formation of POAH is favored as pH of extracellular medium declines toward pKa of pyrazinoic acid (2.9); this enhances microbial killing MOA: inhibits transcription of mycobacterial fatty acid synthase I (FASI)-->reduces mycolic acid synthesis and intracellular pH; disrupts membrane transport by POAH Side effects: 1. hepatotoxicity (most serious) 2. hyperuricemia-occurs in most patients from inhibiting excretion of uric acid 3. Acute gout 4. arthralgias 5. nausea and vomiting 6. fever |
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Describe ethambutol
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MOA (static):
inhibits arabinosyltransferase-->disrupts mycobacterial cell wall-->increases penetration of other agents (rifampin FQs) 1/2 excreted in urine and 1/2 in bile (monitor renal and hepatic function) Side effects: 1. retrobulbar neuritis (most serious)-causes red-green color blindness and loss of visual acuity (dose-dependent, generally reversible upon discontinuation) 2. hyperuricemia w/ subsequent acute gout attack |
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Describe cycloserine
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MOA:
inhibits alanine racemase and D-ala-D-ala synthetase-->interferes w/ cell wall synthesis Side effects: CNS toxicity-headache, tremors, psychoses and convulsions |
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Describe ethionamide
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MOA:
pro-drug; active intermediate inhibits enoyl-ACP reductase of FAS2-->inhibits of mycolic acid synthesis-->inhibits mycobacteria cell wall synthesis Side effects: 1. gastric irritation 2. hepatotoxicity 3. peripheral neuropathies 4. optic neuritis note-supplementation w vitamin B6 alleviates or lessen the severity of side effects |
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Describe streptomycin
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aminoglycoside; cidal
less effective and more toxic than many other drugs polycation-doesn't readily penetrate cells (only effective against extracellular organisms) given IV or deep IM injection (painful) MOA: diffuses through porin channels into periplasmic space and then cytoplasms by moving down electrochemical gradient generated by organism’s ETC; once inside: 1. inhibits initiation of protein synthesis-->misreading of mRNA-->synthesis of faulty proteins 2. premature termination of protein synthesis (breaks polysomes into nonfunctional monosomes) Side effects: 1. nephrotoxicity-reversible (damaged epithelial cells regenerate) 2. ototoxicity-permanent (sensory hairs in inner ear don't regenerate) dose must be adjusted according to renal function |
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Describe kanamycin and amikacin
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aminoglycosides; act similarly to streptomycin
Amikacin- less toxic and lower resistance Side effects-nephrotoxic and ototoxic; don't use w/ streptomycin |
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Describe capreomycin
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mixture of 4 active cyclic peptides (mostly IA and IB); given by IM injection (painful)
MOA: inhibits protein synthesis; static against most strains Side effects: 1. nephrotoxic 2. ototoxic (hearing loss and tinnitus) note- don't give w/ streptomycin 3. eosinophilia (common) note-used when 1st line agents are inadequate or cannot be taken |
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Describe para-aminosalicyclic acid (PAS)
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reserved for situations when first line agents are inadequate or cannot be taken
MOA: competes with p-aminobenzoic acid in the synthesis of folic acid (static) metabolized by acetylation; competes w/ INH for metabolizing enzymes-->increases levels of INH Side effects: 1. GI-nausea, vomiting, diarrhea, anorexia, epigastric pain, abdominal distress 2. fever and malaise 3. joint pain 4. High drug concentrations in urine cause crystalluria |
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Describe flouroquinoles (FQs) in TB treatment (levofloxacin, moxifloxacin, gatifloxicin)
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MOA (cidal):
inhibit bacterial DNA gyrase (topoisomerase II)-->strand scission Side effects (well tolerated) 1. nausea 2. headache 3. dizziness 4. rash 5. pseudomembranous colitis (most serious)-associated w/ overgrowth of Clostridium difficile due to antibiotic-induced loss of normal flora in intestinal tract |
