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98 Cards in this Set
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Penicillins |
Water soluble - widely distributed to all organs but CNS Acid-sensitive Acid-stable - phenoxypenicillin V [PEN-V], oxacillin, amoxicillin, carbenicillin indanyl Very selective toxicity [high chemotherapeutic index] Gram positive microbes Mechanism - Covalent binding to transpeptidases/penicillin binding proteins - inhibition of transpeptidation reaction [cross-linking of cell wall] - activation of murein hydrolases [autolysins] Mechanism of resistance: Pencillinases [beta lactamases] break lactam ring structure [e.g. staphylococci] - structural change in PBPs [e.g. methicillin-resistant staphylococcus aureus [MRSA], penicillin- resistant pneumococci] - change in porin structure Meninges inflamed - penetrate CSF - IV treatment for meningitis Adverse effects: - Hypersensitivy Rxn: Major penicillin adverse effect [5-8% allergies] - Cross-reactivity w/ beta-lactams, ex aztreonam - Hapten = major antigenic determinant - Benzylpenicilloic acid - seizures - Neutropenia [Naficillin] - Intestinal nephritis [Methicillin]
Probenecid - tubular secretion blocker
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Pen-G + Pen-V |
Narrow spectrum Penicillinase/B-lactamase sensitive Spectrum: Strepto, Pneumo, Menigo, T. Pallidum |
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Dixloxacillin, Nafcillin, Methicillin |
Very Narrow spectrum Penicillinase/B-lactamase resistant Spectrum: Effective Only against B-Lactamase producing Staph Except MRSA |
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Amoxicillin, Ampicillin |
Extended spectrum Penicillinase/B-lactamase sensitive Aminopenicillin Spectrum: -Gram+ve: Steptococci [BUT not staph] -Gram-ve: E. coli, H influenza, and Proteus, Listeria monocytogenes[Ampicillin], Borrelia Burgdorferi[Amoxycillin], H. Pylori [Amoxycillin] species Show synergism with Beta lactamase inhibitors and aminoglycosides Amoxicillin - Clavulanate [Augmentin] Amoxicillin - Gentamycin [Ampiclox] Ampicillin - Sulbactam [Unsayn] Ampicillin - Gentamycin [Amclox] Adverse effects: Rash, 90% for mononucleosis pts, self limiting, often does not recur |
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Piperacillin, Ticarcillin, Azlocillin, Carbenicillin |
Extended-spectrum penicillinase/B-lactamase sensitive Antipseudomonal Spectrum: Gram-ve rods inclusing pseudomonas aeruginosa Show synergism with Beta lactamase inhibitors and aminoglycosides Piperacillin - Tazobactam [Zosyn] Ticarcillin - Claculanate [Timentin] |
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Clavulanate, Sulbactam, Tazobactam |
B-lactamases inhibitors Must be used with penicillins to show antibacterial activity In combination - acts as a suicide inhibitor of B-lactamas enzymes by serving as a surrogate substrate for these enzymes |
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Cefazolin, cephalexin |
Cephalosphrins - First generation Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides - interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] Spectrum: gram+ve cocci [not MRSA], E.coli, Klebsiella pneumoniae and some other proteus species - surgical prophylaxis - does not enter CNS - Probenecid - blocks tubular secretion Side effects: Hypersensitivity - rashes and drug fever most common - Renal Toxicity: tubular necrosis, interstitial nephritis - enhanced by aminoglycosides - positive coombs test - Recommended to not give penicillin allergic pts |
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Cefotetan, Cefaclor, Cefuroxime |
Cephalosporins - Second generation Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides - interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] Spectrum: increased gram-negative coverage, including some anaerobes - Only cefuroxime enters CNS - Probenecid - blocks tubular secretion Side effects: Hypersensitivity - rashes and drug fever most common - Cefuroxime & Cefotetan: disulfiram effect [methylthiotetrazole induced inhibition of aldehyde dehydrogenase], bleeding, platelet disorders - positive coombs test - Recommended to not give penicillin allergic pts |
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Ceftriaxone, Cefotaxime, Cefdinir, Cefixime |
Cephalosporins - Third generation Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides - interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] Spectrum - Gram positive & Gram negative cocci [neisseria gonorrhea], plus many gram-negative rods Pharmacokinetics: Most enter CNS - important in empiric management of meningitis & sepsis • Ceftriaxone - largely eliminated in the bile Probenecid - blocks tubular secretion Side effects: Hypersensitivity - rashes and drug fever most common • positive coombs test • Recommended to not give penicillin allergic pts |
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Cefepime |
Cephalosporins - Forth generation Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides - interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] Spectrum: wider spectrum - Resistant to most beta- lactamases - enter CNS - Probenecid - blocks tubular secretion Side effects: Hypersensitivity - rashes and drug fever most common - positive coombs test - Recommended to not give penicillin allergic pts |
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"LAME" |
Organisms not covered by cephalosporins Listeria monocyogenes Atypricals [E.g. Chlamydia, Mycoplasma] MRSA Enterococci |
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Imipenem & Meropenem |
Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides - interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] Spectrum: Gram- positive cocci, gram negative rods [enterobacter, Pseudomonas spp.], and anaerobes - important in-hospital agents for empiric use in severe life-threatening infections Pharmacokinetics: Imipenem is given w/ cilastatin, a renal dehydropeptidase inhibitor - inhibits imipenem's metabolism to a nephrotoxic metabolite - Renal elimination - decrease dose in renal dysfunction Side effects: GI distress - drug fever [partial cross-allergenicity w/ penicillins] - CNS effects - including seizures w/ imipenem in overdose or renal dysfunction |
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Aztreonam |
Mechanism: Bacterial cell wall is cross-linked polymer of polysaccharides & pentapeptides • interact with cytoplasmic membrane-binding proteins [PBPs] to inhibit transpeptidation rxn involved in cross-linking [cell wall synthesis] • Resistant to beta-lactamases Used: Gram negative rods [IV drug] [Klebsiella spp. Pseudomonas spp. Serratia spp.] • No cross-allergenicity w. penicillins or cephalosporins Toxicity: Vertigo, usually non-toxic; occasional GI upset |
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Vancomycin |
Mechanism: Binds at the D-ala muramyl pentapeptide to sterically hinder the transglycosylation rxns [indirectly prevents transpeptidation] involved in elongation of peptidoglycan chains Spectrum: Gram +ve - MRSA, Entercocci, clostridium difficile [backup drug] Pharmacokinetics: No GI absorption - always given IV except in tx of C. Difficile colitis [oral admin] • Minimal CSF concentrations • excreted unchanged by kidneys - decreased dose in renal impairment [CR CL] Adverse Effects: Rapid IV infusion - histamine release - diffuse flushing [red man syndrome] - Type 1 H/S - pre tx w. antihistaminics helps - Ototoxicity, Nephrotoxicity [increased w. concomitant aminoglucoside] - Reversible neutropenia [w. prolonged course] |
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Imipenem [IV] |
- Carbapenems: Beta Lactams - Resistant to beta-lactamases - Broad spectrum: Gram +ve and -ve rods & anaerpbes; DOC for Enterobacter - Pseudomonas: Resistance rapid - use with aminoglycosides - Inactivated: Renal dihydropeptidase I Toxicity: CNS toxicity [high doses/plasma levels] - Confusion, encephalopathy & seizures [50% of pts] - CROSS SENSITIVITY in pts w. penicillin allergies |
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Meropenem & Ertapenem |
- Dipeptidase- resistant carbapenem - Has decreased risk of seizures |
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Bacitracin |
- inhibits cell wall synthesis - Topical application b/c Nephrotoxic on systemic use - minor skin & ocular infections - combined polymyxin & neomycin in ointments and creams [triple antibiotic] - Spectrum: Gram +ve cocci [Staphlyococci & strephtococci] |
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Cycloserine |
- very unstable & acid pH 2nd Generation TB drugs Mechanism: inhibits cell wall synthesis Spectrum: inhibits many gram +ve and gram -ve organisms - Tuberculosis caused by M. Tuberculosis resistant to 1st-line agents Adverse effects: serious dose related CNS toxicity [sedation, headache, tremor, vertigo, confusion, acute psychosis & convulsions] Neurological toxicity is minimized by giving pyridoxine 150mg/d |
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Fosfomycin |
- Newer antibiotic - inhibits very early stage of bacterial cell wall synthesis Spectrum: active against both gram +ve and gram -ve organisms [E.coli, Citrobacter species, Klebsiella species, Proteus species, & Serratia marcescens] - Uncomplicated UTI due to E. Coli or Enterococcus faecalis in women - orally as a single dose - Safe during pregnancy |
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Aminoglycosides |
Mechanism: Block association of 50S subunit with 30S- m RNA complex - misreading of code- incorporation of wrong amino acid |
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Linezolide |
Oxazolidinones Mechanism: block association of 50S subunit w. 30S- m RNA complex - No cross-resistance w/ other IPS Spectrum: bactericidal Steptococci, bacteriostatic against staphylococci & enterococci Uses: Vancomycin resistant E. faecium, VRE & PNSP Adverse Effects: bone marrow suppression [platelets], superinfections, inhibit MAO |
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Tetracycline, demeclocycline, doxycycline, minocycline |
Mechanism: Block the attachment of aminoacyl tRNA to acceptor site[Static] - reversible binding to 30S subunit - Bacteriostatic Pharmacokinetics: Oral admin - Chelate metal ions - Ca++, Al+++, Fe++, Mg++ - Not absorbed - don't administer w. food, milk, antacids etc. Distribution: Not to CNS pr synovial fluid - concentrates in teeth, bone - discolouration of teeth & hypoplasia of enamel - liver[bile], kidney - nephrotoxicity except Doxycycline, hepatotoxicity [fatty degeneration] - cross the placenta & excreted in milk Excretion: through Urine except for doxycycline Spectrum: Rickettsial infection - DOC for Rocky Mountain spotted fever - Spirochetal infections - Lyme disease & Relapsing Fever -- Borrelia Burgdorferi & B. recurrentis respectively - Mycoplasma pneuumoniae - alternative for macrolide for infection caused by mycoplasma pneumoniae - Chlamydia tachomatis - Brucellosis - H. pylori - SIADH - Demelocycline inhibits the action of ADH in renal tubule Adverse effects: GIT - nausea/vomitting m/c [superinfection risks] - Photo toxicity - Demeclocycline - erythema and exacerbating sunburn [V-neck shaped bright red rashes in the sun exposed area] - Fanconi syndrome - expired tetracycline - Diabetes insipidus: demeclocycline due to blockage of D2 receptor on collecting duct |
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Tigecycline |
- Tetracycline analogue - Glycylcyline - semisynthetic derivative of minocycline Uses: Tx of complicated skin and skin structure infections caused by susceptible organisms including - MRSA - Vancomycin-sensitive enterococcus faecalis - Tx of complicated intra-abdominal infections |
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Resistance of Tetracyclines |
- plasmid mediated - M/C mechanism: Decreased uptake of tetracyclines efflux pumps - major mediators - Altered ribosomal proteins or RNA are secondary mechanisms |
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Chloramphenicol |
Reversible inhibitor of protein synthesis - bacteriostatic broad spectrum Pharmacokinetics - Well absorbed, CNS levels= serum levels - excreted in urine - Glucuronidation in liver is rate-limiting step for inactivation/ clearance Resistance: Key mechanism of resistance is plasmid mediated - Chloramphenicol Acyl Transferase [CAT] - SLOW development Adverse Effects: Gi disturbances followed by fungal superinfections - Anemia - bone marrow depression [reversible] - Aplastic anemia - prolonged use -[irreversible and fatal] - Gray Baby syndrome - newborns and infants are poor glcuronidator's [H.influenzae induced meningitis] - Drug-drug intrxn - inhibits microsomal enzymes Uses: Antibacterial, Typhoid fever, Rocky Mountain spotted fever in children, meningitis in both adult & children - ace-in-the-hole drug |
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Macrolides |
Bacteriostatic or bactericidal depending on dose Pharmacokinetics: Absorbed from GI [Acid-labile] - use enteric coating or erythromycin esters - CNS distribution - Crosses placenta - excreted in bile - levels 50x higher than in plasma - half-life 2-5hrs except for azithromycin Adverse effects: GI distress - stimulation of motilin receptors by all macrolides most common - Exception Clarithromycin - Hepatotoxicity - erythromycin estolate, Cholestatic jaundice - Microsomal enzyme inhibition - drug - drug interaction. Oral anticoagulants, digoxin, non-sedating antihistamines; not with azithromycin - increased GT prolongation [erythromycin] - Ototoxicity [erythromycin] Spectrum: Gram +ve bacteria, some gram -ve - backup for penicillins in pencillin sensitive patients [only for gm +ve] Resistance: Staph resistance, some streptococci & pneumococci - plasma mediated - altered [methylated] rRNA - Esterase which hydrolyzes erythromycins |
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Clarithromycin |
- newer macrolide antibiotics - used in combination therapy against H.Pylori & MAC - Less GI effects |
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Azithromycin |
- Minimal P450-based interactions [excreted by kidney] - Tissue levels 10-100 x Plasma levels; t1/2 = 2-4 days - Mycobacterium avium-intracellular in AIDS patients [DOC] - ONLY Macrolide safe in pregnancy |
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Telithromycin |
Ketolide - structurally related to macrolides Uses: TX of community- acqired pneumonia caused by susceptible stains of: streptococcus pnemoniae [including multidrug resistant isolates], Haemophilius influenzae, chlamydophila pneumoniae, moraxella catarrhalis, mycoplasma pneumoniae |
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Clindamycin |
Lincosamide antibiotic: bacteriostatic Mechanism: both MOA & MOR Spectrum: Narrow, some gm +ve, bacteroides fragilis, other anerobes NO CNS Uses: Endocarditis prophylaxis, clinical value in osteomyelitis [only caused by S. Aurieus], PID Adverse Effects: GI upset, superinfections, hepatotoxic |
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Quinupristin and Dalfopristin [SynercidTM] |
Streptogramins - Peptide macrolactones - Intravenous, 80% excreted in bile & 20% urine - Potent inhibitor of CYP3A4 - Wide range of only gram +ve bacteria [Staphylcocci resistant methicillin, quinolones & vancomycin] [Pneumococci - resistant to Penicillin] [E.Faecium resistant to Vancomycin] |
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Aminoglycosides |
Water soluble Mechanism: Bactericidal - irreversible inactivation of ribosomes - Multiple effects on translation - interfere w. initiation, misreading of mRNA, break up polysomes ["streptomycin monosomes"] Pharmacokinetics: Poor oral absorption - given IV sometimes IM - NO CNS and EYE distribution - no significant host metabolism - excreted unchanged - glomerular filtration - very high concentrations in proximal tubule cells Uses: Non-resistant gram -ve infections - E.coli, Proteus, Pseudomonas [gentamicin > tobramycin > amikacin] Adverse Effects: Dose-dependent - plasma concentration & time at high concentrations are critical factors, monitor closely - Nephrotoxicity - high concentrations of AG in renal cortex [usually reversible] - Ototoxicity - high concentrations of AG in inner ear, loss of vestibular and/or auditory function [may be reversible] - Contact dermatitis - Neuromuscular blockade Resistance: anaerobes resistant - oxygen-dependent uptake - increased bacterial metabolism of AG - adenylation, acetylation, phosphorylation |
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Spectinomycin |
- Related to Aminoglycosides structurally and pharmacokinetically - Related to tetracyclines mechanistically [30S IPS] - used against drug-resistant gonococci or in penicillin allergic pts. w/ gonorrhea |
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Sulfonamides |
Mechanism: PABA analogs, enter into a normal metabolic pathway, but then block that pathways - Competitive inhibitor of dihydropteroate synthase - bacteriostatic Pharmacokinetics: Oral, some topical - well absorbed from GI, high PPB, well distributed including to CNS - acetylation yields inactive metabolite [less water soluble] Uses: Topical for burns- Silver sulfadiazine - ulcerative colitis: Sulfasalazine, Mesalamine - not absorbed, split by gut bacteria reductase to release 5- aminosalicylate - Sulfonamides alone not used as antibiotic Adverse Effects: Allergic rxns - fever, rash etc. - Cross- reactivity w. other sulfonamides - carbonic anhydrase inhibitors, thiazides, furosemide, sulfonylurea hypoglycemis - Crystalluria - Stevens - Johnson- syndrome Type IV: fever, malaise - hemolytic anemias - G6PDH deficiency - Kernicterus in newborns Resistance - Mutations causing overproduction of PABA - loss of permeability
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Trimethoprim |
Dihydrofolate Reductase Inhibitors - Readily absorbed from GI - wide distribution, including CNS - Excreted in urine - Used alone for UTI but usually combined w. a sulfonamide Adverse effects: Megaloblastic anemia, leukopenia, granulocytopenia - treat with folinic acid |
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Fluoroquinolones |
Mechanisms: Inhibits DNA replications, inhibits DNA gyrase [Topoisomerase II] & IV • Fluroinated analogues of nalidixic acid Pharmacokinetics: Well absorbed & distributed after oral admin •Iron & Calcium limit absorption • Excreted in urine - blocked by Probenecid Uses: UTIs particularly when resistant to Cotrimoxazole • STDs/PIDs - Chlamydia [Ofloxacin], Gonorrhea [Cipro/ Ofloxacin] • Skin, soft tissue & bone infection by gm -ve organisms [except norfloxacin] • Diarrhea due to Shigella, Salmonella, E. coli, Campylobacter [any quinolone] •PNSP [Levofloxacin] Adverse Effects: Nausea & vomiting •Phototoxicity & rashes, All quinolone increase QT interval •Blocks theophylline clearance - cannot be co-administered •Connective tissue disorders - tendonitis or tendon rapture [adult] myalgia & leg cramps [children] NOT DURING PREGNANCY Resistance - Altered [mutated] DNA gyrase •No recommended for gonococcus b/c of resistance |
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Trimethoprim - Sulfamethoxazole [Co- trimoxazole] |
Combination is often bactericidal - DOC in Nocardia Spectrum: Gm-ve infections [E.coli, Salmonella, Shihella] • Gm+ve infections [Staph, Strepto, H.influenzae] - Fungus: Pneumocystis jiroveci pneumonia [PCP] - prophylaxis [when CD4 count <200] & tx in HIV infection - Protozoa: Toxoplasma Gondii [Sulfadiazine & Pyrimethamine] both for prophylaxis [when CD4 count <200] & tx in HIV infection - TORCH infection Adverse effects: add typical sulfonamide effects • AIDS patients with Pneumocystis pneumonia [PCP] - Fever, rashes, leukopenia, diarrhea |
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Norfloxacin |
Fluoroquinolones - 1st Generation Uses: common pathogens that cause urinary tract infections similar to nalidixic acid |
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Ciprofloxacin & Ofloxacin |
Fluoroquinolones - 2nd generation Uses: excellent activity against gram -ve including gonococcus, Chlamydia, many gram+ve cocci, mycobacteria, & mycoplasma pneumoniae • must be used in combination w. other Antitubercular drugs to which strains are susceptible |
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Levofloxacin & Gatifloxacin |
Fluoroquinolones - 3rd generation Uses: less activity against gram-ve bacteria but greater activity against some gram +ve cocci [S. pneumoniae, entercocci, MRSA] good for many drug resistant respiratory tract infection |
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Moxifloxacin & Gemifloxacin |
Fluoroquinolones - 4th Generation Uses: Broadest spectrum fluoroquinolones w/ good activity against anaerobes |
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Nitrofurantoin |
Mechanism: Unknown, but may involve oxidative stress•Bacteriostatic or bactericidal (dependson microbe) Pharmacokinetics: Rapidly absorbed (oral), metabolized ,and excreted in urine (50% as active drug)•Even IV nitrofurantoin does not have a systemic effect Clinical Use: UTI, gram positive or gram negativemicrobes•Most effective if urine pH < 5.5 AdverseEffects: Anorexia, GI disturbances common, headaches•Occasional hemolytic anemia (oxidative)especially if G6PDH deficient, leukopenia, hepatotoxicity Resistance: All Pseudomonas, some Proteus are resistant |
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Amphotericin B |
Mechanism: Polyene antibiotic, binds to ergosterol in fungal membranes & forms artificial "pores" - Resistant strain have low ergosterol Pharmacokinetics: IV, very slow excretion, t 1/2 about 2 weeks [biphasic half life - with an initial half life of about 24 hours - 15days Preparations: Two parenteral formulations - Deoxycholate complex [conventional] - Amphotericin B Lipid Complex [Liposomal Amphotericin B] - lower affinity for drug that does funga membrane [ergosterol] higher affinity for drug than does pt membrane [cholestrol] Uses: Severe systemic mycoses - Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, Sporothrix • Combined with Flucytosine - delay resistance, lower doses needed Adverse effects: 'Amphoterrible' • chills, fever, nausea, vomiting, headache •alleviated by pretx w. NSAIDS, H1 antihistaminics •Dose dependant - Nephrotoxicity (asATN)includes ↓GFR,tubular acidosis,↓K+ & Mg++ & anemia through↓erythropoietin .Nephrotoxicity common, often irreversible (Reduced withliposomal preparation)
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Flucytosine |
Mechanism•Activated by fungal cytosine deaminase—converted to 5-fluorouracil which after triphosphorylation (FUTP) isincorporated into fungal RNA (↓RNA synthesis) • 5FU also forms 5-Flurodeoxyuridinemonophosphate (5 –Fd-UMP)which inhibits Thymidylatesynthase→↓Thymine(↓DNA synthesis) Pharmacokinetics•Orally effective, widelydistributed, including CNS•Excreted in urine-- urine levels10x serum levels Adverse Effects•Low toxicity to patient (notactivated in mammalian cells) Clinical Use•Narrow spectrum •Resistance develops rapidly, use only with amphotericin B |
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Anti- Fungal Azoles |
Mechanisms: Inhibit ergosterol synthesis [fungal CYPs] - inhibits 14 alpha demethylase, a fungal CYP450 enzyme - converts Lanosterol to Ergosterol • Cross inhibition of host CYP450 • decreased host cholesterol synthesis w. some of these drugs Resistance: Occurs due to decreased intracellular accumulation of azoles [other antimicrobials using pump] Pharmacokinetics: Inhibition of hepatic CYP450s • Decreased Steroid synthesis including cortisol & testosterone - Altered metabolism & antiandrogenic effects respectively |
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Ketoconazole |
-1st effective oral antifungal for systemic disease - Absorbed & distributed, except to CNS Pharmacokinetics: Absorption is decreased by antacids [as azoles slightly acidic] |
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Itraconazole |
- Broader spectrum - doesn't cross BBB - fewer adverse effects then Ketoconazole - DOC in Blastomycoses, Sporotrichoses Pharmacokinetics: Absorption is increased by food [as acidity increases w. food] |
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Voriconazole |
- effective against a variety of fungal - including invasive Aspergillosis, fluconazole-susceptible & resistant Candida infections & Cryptococcus neoformans |
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Fluconazole |
- Water-soluble azole Uses: Systemic fungal infection - less toxic AMB • Good CSF delivery [prophylaxis & suppression of cryptococcal meningitis] • selective for fungal P450s Pharmacokinetics: penetrates into CSF - used in meningeal infection |
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Caspofungin |
Echinocandin Antifungal Drugs Mechanisms: Inhibits the synthesis of B[1,2]- D-glucan[essential fungal part of cell wall] Uses: Treatmentof invasive Aspergillusinfections in patients who are refractory or intolerant of other therapy –Treatmentof candidemia andother Candidainfections (1) Intra-abdominal abscesses (2) Esophageal and peritonitis in pleuralspace (3) Empirical treatment for presumedfungal infections in febrile neutropenic patients Adverse effects: Hypotensionand tachycardia • Fever,chills and headache • Rash • Anemias • Hypokalemia |
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Griseofulvin |
Mechanism: Disrupt microtubular structure Uses: Only against Dermatophytes [oral] - concentrates newly formed keratinized tissue Adverse Effects: Potent CYP450 Induce • Disulfiram like effect |
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Terbinafine |
Mechanisms: Inhibits squalene epoxidase [erogsterol synthesis] Adverse effects: Possible Hepatotoxicity |
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Amantadine & Rimantadine |
Mechanism: Block viral uncoating by blocking M2 protein channel - Give in first 48hrs of contact - Orally - protects against and treats Influenza A Adverse Effects: Anticholinergic [GI intolerance & CNS effects] |
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Oseltamivir [Tamiflu] |
- Effective against all common influenza virus stains - pro-drug activated in gut and liver - Well tolerated, some transient nausea & vomiting |
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Zanamivir [Relenza] |
Influenza A and B - Effective early in infection [>#2 days] Adverse Effects: Bronchospasm in asthmatics |
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Acyclovir |
Mechanism: Guanosine analogue, activated by thymidine kinase • initial phosphorylation requires viral kinases [Basis of selection action of acyclovir] • subsequent phosphorylations use host enzymes • acyclovir triphosphate is substrate for viral polymerase Uses: Manage, but not cure herpes • HSV and VZV NOT CMV Pharmacokinetics: Oral, intravenous, or tropical Adverse effects: Crystalluria [accumulation of less water soluble metabolite in kidney] - maintain hydration strictly • Not hematotoxic [bone marrow cells doesn't contribute in phosphorylation] |
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Valacyclovir |
Mechanism: Valine ester of acylcovir - pro drug • The valine analog is actively transported from the gut • cleaved to yield acyclovir uses: effective against Acyclovir resistant strains but not effective in TK strains |
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Ganciclovir |
Mechanism: inhibition of viral genome replication Tx. of CMV • better substrate than acyclovir for host kinases • triphosphate is better substrate the acyclovir triphosphate for host polymerases HIV with P. Jirovecy& CMV • Do not use Cotrimoxazole& Gancyclovirtogether (HIV,bothdrugs causes BMS • Do not use Pentamidine& Foscarnettogether (additive hypocalcemia) |
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Foscarnet |
Mechanism: Inhibits viral polymerases [DNA, RNA, RT] not a nucleoside analog - instead a pyrophosphate Uses: effective against ganciclovir- resistant CMV & acyclovir resistant HSV - IV Adverse effects: Nephrotoxic - acute tubular necrosis w. prominent hypocalcemia • penile ulceration - due to increased level of ionised drug in the urine • Hallucination |
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Cidofovir |
DeoxyCytidine analog, phosphonate-monophosphate analog Uses: IV for CMV retinitis Adverse effects: Renal toxicity - dose limiting |
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Nucleoside Reverse Transcriptase Inhibitors [NRTIs] |
Mechanism: Prodrug activated by non specific kinases - recall all 'ovirs' • causes chain termination • Not complete cross resistance btw 2 NRTIs acting through different nucleotides • commonly 2 NRTIs are combine w. 1 PI |
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Zidovudine/Azidothymide [AZT] |
NRTIs Mechanism: Thymidine analog [dideozynucleoside] • Phosphorylated nonspecifically to a triphosphate that can inhibit HIV reverse transcriptase • Resistance occurs due to mutation in gene that code for RT • inhibits stable infection of new cells Pharmacokinetics: well absorbed from GI tract • widely distributed, CNS~60% of serum level Uses: temporarily reduces morbidity and mortality from HIV • use in three drug cocktail Adverse Effects: Bone marrow depression, CNS [asthenia, headaches, muscles pain, agitation, insomnia, tingling sensations] Drug interactions:↑levelof AZT: Azole antifungals,Cimetidine (↓CYP450) , Indomethacin, Probenecid, (↓renal clearence) TMP-SMX • ↓levelof AZT: Rifampin (↑CYP450) |
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Nevirapine |
First generation oral NNRTI Mechanism: Non-competitive RT inhibition, binds near but not in active site • CYP3A substrate and inducer Uses: can be active against AZT-resistant HIV • Single dose can reduce vertical transmission by 50% Adverse Effects: Life threatening skin rash & abnormal LFT |
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Efavirenz |
NNRTI Adverse Effects: causes insomnia & dysphoric dreams [in >50% pts] |
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Indinavir & Ritonavir |
HIV Protease Inhibitors Mechanism: Aspartate protease [pol gene encoded] is a viral enzyme that cleaves precursor polypeptide in HIV buds to form the protein of mature virus core • the enzyme contains a dipeptide structure not seen in mammalian protein, PIs bind to this dipeptide, inhibiting the enzyme • Resistance occurs via specific point mutation in the pol gene, such that there is not complete cross resistance btw different PIs Clinical Uses: Used in combination regimen with 2 NRTIs Adverse effects: Indinavir • Nephrolithiasis • GI distress • Thrombocytopenia • Inhibition of CYP450 [3A4 isoform] Ritonavir • GI distress • Asthenia & paresthesia • Major drug interactions - induces CYP1A2 & inhibits major CYP4503A4 & CYP4502D6 • booster for other protease inhibitors - blocks their metabolism General • syndrome of generalized lipid & carbohydrate metabolism [cushingnoid effect, insulin resistance, hyperlipidemia] |
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Enfuvirtide |
Fusion inhibitor Mechanism: interferes w/ entry of HIV1 into hot cells by inhibiting the fusion of the virus and cell membranes [through gp41] Uses: Reserved for individuals who have advanced disease or show resistance to current HIV tx |
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Raltegavir |
Integrase inhibitor Mechanism: inhibits the catalytic activity of integrase • Prevents integration of the proviral gene into human DNA Uses: used with other agent in tx - experienced pts w. virus that shows multidrug resistance and active replication |
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Maraviroc |
CCR5 antagonist Mechanisms: selectively & reversibly binds to the chemokine [C-c motif receptor 5[CCR5]] coreceptors located on human CD4 cells • Inhibits gp120 conformational change required for CCR5- tropic HIV-1 fusion with the CD4 cell and subsequent cell entry Uses: In combination w/ other antiretroviral agents in tx. experienced pts w. evidence of viral replication and HIV1 strains resistance to multiple antiretroviral therapy |
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HAART |
Highly Active Antiretroviral Therapy - Combination of 3 or 4 drugs Preferred NNRTI- based: combines efavirenz w. lamivdine or emtricitable & zidovudine or tenofovir Preferred PI based: combines lopinavir; ritonavir w. zidovudine & lamivudine or emtricitabine |
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Ribavirin |
Inhibitors of Viral Nucleic Acid Synthesis Mechanism: Anti-metabolite, blocks GMP formation Uses: Effective as aerosol for respiratory syncytial virus [RSV] • use palivizumab for prophylaxis against RSV • Given by aerosol for immunosuppressed individuals w. pre-existing respiratory or cardiac disease Adverse Effects: Teratogen |
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Chloroquine |
Anti- Malarial Mechanism•Alters metabolism of hemoglobin byparasite, also blocks nucleic acid synthesis Pharmacokinetics•Oral or parenteral•Rapid, complete absorption; widedistribution•Excreted in urine, 25% asmetabolite•Loading dose necessary for acutetreatment Uses•"Highly effective blood schizonticide“•Acute: Clears parasitemia from all four Plasmodia –Curativefor P.malariaeandP.falciparum–Usedwith primaquine for P. vivax and P. ovale •Prophylactic: Begin 1 week beforetravel, continue four weeks after return - Preferreddrug for prophylaxis against all four species Adverse Effects: GI • mild headache, exacerbate psoriasis/porphyria • Visual impairment - long term or high dose Resistance: Widespread in South America, Africa, Asia • "P-glycoprotein" pumping mechanism • block w. verapamil in vitro |
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Mefloquine |
Mechanism: UNKNOWN Pharmacokinetics: Oral • well absorbed and distributed • Metabolized in liver, excreted in feces Uses: Chloroquine-resistant malaria Adverse Effects: CNS, possible psychotrophic effects 'g' |
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Fansidar [Pyrimethamine- Sulfadoxine] |
Anti-folate combination, typical effects Pharmacokinetics: Well absorbed & distributed, excreted in urine Uses: Effective blood schizonticide for P. falciparum • slow-acting; cannot be used alone for acute attacks Multi-drug resistance to fansidar and chloroquine common |
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Atovaquone plus proguanil |
Mechanism: (1) Atovaquone selectively inhibits parasitemitochondrial electron transport (2)Proguanil’s metabolite cycloguanil, inhibits dihydrofolate reductase Uses: to prevent or treat acute, uncomplicated P. falciparummalaria–Adverseeffects: GI distress • Increased hepatic transaminase • Headache • Dizziness |
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Quinine and Quinidine |
Anti-Malarial Chemotherapy Uses: Treat uncomplicated chloroquine-resistant P. falciparum malaria Adverse Effects: Cinchonism • Overdose of quinine or its natural source and cinchona bark • Symptoms - flushed & sweaty skin, ringing of the ears, blurred vision, impaired hearing, confusion |
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Primaquine |
Mechanism: Tissue schizonticide Pharmacokinetics: oral, well absorbed & distributed, extensively metabolized Uses: Combination w. chloroquine for prophylaxis Adverse Effects: GI distress, hemolytic anemia in G6PDH deficiency |
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Artemisinin |
Anti-Malarial Chemotherapy Traditional Chinese medicine Pharmacokinetics: Oral, very short t1/2 • activated by oxidative metabolism - free radicals, alkylation Uses: Rapidly-acting blood schizonticide - particularly useful for multi-drug resistant P. falciparum |
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Metronidazole & Tinidazole |
Anti-Protozoal Drugs Mechanism: Tissue amebicide • Nitroimidazole - activated by electron donation & produce free radicals as MOA • Particularly effective for anaerobic/hypoxic sites Pharmacokinetics: Oral/IV • well absorbed & distributed, including CNS, bone • cleared in urine following hepatic metabolism Uses: Urogenital trichomoniasis - Trichomonas vaginalis • Giardiasis - Giardia • Amebiasis - Entamoeba histolytica • Anaerobic bacterial infections below diaphragm - c. diff, bacteroides fragilis, Gardinella vaginalis & Acne Rosacea • H. Pylori Adverse Effects: Nausea, headache, dry month • Stomatitis, metallic taste, leukopenia, cystitis, reversible peripheral neuropathy • Disulfiram effect |
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Pentamidine |
Anti-Protozoal Drug Pharmacokinetics: IV, IM or Aerosol • concentrates in liver, spleen, kidneys • slowly released from those sites • Doesn't enter CNS Uses: Aerosol used for tx/prophylaxis against PCP Adverse Effects: can cause respiratory stimulation followed by depression, hypotension, anemia • less common in aerosol administration |
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Iodoquinol |
Anti-Protozoal Drug Uses: Local tx of acute and chronic intestinal amebiasis • asymptomatic cyst passers |
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Paromomycin |
Anti-Protozoal Drug Aminoglycoside Uses: Acts locally on ameba • treat acutes and chronic intestinal amebiasis |
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Mebendazole |
Mechanism: Blocks microtubule synthesis, block vesicle & organelle movement Wide spectrum anti-helmintic Pharmacokinetics: Oral, less than 10% absorbed • rapidly metabolized, excreted in urine Uses: effective against pinworm, hookworm, ascaris Adverse Effects: GI effects, possibly embryotoxic |
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Albendazole |
Anti- Helmintic Chemotherapy Mechanism: Interferes w. microtubule aggregation, alters glucose uptake Pharmacokinetics: rapidly & completely metabolized in liver, conjugates excreted in urine Use: Wide Spectrum anti-helmintic |
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Praziquantel |
Anti-Helmintic Chemotherapy Mechanism: Increases membrane permeability to Ca2+, resulting in contraction & paralysis Pharmacokinetics: 80% bioavailability [oral admin] • Rapid and extensively metabolized - cleared in urine Uses: tx. for all schistosomes, some trematodes & cestodes Adverse Effects: Headache, dizziness, drowsiness may occur |
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Thiabendazole & Mebendazole |
Anti-Helmintic Chemotherapy Mechanism: block microtubule formation Pharmacokinetics: 80% bioavailability [oral admin] • Rapid and extensively metabolized - cleared in urine Uses: Thiabendazole: broad spectrum - cutaneous larva migrans, strongyloidiasis • Mebendazole - ascariasis, trichuriasis, hookworm, pinworm, systicercosis, echinococcus infestations Adverse Effects: abdominal pain, diarrhea |
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Pyrantel pamoate |
Anti-Helmintic Chemotherapy Mechanism: Acts as a depolarizing neuromuscular blocking agent on the nicotinic receptor • increases the effects of acetylcholine and inhibits cholinesterase in the worm Uses: ascariasis, pinworm [E. vermicularis], hookworm whipworm [Trichuris trichiura], Trichostrongylus Adverse Effects: nausea, vomitting, diarrhea, anorexia |
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Ivermectin |
Anti-Helmintic Chemotherapy Mechanism: increases chloride permeability thus polarizing cells, which leads to paralysis Uses: strongyloidiasis, onchocerciasis |
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Isoniazid |
Anti-Mycobacterial Chemotherapy Mechanisms: Blocks synthesis of Mycolic acids for mycobacterial cell wall • Bactericidal in growing cells only Pharmacokinetics: •Well absorbed and distributed afteroral administration•CNS levels ~20% of serum level;Intracellular = extracellular•Metabolism key factor inpharmacokinetics-- acetylated in the liver•Genetic differences (polymorphism)in acetylation•Fast acetylatorsmay require higher doses•"Fast" acetylators--50% of US Blacks and Whites, mostEskimos, Asians, Native Americans•t1/2for “Fastacetylators < 1.5 hrs, "slow"acetylators-- t1/2 > 3 hrs•Excretion-Urine (INH and acetylated product) •Alter dosing in hepatic, not renaldisease Uses: Prophylaxis - used alone for TB exposure, tuberculin convertors • combination chemotherapy for TB w. ethambutol, rifampin, or pyrazinamide Adverse Effects: Hepatoxicity - increases w. age of pt,more common in alcoholics, may increase during pregnancy, increased w. age after 35YO; use rifampin for prophylaxis in older pts. • Peripheral and central neuropathy - tx w. pyridoxine [Vitamin B6] - slow acetylators Resistance: can develop rapidly - already present • 10% of isolates in US resistant • deletion of katG gene in mycobacterium |
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Ethambutol |
Anti-mycobacterial Chemotherapy Mechanism: Inhibits synthesis of mycobacterial cell wall glycan Pharmacokinetics: Well absorbed & distributed •CNS level variable 4-60% of serum • most excreted in urine - accumulates in renal failure Adverse Effects: Dose-dependent optic neuritis •decreased acuity •loss of red-green differentiation Resistance: rapid - use in combination |
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Rifampin |
Anti-Mycobacterial Chemotherapy Mechanism: Inhibits bacterial RNA synthesis •Bactericidal Pharmacokinetics: Well absorbed & distributed •excreted in bile Use: Combination chemotherapy for active disease, single agent prophylaxis for INH-intolerant pts •Meningococcal pts Adverse Effects: Inducer or microsomal enzymes •alters t1/2 of anticoagulants, oral contraceptives •Hepatotoxic •"Flu-like" syndrome •Gives orange color to body fluids |
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Pyrazinamide |
Anti- Mycobacterial Chemotherapy Mechanism: Unknown - but activated by mycobacterium Pharmacokinetics: oral, absorbed, distributed Use: Bacteriostatic Adverse Effects: Hyperuricemia Rapid Resistance |
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Streptomycin |
Anti-Mycobacterial Chemotherapy For severe [life threatening] cases |
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Rifabutin |
Mechanism: Inhibits DNA- dependent RNA polymerase in E.coli & interferes w. DNA synthesis in M. tuberculosis Uses: preventation & tx of disseminated atypical mycobacterial infection AIDS pts Adverse Effects: inducer of CYP450 |
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Para-aminosalicylate [PAS], Cycloserine, Ethionamide |
Second Line Anti-TB Drugs - Toxicity outweighs therapeutic effects except for highly resistant strains |
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Ethionamide |
Second Line Anti-TB Drugs Mechanism: Blocks synthesis of mycolic acid Adverse Effects: Intense gastric irritation, Neurologic symptoms [Pyridoxine given] & hepatotoxicity |
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Sulfones |
Leprosy drugs Mechanism: Inhibit the synthesis of folic acid by M.Leprea and exhibit a bacteriostatic action |
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Dapsone |
Leprosy Drugs Mechanism: Inhibit the synthesis of folic acid by M. Leprea and exhibit a bacteriostatic action Pharmacokinetics: Oral administered, Absorbed from the gut and widely distributed throughout body fluids and tissue. • Retained in skin, muscle, liver & kidney Adverse Effects: GI disturbances • Peripheral Neuropathy • Optic neuritis • Blurred vision • Proteinuria & Nephrotic syndrome • Lupus-like syndrome & Hematologic toxicity |
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Clofazimine |
Mechanism: Enhances phagocytic activity of Neutrophils & Macrophages - reduces the motility of Neutrophils and the ability of Lymphocytes to transform Uses: Bactericidal against M. Tuberculosis is bacteriostatic against M. Leprae and active against M. avium intracellulare • use in combination with Dapsone & Rifampin for the tx of Lepromatous Leprosy Adverse Effects: GIT distrubances - anorexia, N/V, abdominal pain and diarrhea • Photosensivity, skin discoloration [randing from red-brown to nearly black] • sweat, tears, sputum, feces, urine during therapy |
