1. Definition: Bacteriostatic
    When a drug stops the growth of the bacterial colony by inhibiting a step the the metabolism of the drug, but does not actually kill the bacteria.

    Forms a plateau in the bacterial colony numbers.

    • We're ECSTaTiC about bacteriostatics
    • Erythromycin Clindamycin Sulfamethoxazole Trimethoprim Tetracyclines Chloramphenicol
  2. Definition: Bacteriocidal
    When a drug actually kills the bacteria so that the number of bacteria dramatically decreases after administration of the drug

    • Very Finely Proficient At Cell Murder
    • Vancomycin Fluoroquinolones Penicillin Aminoglycosides Cephalosporins Metronidazole
  3. Antibacterial Drugs: Blocks cell wall synthesis by inhibition of peptidoglycan cross-linking
    • Penicillin
    • ampicillin
    • ticarcillin
    • pipericillin
    • imipenem
    • aztreonam
    • cephalosporins
  4. Antibacterial Drugs: Blocks peptidoglycan synthesis
    • Bacitracin
    • Vancomycin
  5. Antibacterial Drugs: Disrupts bacterial cell membranes
  6. Antibacterial Drugs: Disrupts nucleotide synthesis (antimetabolyte)
    • Sulfonamides
    • Trimethoprim
  7. Antibacterial Drugs: Disrupts DNA topoisomerases
  8. Antibacterial Drugs: Disrupts mRNA synthesis
  9. Antibacterial Drugs: Blocks protein synthesis at 50S ribosomal subunit
    • Chloramphenicol
    • macrolides
    • clindamycin
    • streptogramins (quinupristin, dalfopristin)
    • linezolid
  10. Antibacterial Drugs: Blocks protein synthesis at the 30S ribosomal subunit
    • Aminoglycosides
    • Tetracylcines
  11. Antibacterial Drug: Penicillins (general)
    • General considerations: can enhance activity if beta-lactamase inhibiitors (clavulanic acid, sulbactam), synergy w/ aminoglycosides against pseudomonal and enterococcal species
    • Pharmacokinetics: eliminated by active tubular secretion that can be blocked by probenecid, dose needs to be reduced with renal dysfn
    • Side effecets: hypersensitivity - types I-IV, urticarial skin rash common, but severe anaphylaxis reactions are possible, assume complete cross-allergenicity btw individual penicillins, Jarish-Herxheimer rxn when treating syphilis
  12. Antibacterial Drug: Penicillin
    • Characteristics: Pen G (IV), Pen V (PO)
    • Prototype beta-lactam antibiotics
    • Mechanism:
    • 1. binds to penicillin-binding proteins
    • 2. blocks transpeptidase cross-linking of cell wall
    • 3. Activate autolytic enzymes
    • Spectrum: narrow
    • Clinical use: bacteriocidal for gram + cocci, gram + rods, gram - cocci and spirochetes, treponema pallium, not penicillase resistant
    • Toxicity: hypersensitivity reactions, hemolytic anemia
    • Benzathing penicillin G: respository form (half life of 2 weeks)
  13. Antibacterial Drug: Methicillin, Nafcillin, Dicolxacillin
    (penicillinase-resistant penicillins)
    • Mechanism:
    • 1. binds to penicillin-binding proteins
    • 2. blocks transpeptidase cross-linking of cell wall
    • 3. activates autolytic enzymes
    • Spectrum: very narrow
    • Clinical use: s. aureus (except for MRSA; resistant bc of altered PBP-target site)
    • Toxicity: hypersensitivity reactions, methicillin causes interstitial nephritis
    • Elimination: in bile

    Use NAF (naficillin) for STAPH
  14. Antibacterial Drug: Ampicillin, Amoxicillin
    • Mechanism:
    • 1. binds to penicillin-binding proteins
    • 2. blocks transpeptidase cross-linking of cell wall
    • 3. activates autolytic enzymes
    • Spectrum: broad: Also combine with clavulanic acid (penicillinase inhibitor) to enhance spectrum
    • Clinical use: extended spectrum penicillin- certain gram + (not staph) and gram - rods, borrelia burgdorferi (amox), h pylori (amox)
    • Toxicity: hypersensitivity reactions, amipicillin rash; pseudomembranous colitis, GI distress
    • Elimination: undergoes enterohepatic cycling, but excreted by kidney

    AMPed up on penicillin

    • Coverage: ampicillin/amoxicillin HELPS kill enterococci
    • Haemophilus influenze
    • E coli
    • Listeria monocytogenes (amp)
    • Proteus mirabilis
    • Salmonella
    • Enterococci
  15. Antibacterial Drug: Ticaracillin, carbenicillin, piperacillin
    • Mechanism:
    • 1. binds to penicillin-binding proteins
    • 2. blocks transpeptidase cross-linking of cell wall
    • 3. activates autolytic enzymes
    • Spectrum: extended spectrum
    • Clinical use: pseudomonas spp. gram -ve rods, susceptible to penicillinase; use with clavulanic acid (beta-lactamase inhibitor)
    • Toxicity: hypersensitivity reactions

    TCP Takes Care of Pseudomonas
  16. Antibacterial Drug: Cephalosporins
    • Mechanism: B-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases, bacteriosidal
    • Clinical use:
    • 1st generation
    • - cefazolin, cephalexin
    • - gram + cocci
    • - PEcK: Proteus mirabilis, E Coli, Klebsiella
    • - surgical prophylaxis
    • - no CNS entry
    • 2nd generation
    • - cefoxitin, cefaclor, cefuroxime
    • - gram + cocci, some anaerobes
    • - HEN PEcKs: Haemophilus influenzae, Enterobacter aerogenes, Neisseria, Proteus mirabilis, E Coli, Klebsiella pneumoniae, Serratia marcencens
    • - CNS entry
    • - resistant to most beta-lactamases
    • 3rd generation:
    • - ceftriaxone, cefotaxime, ceftazidime
    • - serious gram - infections resistant to other B-lactams, meningitis (most penetrate the BBB) & sepsis
    • - Ex: ceftazidime for pseudomonas
    • - Ex: ceftrizxone for gonorrhea
    • - most enter CNS (not cefoperazone)
    • 4th generation
    • - cefepime
    • - gram -ve (pseudomonas) and gram + (wider spectrum)
    • - resistant to most beta lactamases
    • - enters CNS
    • -Toxicity: hypersensitivity rx, cross hypersensitivity w/ penicillins, nephrotoxicity of aminoglycosides are increased, disulfiram-like rxn w/ ETOH, + COOMBS test
    • if PCN allergy: for gram + use macrolide, for gram - use aztreonam
  17. Antibacterial Drug: Aztrenoman
    • Mechanism: monobactram resistant to B-lactamases, inhibits cell wall synthesis (binds to PBP3), synergistic w/ aminoglycosides, no cross-allergenicity w/ penicillins
    • Clinical use: Gram -ve rods, Klebsiella, pseudomonas, serratia, no activity against gram +ve or anaerobes
    • used in penicillin-allergeic pts and renal insufficiency pts who cannot tolerate aminoglycosides
    • Toxicity: usually nontoxic, occasional GI upset, no crossreactivity w/ PCN or cephalosporins
    • Administration: IV
  18. Antibacterial Drug: Imipenum/Cilastatin, Meropenem
    • Mechanism:
    • Imipenum: broad spectrum, B-lactamase-resistant carbapenem, always administered with cilastatin (inhibitor of renal dihydropeptidase I) to decrease inactivation in the renal tubules
    • Clinical use: Gram + cocci, gram - rods, and anaerobes.
    • DOC for Enterobacter
    • Significant side effects limit use to life-threatening infections, or after other drugs have failed.
    • Meropenem, reduced risk of seizures & is stable to dihydropeptidase I
    • Toxicity: GI distress, skin rash, CNS (toxicity - seizures), @ hi plasma levels
    • Elimination: renal

    w/ imipenem "the kill is LASTIN' with ciLASTIN"
  19. Antibacterial: Vancomycin
    • Mechanism: inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of the cell wall precursors, bacteriocidal, resistance occurs w/ amino acid change of D-ala D-ala to D-ala D-lac, doesn't interfere w/ PBPs
    • Clinical use: used for serious, gram +ve multidrug-resistant organisms like s. aureus and c. diff (pseudomembranous colitis)
    • Toxicity: Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing, Red Man Syndrome. (can largerly be prevented by pretreatment w/ antihistamines and slow infusion rate), well tolerated
    • Resistance: VRSA, VRE strains
    • PK: IV and PO (not absorbed) in colitis, most enters tissues, renal elimination
    • Well tolerated in generatl does NOT have many problems
  20. Antibacterial: Protein Synthesis Inhibitors 30S & 50S
    • 30S: Buy AT 30
    • A = Aminoglycosides (streptomycin, gentamycin, tobramycin, amikacin) [bacteriocidal]
    • T = Tetracyclines [bacteriostatic]

    • 50S: CCELL (sell) at 50
    • C = Chloramphenicol [bacteriostatic]
    • C = Clindamycin [bacteriostatic]
    • E = Erythromycin [bacteriorstatic]
    • L = Lindcomycin [bacteriostatic]
    • L = Linezolid [variable]
  21. Antibacterial: Aminoglycoside (30S)
    • Drugs: Gentamicin, Neomycin, Amikacin, Tobraycin, Streptomycin
    • Mechanism: bacteriocidal; inhibition formation fo the inital complex and cause misreading of mRNA, requires O2 for uptake and thus is ineffective against anaerobes
    • Clinical use: severe gram - rod infections, synergistic w/ B-lactam abx, Neomycin is used for bowel surgery
    • Toxicity: Nephrotoxicity (especially when used w/ cephalosporins), Ototoxicity (especially when used with loop diuretics), Teratogen
    • PK: polar, not well absorbed orally, low Vd, renal elimination

    • "Mean" GNATS canNOT kill anaerobes
    • amiNOglycosides:
    • N = need O = oxygen
    • N = nephrotoxicity O = ototoxicity
  22. Antibacterial: Tetracyclines (30S)
    • Drugs: Tetracycline, doxycycline, demeclocycline, minocycline
    • Mechanism: bacteriostatic, binds to the 30S and prevents attachment of aminoacyl-tRNA; limited CNS penetration
    • Elimination: doxycycline is fecally elminated and can't be used in renal failure
    • Absorption into gut is inhibited by milk, antacids, or Fe-containing compounds
    • Clinical use: Vibrio cholera, Acne, Chlamydia, Ureaplasma, Urealyticum, Mycoplasma pneumonia, Tulermia, H. pylori, Borrelia burgorferi (Lyme disease) Rickettsia
    • VACUUM THe BedRoom
    • Toxicity: GI distress, dicolouration of teeth, inhibition of long bone growth in children, photosensitivity, CONTRAINDICATED IN PREGNANCY
  23. Antibacterial: Tetracycline: Doxycycline
    • more activity overall than tetracyline HCL
    • special use: prostatitis - reaches high levels in the prostatic fluid
  24. Antibacterial: Tetracycline: Minocycline
    in saliva and tears at high concentrations, uses in meningococcal carrier states
  25. Antibacterial: Tetracycline: Demeclocycline
    More use in SIADH by blocking the ADH recpetor function in the collecting ducts
  26. Antibacterial: Macrolides (50S)
    • Drugs: Erythromycin, azithromycin, clarithromycin
    • Mechanism: inhibit protein synthesis by blocking translocation of the ribosomal subunit, bacteriostatic
    • Clinical use: URI, pneumonias, STD (gram + cocci), streptococcal infections in patients that are allergic to PCN, mycoplasma, legionella, chlamydia, neisseria, campylobacter jeuni, MAC, h. pylori
    • Toxicity: prolongs QT interval (especially erythromycin), GI discomfort (most common cause of noncompliance, due to motilin receptor activation), acute cholestatic hepatitis, eosinophilia, skin rash, increases the [ ] of theophyllines & oral anticoagulants, reversible deafness @ hi doses
    • PK: inhibit P450
  27. Antibacterial: Chloramphenicol (50S)
    • Mechanism: inhibits 50S peptidyltransferase activity, bacteriostatic
    • Clinical use: meningitis (h. influenzae, neisseria meningititids, strep. pneumo) conservative use owing to toxicity
    • Toxicity: anemia (dose dep), aplastic anemia (dose indep), Gray Baby Syndrome (in preme bc they lack the liver UDP-glucuronyl transferase)
    • PK: PO, good tissue distribution (into CSF too!), hepatic glucuronidation (dose reduction needed in liver failure and neonates), inhibition of CYP450
  28. Antibacterial: Clindamycin (50S)
    • Mechanism: blocks peptide bond formation at 50S ribosomal subunit, bacteriostatic, not a macrolide
    • Clinical use: treats anaerobic infections (bacteroides fragilis, clostridium perfringes), narrow spectrum gram + cocci (including community MRSA), osteomyelitis (bc it concentrates in bone)
    • Toxicity: pseudomembranous colitis (c. diff overgrowth), fever, diarrhea

    treats anaerobes above the diaphragm
  29. Antibacterial: Linezolid (50S)
    • Mechanism: inhibit formation of intiial complex in bacterial translation systems by preventing formation of N-formylmethionyl-ribosome-mRNA complex
    • Spectrum: tx of VRSA, VRE, drug resistant pneumococci
    • Side effects: bone marrow suppression (platelets)
  30. Antibacterial: Streptogramins: Quinupristin-Daflopristin (50S)
    Mechanism: several: binding to sites on 50S subunit, prevent the interaction of amino-acyl-tRNA w/ acceptor site, stimulate it dissociation from ternary compplex, decreases the release of completed polypeptide by blicking its extrusion
  31. Antibacterial: Polymyxins
    • Drugs: polymyxin B, polymyxin E
    • Mechanism: bind to cell membranes of bacteria and disrupts the osmotic properties
    • Characteritics: polymyxins are cationic, basic proteins that act like detergents
    • Clinical use: resistant gram -ve infections
    • Toxicity: neurotoxicity, acute renal tubular necrosis

    MYXins MIX up the membrane
  32. Antibacterial: Sulfonamides
    • Drugs: Sulfamethoxazole SMX), sulfisoxazole, sulfadiazine
    • Mechanism: PABA antimetaboltes inhibit dihydropteroate synthesase, bacteriostatic
    • Clinal use: gram +, gram -, nocardia, chlamydia, toxo, p. jiroveci simple UTI (triple sulfa or SMX), sulfonamides alone not used much due to resistance, sulfasalazine: uclerative colitis, RA, + Ag in burns
    • Toxicity: hypersensitivity reactions, hemolysis of G6PD deficient, nephrotoxicity (tubulointerstital nephritis), photosensitivity, kernicterus in infants, displaces other drugs from albumin (ie warfarin)
    • PK: hepatically acetylated (conjugation), renal excreted metabolites cause crystalluria, high protien binding
  33. Antibacterial: Trimethoprim
    • Mechanism: inhibits dihydrofolate reductase, bacteriorstatic
    • Clinical use: combined w/ sulfonamides (TMP-SMX), sequentially blocks folate synthesis, combination used for recurrent UTI infections, shigella, salmonella, pneumocystis jiroveci pneumonia
    • Toxicity: megaloblastic anemia, leukopenia, granulocytopenia (may alleviate with supplemental folinic acid)

    TMP = Treats the bone Marrow Poorly
  34. Antibacterial: Sulfa Drug Allergies
    if pts don't tolerate sulfa they can't be given any of the sulfa drugs including: sulfasalazine, sulfonylureas, thiazide diurectics, acetazolamide, or furosemide
  35. Antibacterial: Fluoroquinolones
    • Drugs: ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, moxifloxacin, etc. naldixic acid (a quinolone)
    • Mechanism: inhibits DNA gyrase (topoisomerase II & IV), bactericidal, can't take with antacids (Fe/Ca limit absorption)
    • Clinical use: gram - rods of urinary tract or GI tract (including pseudomonas), neisseria, some gram +ve, PID, STD, UTI
    • Toxicity: GI upset, superinfections, skin rash, headache, dizziness, CONTRAINDICATED IN PREGNANCY and CHILDREN bc animal studies show cartilage damage, tendonitis, tendon ruptures in adults, leg cramps and myalgias in kids
    • PK: reanl elmilation (inhibited by probenecid)

    fluoroquinoLONES hurts the attachment to BONES
  36. Unclassified Antibacterial: Metronidazole
    • Mechanism: forms toxic metabolites in the bacterial cell that damages DNA, bactericidal, antiprotozoal
    • Clinical: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Aanaerobes (bacteroides, clostridium), triple therapy for h. Pylori (metronidazole + bismuth + amoxacillin/tetracycline)
    • Toxicity: disulfiram-like rxn w/ ETOH; headache, metallic taste

    • GET GAP on the Metro!
    • Anaerobic infections below the diaphragm

    Get BaCk on the Metro, G!
  37. Antibacterial: Rifampin
    • Mechanism: inhibits DNA-dep RNA polymerase
    • Clinical use: mycobacterium tuberculosis delays resistnace to dapsone when used for leprosy, meningococcal prophylaxis & chemoprophylaxis in children with h. flu type B exposure
    • Toxicity: minor hepatotoxicity, drug interactions (increased P-450), orange body fluids (nonhazardous)
  38. Antibacterial Choices for STDs:
    • Treponema: PenG (+benzamine to last longer), may try to desensitize
    • Gonorrhea: ceftriaxone (3rd gen ceph) -ax drugs
    • Chlamydia: macrolides or tetracyclines
    • Trichamonas: macrolides
  39. Antibacterial Choices for common infections
    • Listeria: ampicillin, + -ax if young/elderly
    • Neonatal or elderly meningitis: ampicillin + -ax drug
    • Meningitis: adult/empiric -ax drug (give an axe to the head
    • UTI, PJP, community aquired MRSA: TMP-SMX
    • Hospital aquired MRSA: vancomycin
    • Empiric treatment for pneumonia: -penums
    • Pneumonia: macrolide
    • (causes: typical - strep pneumo, atypical mycoplasma, listeria)
    • Most broad abx: meropenum, amipenum-should be comebined with cilastatin to prevent amipenum toxicity NOT A STATIN!
    • Gram -: -ax drugs, fluoroquinolones
    • Gram +: vanco
  40. Antituberculosis Drugs
    RESPIre = Rifampin, Ethambutol, Streptomycin, Pyrazinamide, Isoniazid

    • - Combination therapy is the rule
    • - Primary drug combo: rifampin, ethambutol, isoniazid, pyrazinamide
    • - Back up drugs: aminoglycosides (streptomycin, amidacin, kanamycin), fluoroquinolones, capreomycin (markedhearing loss), cycloserine (neurotoxic)
    • - Prophylaxic tx: INH, rifampin if intolerant
  41. Anti-TB Drug: Ethambutol
    dose dep retrobulbar neuritis = decreased visual acuity and redgreen discrimination
  42. Anti-TB Drug: Priazinamide
    side effects: hepatitis, hyperuricemia (100% of ppl)
  43. Anti-TB Drug: Streptomycin (aminoglycoside)
    • Mechanism: protein synthesis inhibition
    • Side Effects: deafness, vestibular dysfn, nephrotoxicity
  44. Anti-TB Drug: Isoniazid
    • Mechanism: inhibits mycolic acid synthesis, prodrug that requires catalase conversion, high resistance
    • Side Effects: hepatitis, peripheral neuritis (use B6), siderblasitc anemia (use B6), SLE-like sydnrome- slow acetylators
  45. Anti-mycobacterial drug: M. Avium-Intracellulare
    • Prophylaxis: azithromycin
    • Tx: azithromycin, rifampin, ethambutol, streptomycin
  46. Anti-mycobacterial drug: M. leprae
    • Prophylaxis: none
    • Tx: Dapsone, rifampin, clofazimine
  47. Anti-Fungal: AMPHOTERICIN B
    see p. 192 in FA for good picture
    • Mechanism: binds ergosterol (unique to fungi), and tears holes in mb to allow for elyte leakage
    • Clinical use: wide spread systemic mycoses (crypto, blastomyces, cocciodiodes, aspergillus, histo, candida, mucor), intrathecally for fungal meningitis, does not cross BBB
    • Toxicity: Fever/chills (shake'n'bake), hypotension, nephrotoxicity (dose dep), arrhythmias, anemia (less EPO), IV phlebitis, (essentially amphoterrible!), hydration reduces nephrotoxicity, liposomal ampho reduces toxicity and Na loading (allowing less amp B to be needed)
    • PK: IV slow infusion, poor CNS penetration, slow clearance (t1/2 >2 wks)weeks
  48. Anti-Fungal: NYSTATIN
    • Mechanism: binds to ergosterol, tears holes in mb to allow for elyte leakage
    • Toxicity: too toxic for systemic use
    • Clinical use: 'swish and swallow' for oral candidiasis (thrush), topical for diaper rash or vaginal candidiasis
  49. Anti-Fungal: AZOLES
    • Drugs: fluconazole, ketoconazole, clotrimazole, any -azole drug
    • Mechanism: inhibit ergosterol synthesis at 14-alpha-demethylase (P450 enzyme), resistance if it cant be [ ] inside the cell
    • Clinical use: systemic mycoses
    • fluconazole: for cryptococcal meningitis in AIDS (bc it can cross the BBB)
    • candida infections of all kinds
    • Ketoaconazole: blastomycoeces, coccidioides, histo, candida, hypercortisolism
    • Clotrimazole/miconazole for topical fungal infections
    • Itraconazole/Voriconazole: DOC for balstomycoses, sporotrichoses, aspergillosis, back up drug
    • Toxicity: hormone synthesis inhibition (gynecomastia), liver dysfn (inhibits CYP-450), fever/chills
    • PK: PO, absorption decreased by antacids, increased itraconazole by food
  50. Anti-Fungal: FLUCYTOSINE
    • Mechanism: 5FU is formed by activated fungal cystosine deaminase that can:
    • a) 5FU be incorporated into fungal RNA
    • b) 5FU inhibits DNA synthesis by conversion to 5-Fd-UMP by thymidylate synthase, which decreases thymine
    • Clinical use: systemic fungal infections (candida, crypto), in combo with ampB
    • Toxicity: n/v/d, bone marrow suppression, enters CNS
  51. Anti-Fungal: CASPOFUNGIN
    • Mechanism: inhibits cell wall synthesis by inhibiting synthesis of B-glucan
    • Clinical use: invasive aspergillosis
    • Toxicity: GI upset, flushing
  52. Anti-Fungal: TERBINAFINE
    • Mechanism: inhibits fungal enzyme squalene epoxidase
    • Clinical use: dermatophytoses (oncomycosis)
    • Side effects: GI distress, rash, headahe, increased LFT = hepatoxicity
  53. Anti-Fungal: GRISEOFULVIN
    • Mechanism: interferes with microtubule function; disrupts mitosis, deposits in keratine-containing tissues (ie nails)
    • Clinical use: oral tx of superficial infections, inhibits dermatophytes (tinea, ringworm)
    • Toxicity: teratogenic, carcinogenic, confusion, headaches, increased P450, warfarin metabolism, disulfiram-like rxn
  54. Anti-Viral endings:
    • -avir = AIDS virus drugs
    • -ivir = Influenza virus drugs
    • -ovir = herpes virus drugs
  55. Anti-Viral: Amantadine
    • Mechanism: blocks viral penetration/uncoating (M2) protein; may buffer pH of endosome, causes release of DA from intact nerve terminals
    • A man to dine takes of his coat
    • Clinical use: prophylaxis and tx of influenza A, parkinson's disease
    • Toxicity: ataxia, dizziness, slurred speech
    • Mechanism of resistance: Mutated M2 protein, 90% of all influenza A strains are resistance, so not used
    • Safer derivative: Rimandatine: fewer CNS side efects (doesn't cross BBB)
    • Amantadine blocks influenza A and rubellA and causes problems in the cerebellA
  56. Anti-Viral: Zanamivir, Ostelamivir
    • Mechanism: inhibits influenza neuroaminidase, decreases release of viral progeny, decreased penetration
    • Clinical use: influenza A and B, mostly prophylaxis but may decrease by 2 - 3 days
  57. Anti-Viral: Ribavirin
    • Mechansism: damages RNA (prevents end-capping), inhibits syntehsis of guanine nucleotides by competitively inhibiting IMP dehydrogenase
    • Clinical use: RSV, chronic hep C, RSV, Lassa fever, Hantavirus
    • Toxicity: hemolytic anemia, severe teratogenicity, upper airway irritation
  58. Anti-Viral: Acyclovir
    • Mechanism: monophosphorylated by HSV/VZV thymdine kinase guanosine analg, triphosphate formed by cellular enzymes, preferentially inhibits viral DNA pol by chain termination
    • Clinical use: HSV, VZV, EBC, used for HSV-induced mucocutaneous and genital lesions, encephalitis, prophylaxis in immunocompromised pts, herpes zoster should use famiciclovir, no effect on latent HSV/VZV
    • Toxicity: well tolerated
    • Mechanism of resistance: lack of thymidine kinase
  59. Anti-Viral: Ganciclovir
    • Mechanism: 5'-monophosphate formed by CMV viral kinase or HSV/VZV thymidine kinase, guanosine analogue, triphosphate formed by cellular kinases, preferentially inhibits viral DNA polymerase
    • Clinical use: MCV, especially immunocompromised pts
    • Toxicity: leukopenia, neutropenia, thrombocytopenia, renal toxicity, more toxic to host enzymes than acyclovir
    • Mechanism of resistance: mutated CMV DNA pol or lack of viral kinase
  60. Anti-Viral: Foscarnet
    • Mechanism: viral DNA polymerase inhibior that binds to the pyrophosphate-binding site of enzyme, does not require activation by viral kinase
    • Clinical use: CMV retinitis in immunocompromised pts when gancyclovir fails; acyclovir-resistant HSV
    • Toxocity: nephrotoxicity
    • Mechanism of resistance: mutated DNA pol

    FOScarnet = pyroFOSphate analogue
  61. Common antiviral treatments and diseases
    • Herpes (-ovir, needs to be phosphorylated)
    • CMV: gancyclovir, foscarnet
    • HIV: NRTI, NNRTI, -avir, protease inhibitors
    • Hep C: Interferon alpha + Ribaviron
  62. Anti-Virals that block viral penetration/coating
    Amantadine, enfuvirtide, maraviroc
  63. Anti-Virals that inhibit DNA pol
    Acyclovir, foscarnet (not phosphorylated), ganciclovir (phosphoryalted)
  64. Anti-virals that inhivir viral RNA pol
    • Foscarnet
    • ribavirin
  65. Anti-Virals that inhibit viral neuroaminidase
    • zanamivir
    • osteltamavir
  66. HIV treatment
    • RTI: Reverse Transcriptase Inhibitors-original inhibitors of reverse transcriptases are ucleoside antimetabolites that are converted to active forms via phosphorylation ractions
    • NRTI: Non Reverse Transcriptase Inhibitors-made in most combo drug regimens, used w/ protease inhibitors, highly active antiretrovial therapy (HAART) = decreased viral RNA, reversal of decline in CD4 cells, decrease opportunistic infections
    • Protease inhibitors
    • Fusion inhibitors
  67. Reverse Transcriptase Inhibitors: Nucleosides
    Drugs: Zidovudine (formerly AZT), didanosine (DDI), Zalcitabine (DDC), Stavudine (D4t), laivudine (3TC), abacavir

    have YOU (vudine) with my nuclear (nucleosides) family?

    • Mechanism: preferentially inhibits RT of HIV; prevents incorporation of DNA copy of viral genome into hose DNA
    • Toxicity: bone marrow suppression (neutropenia, anemia), peripheral neuropathy, lactic acidosis

    clinical use: when CD4 coutnts get low (~500 cells/mm3) or high viral load
  68. Reverse Transcriptase Inhibitors: Non-nucleosides
    Drugs: Nevirapine, Efavirenz, Delavirdine

    Never Ever Deliver nucleosides

    • Mechanism: perferentially inhibits the RT of HIV; prevents incorporation of DNA copy of viral genome into host DNA
    • Toxicity: bone marrow suppression (neutropenia, anemia), peripheral neuropathy, rash, megaloblastic anemia (ZDV)
    • (~500 cells/mm3) or high viral load
  69. Nucleoside Reverse Transcriptase Inhibitors: Zidovudine (AZT)
    • Characteristics: nucleoside
    • Mechanism: phosphorylated nonspecifically to a triphosphate = inhibits reverse transcriptase by competing with natural nucleotides, can also be incorporated into viral DNA = chain termination
    • Toxicity: hematoxocity (majoy & dose limiting), headache, asthenia, myalgia, peripheral neuropathy
    • Clinical use: general prophylaxis and during pregnancy to reduce fetal transmission
  70. Nucleoside Reverse Transcriptase Inhibitors: Didanosine, DDI
    • Mechanism: phosphorylated nonspecifically to a triphosphate = inhibits RTase, incorporated into viral DNA = chain termination
    • Toxicity: pancreatitis (major/dose limiting), peripheral neuropathy, hyperuricemia, liver dysfn
  71. Protease Inhibitors: -navir ending
    • Mechanism: aspartate protease (pol gene encoded) is a viral enzyme that cleaves precursor polypeptides in HIV pbuds to form proteins of the mature virus core, this enzyme contains dipeptide structure that is not seen in mammilian proteins: PIs bind to this protein = inhibiting the enzyme
    • Resistance: via specific point mutation in pol gene = not complete resistance btw different PIs
    • Clinical uses: always in combo with 2 NRTIs - Indinavir, ritonavir, saquinavir (least toxic, low oral bioavailability, predisposition to developing resistance)
    • Toxicity: nephrotoxicity
    • Mechanism of resistance: mutated DNA polymerase

    NAVIR (never) TEASE a proTEASE
  72. Protease Inhibitor: Indinavir
    • Clinical use: in combo with ritonavir
    • Side effects: crysalluria (maintain hydration)
    • Genearl: sydnreom of disordered lipid and CHO metabolism w/ central adiposity and insulin resistance
  73. Protease Inhibitor: Ritonavir
    • Clinical use: in combo with Indinavir
    • Side effects: major drug interactions: induces CYP 1A2 and inhibits major P450 isoforms (3A4, 2D6)
    • General: sydnreom of disordered lipid and CHO metabolism w/ central adiposity and insulin resistance
  74. Fusion Inhibitors: Enfuvirtide
    • Mechanism: binds tcells the gp41 subunit; inhibit confirmational chg needed for fusion with CD4 = block entry and subsequent replication
    • Toxicity: hypesensitivity reactions, rxns at subcutaneous injection site, increased risk of bacterial pneumonia
    • Clinical use: persisten viral replication in spite of antiretroviral therapy, used in combo w/ other drugs
  75. Fusion Inhibitors: Maraviroc
    Mechanism: blocks CCR5 proein on T cell surface = viral entry inhibited
  76. Antiprotozoal Agents: Antimalarial
    • Clinical uses:
    • Chloroquine-sensitive regions: Prophylaxis = chloroquine +- primaquine, back up = hydroxychloroquine, primaquine, pyrimethamine-sufladoxine
    • Specifically:
    • p. falciparum - chloroquine
    • p. malariae - chloroquine
    • p. vivax - chloroquine + primaquine
    • p. ovale - chloroquine + primaquine

    • Chloroquine-resistant areas:
    • Prophylaxis = mefloquine, backup doxy, atovaquone-proguanil
    • Tx = quinine +- doxy, clinda, pyrimethamine

    Side effects: hemolytic anemia in G6PD deficiency (primaquine, quinine), cichonism (quinine)
  77. Antiprotozoal Agents: Helminthic Infections
    • Most intestinal nematodes (worms)
    • - Mebendazole (decreases glu uptake and decreases microtubular structure)
    • - Pyrantel pamoate (NM agonist = spastic paralysis)

    • Most cestodes (tapeworms) & trematoads (flukes)
    • - Praziquantel (increases Ca influx, increases vacuolization)
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