Pharm Block 3

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Pharm Block 3
2011-07-28 15:55:19

Block 3 drugs
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  1. cell wall inhibitors
    • work on gram + bacteria
    • peptidoglycan layer - stains violet
    • inhibit transpeptidase enzyme (holds NAG and NAM together)
  2. beta - lactam antibiotics
    • possess a four member nitrogen - containing Beta lactam ring
    • penicillins and cephalosporins
  3. MOA of Beta Lactam antibiotics
    • binding to Penicillin binding proteins
    • inhibition of transpeptidase enzymes
    • activation of autolytic enzymes bond of cell wall
  4. resistance to beta lactams
    • enzymatic hydrolysis of the beta lactam ring by beta lactamases. MC
    • alteration of penicillin - binding proteins (is principle mech of resistance in methicillin - resistant staphylococci
    • reduced permeability in Gram - neg. cell membranes
  5. Penicillin
    • beta lactam ring
    • normally do not cross BBB (except in meningitis since inflammation decreases the filtration coefficient)
    • usually excreted unchanged in urine
    • vary in bioavailability because of their varied resistance to gastric acid
  6. Probenecid
    • competitively inhibits the renal tubular secretion of penicillin
    • increases the concentration of penicillin and prolongs its activity - not excreted in the urine
    • inhibitis the renal elimination of penicillin
    • reduced frequency of dosing and high blood levels of penicillin
  7. resistance to penicillins
    • MOA: production of beta lactamases (penicillinase)
    • S. Aureus changes PBP for Methicillin
  8. Narrow spectrum penicillin - penicillinase susceptible
    • Drug: Penicillin G (IM)
    • MOA: highly susceptible to beta lactamases - going to get deteriorated; sensitive to beta lactamase
    • DOC: Treponema pallidum (Syphilis)
    • notes: limited spectrum of action, infections due to strep, meningiococci, gram+ bacilli; strains of pneumococci, staph aureus and N. gonorrhoea are resistant
  9. Narrow spectrum - penicillinase resistance
    • Drugs: methicillin, nafcillin, oxacillin
    • MOA: drugs resistant to inactivation by beta lactamases, therefore bacteria must alter shape of penicillin binding protein
    • Uses: Rx of staph infections; MRSA & MRSE - resistant
    • #2 DOC: staph and strep
    • Notes: Methicillin causes interstitial nephritis
  10. Broad spectrum penicillin - penicillinase susceptible
    • Drugs: ampicillin, amoxicillin
    • MOA: susceptible to inactivation by beta lactamases; wider spectrum of action than penicillin G
    • Uses: all the uses of penicillin G plus infections caused by enterococci, Listeria monocytogens, E.coli, Proteus mirabillis, H. influenza
    • combination: beta lactamase inhibitors (clavulinic acid), spectrum/intensity of these drugs greatly increases
  11. Broad spectrum penicillins - penicillinase resistant
    • Drugs: piperacillin, ticarcillin
    • MOA: good activity against gram neg. rods
    • Uses: Pseudomonas**, Enterobacter
    • Notes: synergistic action with aminoglycosides; resistant to beta lactamse; cystic fibrosis patients will be resistant after 25 years
  12. beta lactamase inhibitors
    • Drugs: Clavulinic acid, Sulbactam and Tazobactam
    • MOA: structurally related to penicillin; no antibacterial effect alone, just inhibits beta - lactamase enzyme; effective only against plasmid encoded beta - lactamases
    • Uses: Gonococci, streptococci, E.coli, and H. influenza can be inhibited; not effective in inhibiting the inducible chromosomal beta lactamases (natural resistance - those produced by enterobacter & Pseudomonas cannot be inhibited)
    • Notes: sold as fixed drug combination with penicilliniase susceptible drugs (broad spectrum) to increase spectrum of action; augmentin (amox +calvulinic acid; increase the spectrum of action
  13. ADR of penicillin
    • relatively safe, widely used
    • hypersenitivity reactions - rare; skin rashes, acute anaphylactic shock
    • alter bacterial flora of the gut - GI disturbances (esp. broad spectrum) - C. diff (treat with metronidazole (#1 DOC) or vancomycin (orally)
    • Cross allerginicity - cross sensitivity is possible; allergic to one may also be allergic to others
  14. Aztreonam
    • monobactam - active only agianst Gr - org
    • resistant to beta lactamase produced by Gr - rods including Pseudomonas, Klebsiella, and Serratia
    • no activity against Gr. + organisms and anaerobes
    • MOA: similar to penicillin - binds to PBP 3
    • Notes: no cross anti-genicity with PCN
    • ADR: GI upset, sperinfection, *vertigo, and headache
  15. Carbepenem, Imipenem, Meropenem, Ertapenem
    • broad spectrum Gram+ or - anerboes
    • Low susceptibility to beta lactamases
    • Notes: pseudomonas infections - give with aminoglycoside; give parenterally
    • Reserve drugs: used only when other antibiotics not effective
    • DOC: rx of enterobacter
  16. Imipenem + Cilastatin
    • rapidly inactivated by renal dehydropeptidase I - req. frequent doses therefore sold with inhibitor of renal dehydropeptidase
    • combination of these drugs prevents hydrolysis by enzymes in the renal brush border
    • Cilistatin: inhibitor of renal dehydropeptidase; increases the plasma 1/2 life of imipenem
    • ADR: GI distress, skin rash, in high doses - CNS toxicity, (confusion, encephalopathy & seizures)
  17. Cephalosporins
    • MOA: similar to penicillins; all are bactericidal (drug will kill bacteria); less susceptible to inactivation by penicillinases
    • Some bacteria produce cephalosporinase (another type of beta lactamase)
    • resistance possible due to decrease in membrane permeability & change in structure of PBP
  18. First Generation Cephalosporins
    • Drugs: Cefazolin (parenteral), cephalexin (oral)
    • Uses: against Gr + cocci and Klebsiella; E. coli and K. pneumonia are sensitive; minimal activity against Gr -; surgical prophylaxis and Rx of infection caused by susceptible organisms
    • Notes no penetration into CSF so no role in tx of meningitis
  19. Second Generation Cephalosporins
    • Drugs: Cefoxitin, Cefotetan, Cefaclor, Cefamanodole, Cefuroxime
    • Uses: Cefoxitin, Cefotetan - Bacteroides fragilis; Cefaclor, Cefamandole, Cefuroxime - H. influenza & M. catarrhlis; used mostly on Gr -, hardly on gram + (1st gen used for that)
    • Cefuroxime - only drug that enters CSF
  20. Third Generation Cephalosporins
    • Drugs: Ceftazidime, Cefoperazone, Cefotaxime, Ceftriaxone, Ceftizoxime
    • Notes: good penetration into BBB (-ax to head: cefotaxime and Ceftriaxone) -> except Cefoperazone & Cefixime; antipseudomonal activity - cefoperazone, ceftazidime; B. fragilis - ceftizoxime
    • ADR: disulfrum like reactions - Cefotetan, cefacocar, cefoperazone
  21. Ceftriaxone & Cefixime
    • Ceftriaxone (parenteral & Cifixime (oral)
    • DOC: Gonorrhea
    • Ceftriaxone - single injection is preferred Rx for acute ottitis media; also used in bacterial meningitis
    • Note: 3rd generation drugs used for serious hospital acquired gram - infections
  22. Fourth Generation Cephalosporins
    • Drugs: Cefepime, Cefpirome
    • Notes: more resistant to inactivation by beta lactamases; excellent penetration into gram - bacteria, much wider spectrum than 3rd generation (both gram - and +
    • reliable antipseudomonal activity
    • reverse drugs; used only if other drugs fail to produce any response
  23. ADR for Cephalosporins
    • Allergic reactions (skin rash to anaphylaxis)
    • less freqent with cephalosporins when compared with penicillins
    • Cross - hypersensitivity between cephalosporins completely possible
    • Cross reaction between penicillins is incomplete, but caution still needed
    • Superinfection - C. Diff
    • history of anaphylaxis - life threatening to penicillin is a contraindication for cephalosporin
    • Pain after I.M. injecition; phlebitis after I.V. injection
    • increases possibility of nephrotox when given with aminoglycosides
    • Cefamandole, Cefoperazone & Cefotetan contain methylthiotetrazole group (MTT group)j
    • can cause disulfrum like reactions with ethanol - Ceph. III
  24. Vancomycin
    • bactericidal glycoprotein
    • MOA: binds to D-Ala-D-Ala terminal of the nascent peptidoglycan pentapeptide side chain -> inhibition of transglycosilation -> prevents the peptidoglycan chain elongation -> inhibition of cross linking of the peptidoglycan chains
    • Must be given IV
    • Resistance: occurs in strains of enterococci and staphylococci (VRE & VRSA); involves decreased affinity of vancomycin for the binding site; replacement of terminal D-Ala by D - Lactate
  25. spectrum of vancomycin
    • narrow spectrum
    • Uses: serious infections caused by drug - resistant Gr + organisms; especially MRSA, penicillin resistant pneumococci and C. diff
    • oral vancomycin - refractory C. diff colitis
  26. ADR for Vancomycin
    • N-Nephrotox, O - Ototox, T - Thrombophlebitis (inflammation of veins)
    • Red man's syndrome - release of histamine (flushing, redness of face, hypotension), this can be prevented by pretreatment with antihistamines; rate of intravenous infusison, should be infused over at least 60 min
  27. Bacitracin
    • MOA: inhibits cell wall synthesis
    • Uses: no more oral; used topically for antibacterial property
    • ADR: marked nephrotox
  28. Cycloserine
    • MOA: inhibits Gram + and Gram - org.; structural analog of D - Ala; inhibits the incorporation of D - Ala; inhibits alanine racemase, which converts L-alanine to D - alanine
    • Uses: almost exclusively to treat TB caused by M. Tuberculosis resistant to first - line agents
    • ADR: dose-related CNS tox, headaches, tremors, acute psychosis & convulsions
  29. Amnioglycosides
    • Drugs: amikacin (broadest specrum among AG), gentamicin (MC used AG), kanamycin, neomycin, streptomycin (TB), tobramycin, netilmicin
    • MOA: bactericidal antibiotics that bind to 30S ribosome and inhibit bacterial protein; interfere with the initiation complex of peptide formation; induce misreading of mRNA, which causes incorporation of incorrect AA into the peptide, resulting in a nonfunctional or toxic protein; cause a breatkup of polysomes into nonfunctional monosomes
  30. MOR(esitance) of Aminoglycosides
    • impaired entry of aminoclycoside into the cell; produces a transferase enzyme or enzymes that inactivate the aminoglycoside; receptor protein on the 30S ribosomal subunit may be delted or altered as a result of a mutation
    • Strep and enterococci develop resistance to aminoglycosides by decreasing penetration
    • Netilmycin and amikacin - resistant to inactivation by bacterial enzymes
    • poorly absorbed orally and must be used parenterally for systemic infection; after injection, aminoglycosides are distributed mainly in the ECF
  31. Spectrum of Aminoglycosides
    • exception: streptomycin
    • all aminoglycosides have good activity against Gram- aerobic bacilli, but lack activity against anaerobes
    • should always be added to a B-lactam antibiotic when treating serious P. aeruginosa infection; synergistic action
  32. Neomycin
    • Not absorbed in the GI tract; oral admin, the intestinal flora is suppressed or modified and the drug is excreted in the feces
    • HEPATIC COMA (decrease in the production and absorption of ammonia from GI tract will be beneficial) decrease coliform flora
    • decrease production of ammonia that causes the levels of free nitrogen to decrease in the blood stream
  33. ADR of Aminoglycosides
    • AmiNOglycosides - Nephrotoxicity and Ototoxicity
    • Ototoxicity - dose and duration related ADR
    • Nephrotox - results in loss of urinary concentrating capacity of tubules
  34. Ototoxicity
    • cochlear damage: results in hearing loss. High frequency sound is affected first, then low frequency
    • Vestibular damage: headache appears first followed by nausea, vomiting, dizziness, nystagmus, vertigo and ataxia
    • do not take with Furosemide or vancomycin!
    • Drugs: neomycin, kanamycin, amikacin - cochlear toxic agents (Neo kan maik you deaf)
    • Streptomycin and gentamicin - most vestibulotoxic (step gently or else you will fall)
  35. Nephrotoxicity of Aminoglycosides
    • Toxic ATN (more with Gentamicin)
    • elderly more prone for this kind of toxicity
    • Neomycin, tobramycin also toxic
  36. Macrolides
    • Drugs: azithromycin, clarithromycin, erythromycin
    • MOA: binds reversibly to the 50S subunit; protein synthesis inhibited because aminoacyl translocation reactions and the formation of initiation complexes are blocked
  37. MOR - macrolides
    • gram + org resistance due to efflux pump (throws out the drug from within the cell); production of methylase enzyme
    • Acquired resistance - specific mutation in the ribosomal RNA of the 50S ribosomal subunit
    • Cross resistance among macrolides is complete
  38. antibacterial activity
    • campylobacter, chlamydia, mycoplasma, legionella, gram+ cocci and some Gr - org
    • Azithromycin and Clarithromycin - similar spectrum but more activity against Chlamydia, MAC, and Toxoplasma
    • Clarithromycin approved for prophylaxis and H. pylori regimen
    • used for atypical bacteria
  39. ADR of Macrolides
    • Gastrointestinal - up to 33% - nausea, vomiting, diarrhea, dyspepsia, MC with erythromycin (activates motilin)
    • Cholestatic hepatitis - rare; 1 to 2 weeks of erythromycin estolate (high risk in pregnant women)
    • Thrombophlebitis - IV Erythro and Azithro - dilution of dose needed; slow administration
  40. drug interactions - macrolides
    erythromycin and clarithromycin only - inhibitors of CYP450; may increase concentrations in co-admin of drugs; causing tox
  41. Tetracyclines
    • Drugs: Chlortetracycline, oxytetracycline, demeclocycline, doxycycline, minocycline
    • MOA: reversibly to the 30 S subunit; block the binding of aminoacyl - tRNA to the acceptor site on the mRNA - ribosome complex; prevents addition of AA to the growing peptide
    • MOR: dev of efflux pumps; decreased activity of the uptake systems
  42. pharmokinetics of tetracyclines
    • orally - mostly absorbed in the upper small intestine
    • portion of the drug remains in the intestinal lumen and modifies intestinal flora - superinfections
    • absorption impaired by presence of food and calcium
    • excreted mainly in the urine; doxycycline - only drug excreted in the stool - can be safely given to patients with renal impairments
  43. Spectrum of action - Tetracyclines
    • broad spectrum antibiotics
    • active against Gram+ and Gram- bacteria including anaerobes
    • active against atypical bacteria such as rickettsiae, chlamydiae, mycoplasma
    • ctive against some protozoa
    • DOC: infections with Mycoplasma pneumona, chlamydia, rickettsia and some spirochetes
  44. Uses of tetracyclines
    • Primary uses: Rx of infections caused by Mycoplasma pneumoniae, chlamydia, Rickettsia, and Vibro
    • Secondary uses: alternative drugs in syphillis
    • Rx: leptospirosis, acne
    • excellent activity in cholera, plague, brucellosis and ameobiasis
    • included in anti H. pylori regimen
  45. Demeclocycline
    • MOA: inhibits the renal actions of ADH
    • used in the management of ADH secreting tumors
  46. ADR of tetracyclines
    • direct local irritation of the GIT causes nausea, vomiting, and diarrhea; superinfection due to effect on the intestinal flora, readily bound to calcium deposited in the newly formed bone or teeth in young children - discoloration and enamel dysplasia; skeletal deformities or growth retardation
    • photosensitivity: esp demeclocycline causes enhanced sensitivity rays
    • vestibular toxicity: dose dependent reversible dizziness and vertigo (more with doxycycline and demeclocycline)
    • C/I in pregnant women and children below 14 years of age - hepatic necrosis
  47. Chloramphenicol
    • Broad spectrum antibiotic
    • inhibits protein synthesis by binding to 50S ribosome subunit
    • inhibits the peptidyl transerase step of protein synthesis
    • ADR: bone marrow depression (reversible suppression of red cell production) -> aplastic anemia; if used in pregnancy -> causes gray baby syndrome
  48. Grey baby syndrome
    • infants lack glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol
    • signs and symptoms: vomiting, flaccidity, hypothermia, gray color (cynosis), shock, and collapse
    • Tx: exchange transfusion
  49. Lincosamides
    • Clindamycin - same MOA as macrolides; inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions
    • Mechanism of resistance: methylation of binding site on the 50S ribosomal subunit
    • Uses: anaerobic infections (bacterioides), prophylaxis of endocarditis in valvular disease, against Pneumocystis carinii and Toxoplasma gondii
    • ADR: GI irritation, Skin rashes, Neutropenia, Superinfection (pseudomembranous colitis, due to C. diff
  50. Streptogramins
    • Quinipristin - dalfopristin combination
    • MOA: inhibits the tRNA synthetase; antibacterial effect include MRSA and VRSA
    • Given IV
    • ADR: arthralgia, myalgia
    • potent inhibitors of CYP3A4, increases plasma levels of cisapride, cyclosporine, diazepam, and warfarin
  51. Linezolid
    • Oxazolidinone group of drugs
    • active against drug - resistant Gr + cocci (VRSA)
    • MOA: binds to a unique site on the 23 S ribosomal RNA of the 50S ribosomal subunit
    • No cross resistance with other protein synthesis inhibitors
    • ADR: thrombocytopenia and neutropenia (esp in immunocompromised pts)
  52. Folate
    • required for DNA synthesis in both bacteria and animals
    • humans cannot synthesize folate, it must be provided in the diet
    • bacteria synthesize their own folate from precursors like PABA
    • Antibiotics (sulfonamides) may compete with PABA for active site on enzyme (dihydropteroate synthase)
  53. sulfonamides - drugs
    • short acting - 4h - sulfisoxazole
    • intermediate acting - 8-12h - sulfadiazine, sulfamethaxazole
    • long acting - sulfadoxine
    • structural analogue of PABA, competitively inhibit the dihydropteroate synthase and the synthesis of folic acid in microbes
  54. sulfonamides
    • active against both Gram+ and neg. organisms, chlamydia and some protozoa but rickettsiae
    • not used alone; combined with trimethoprim or other drugs
    • used alone -> effective for uncomplicated mild uti, but co-trimoxazole is preferred
  55. cotrimoxazole
    • fixed dose combination of sulfamethaxazole and trimethoprim -> cotrimoxazole
    • causes sequential block of folate metabolism
    • individually - bacteriostatic; together - bactericidal &synergistic
    • DOC: Pneumocystis carinii, UTI (uncomplicated), respiratory tract infection, typhoid fever, chancroid
  56. Uses of other sulfa drugs
    • Malaria - sulfadoxine + pyrimethamine
    • Toxoplasmosis & P. Carinii - sulfadiazine + pyrimethamine
    • Nocardiosis - Sulfadiazine
  57. ADR of sulfonamides
    • Hypersensitive reaction - Stevens - Johnson syndrome (allopurinol and ethosuximide; skin rash)
    • Crystalluria - white urine
    • Nausea, vomiting, gastritis
    • hemolysis in those with G-6-PD deficiency
    • Kernicterus - new born; neonatal jaundice bilirubin enters brain
    • cross allergy - other drugs made of sulfa (thiazides); sulfureas (for DM and UC)
    • Resistance - overproduction of PABA; enzyme's less affinity for drug
  58. Trimethorprim/Pentamidine
    • MOA: inhibits bacterial dihydrofolate synthase
    • Uses: combination with sulfonamide causing sequention blockage of folate synthesis
    • DOC: co-trimoxazole of pneumocystis carinii and Uncomplicated UTI
    • ADR: folic acid deficiency -> megaloblastic anemia (use folinic acid)
  59. Fluoroquinolones
    • MOA: binding to subunit A, inhibits DNA gyrase -> inhibits the neg. supercoiling of DNA; inhibits topoisomerase II; deficit of neg. supercoiling to relax the positive supercoiling results in irreparable breakages in the DNA strand
    • Drugs: 1st group (norfloxacin - least active); 2nd group ( active mainly against gram -: ciprofloxacin, lomeflaxacin, ofloxacin, levofloxacin, pefloxacin); 3rd group (active against both gram+ and gram-: sparfloxacin, moxifloxacin, travofloxacin, gatifloxacin)
  60. Ciprofloxacin
    • Most potent, most active against gram- bacteria (E.coli, Kleibsiella, Enterobacter, S. typhi, shigella, Proteus, Neisseria, Gonorrhea, N. Meningitidis, H. influenza, H. ducreyi, Staphylococci, V. cholera
    • DOC: Pseudomonas aeurogenosa
  61. Uses of floroquinolones
    • typhoid fever
    • UTI (complicated): gram neg. (e.coli) -> uncomplicated - cotrimoxazole; complicated - ciprofloxacin
    • Gonorrhoea (DOC - ceftriaxone)
    • Chancroid (DOC - doxycycline)
    • Chlamydia (DOC - ofloxacin - NOT other quinolones)
    • Pseudomonas aeurogenosa - DOC: Ciprofloxacin (only give piperacillin or cephalosporins in pregnant patients or children or elderly)
  62. ADR of flouroquinolones
    • arthropathy in children - don't give this drug to pregnant patients or children or elderly; ruptured tendons
    • Travofloxacin: hepatitis
    • Drug interactions - prolonged QT interval: commonly seen with Sparfloxacin when combined with - procainamide, sotalol, amiodarone, erythromycin, ketaconazole, cimentidine
  63. Rheumatic Fever - Jones Criteria
    • Affects children 5-15
    • Major: carditis, migratory polyarthritis, sydenham's chorea, erythema marginatum, subcutaneous nodules
    • Minor: fever, arthralgia, prolonged PR interval
    • supporting evidence of a recent group of A strep infection
    • DOC: penicillin/erythromycin for 10 days; Benzathine penicillin G every 3 weeks for minimum 5 years as secondary prophylaxis
  64. infective endocarditis
    • Staph and Strep are common causitive agents; strep viridans, staph aureus, coagulase neg staph, candida albicans
    • Tricuspid valve commonly affected
    • nosocomial infection, injection drug use, and prosthetic valve are the common predisposing factors
    • clinical features: fevers, chills and sweats, splenomegaly, petechia, anemia, microscopic hematouria, leuckocytosis
    • duke criteria: two major criteria, or one major and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis; blood culture, echocardiography
    • TX: S.epi/aureus - vancomycin; strep viridans - amox; fungal - anti fungal
  65. meningococcal meningitis
    • N. meningitis, nausea, vomiting, headache, neck stiffness, lethargy, and confusion
    • diagnosis: csf test
    • DOC: ceftriaxone/cefotaxime, penicillin G, chloramphenicol, prophylaxis: rifampin
  66. Mycobacterium infections
    • Mycobacterium tuberculosis, MAC, mycobacterium lepra, mycobacterium bovis
    • GA are ineffective against these slowly growing organisms
    • mycobacterium are notorious for development of resistance, so always combination of drugs used for prolonged period
  67. anti-tuberculosis drugs - first line drug
    • Isoniazid (H)
    • Rifampin (R)
    • Pyrazinamide (Z)
    • Ethambutol (E)
    • Streptomycin
  68. TX of TB
    • First two months - intensive therapy of daily four drugs HRZE, sometimes 5 -> rapidly kill mycobacteria, cause sputum conversion, give symptomatic relief
    • Last four months - maintenance therapy with daily two drugs HR -> prevent hte relapse of the disease
  69. Rifampin
    • MOA: inhibits beta subunit of DNA dependent RNA polymerase enzyme
    • Orally; crosses BBB and abscess/cavity
    • Side effect: changes body fluids to Red/Orange; incReases (inducers) CYP450 -> failure of therapy
    • Uses: TB, M. Leprae, Prophylaxis of Meningiococcus
  70. Isoniazid
    • MOA: inhibits myocolic acid synthesis
    • Uses: TB
    • Side effects: drug induced SLE, Vit B6 def -> peripheral neuropathy, hemolysis if pt has G6PD, hepatotox
  71. Pyrazidamide
    • MOA: unknown
    • Side effect: hepatotox, hyperurecemia (gout)
  72. Ethambutol
    • MOA: inhibits arabinosyl transferase enzyme (inhibit arabinoglactan synthesis)
    • Side effects: eye disturbances - red/green color blindness & optic neuritis in children
  73. TB in AIDS, preggers, and role of steroids in TB
    • AIDS: 9 mth therapy with 3 mth HRZE and 6 mth HR
    • Preggers: same treatment, no change
    • Steroids: generally C/I; used in pleural effusion to prevent/break down the pleural adhesions
  74. MAC infections
    • Clarithromycin plus ethambutol given life long to treat MAC infections in AIDS
    • lifelong prophylaxis with Azithromycin/Clarithromycin/Rifampin to prevent MAC infections in AIDS
  75. Anti-Leprosy drugs
    • Sulfa: Dapsone
    • Anti - tubercular: Rifampin
    • Dye: Clofazamine
    • Other Antibiotics: Minocycline, Clarithromycin, Ofloxacin, Pefloxacin, Sparfloxacin
  76. Dapsone
    • Uses: malaria, TB
    • MOA: competes with PABA to decrease synthesis of Folic acid
    • Side effect: hemolysis if pt has G6PD; dapsone reaction: rash, eosinophilia, jaundice, fever - occurs within 2 mth of therapy - TX - steroids
    • Cross antigenicity with other sulfa drugs
  77. Amphotericin B
    • MOA: interact with ergosterol in funcal cell membrane to form pores - distrupt the membrane permeability; fungalcidal with broad specrum
    • Uses: aspergillus, candida, cryptococcus, histoplasma, mucor, sporothrix; remains drug of choice for nearly all life threatening fungal infections
    • often administered initially and replaced by azoles if chronic therapy required; given IV; slow clearance - 15 day half life, poor penetration into CNS
    • ADR: infusion related - fever, chills, muscle rigor, hypotension (release of histamine), nephrotox ("Amphoterrible"), arrythmias
  78. Nystatin
    • MOA: similar to amphotericin B
    • ADR: too toxic for systemic use; used topicaly in candidiasis; more nephrotoxic
    • Uses: all superfical fungal infections
  79. Azoles
    • MOA: interfere with the synthesis of ergosterol by inhibiting 14-a-demethylase which converts lanosterol to ergosterol
    • resistance - Efflux pump
    • Drugs: ketoconazole (KTZ), Fluconazole, Itraconazole
  80. Ketoconazole (KTZ)
    • Orally acidic environment needed to dissolve drug
    • Not enter CNS well; given IV
    • ADR: high estrogen (gynecomastia, loss of hair and libido, oligospermia)
    • Interactions: CYP inhibitor -> toxicity; oral absorption is reduced by H2 blockers - omeprazole and antacids
    • Uses: mucocutaneous candidiasis and dermatophytoses
  81. Fluconazole
    • Well absorbed orally, enters CNS
    • Least effect on liver enzymes
    • Uses: DOC - esophageal candidiasis&coccidioidomycosis, prophylaxis and RX of cryptococcal meningitis
    • Less side effects than KTZ - can be used in pregnancy
  82. Itraconazole
    • Absorption increased by food
    • Poor penetration to CNS
    • ADR: nausea, vomiting, liver dysfunction, hypokalemia
    • Drug-drug interactions, similar to ketoconazole but to lesser degree
    • DOC: blastomycosis, sporotrichosis
  83. Griseofluvin
    • MOA: binds to microtubules comprising the spindles and inhibits mitosis; incorporates into affected affected keratin - fungistatic
    • Spectrum: dermatophytes only
    • Uses: dermatophyte infection of skin, nail, hair, feet despite given orally
    • ADR: headache, photosensitivity, CYP inducer, C/I in pregnancy
  84. Flucytosine
    • MOA: cytosine deaminase converts 5-flucytosine to 5-fluorouracil ultimately inhibiting DNA synthesis; prodrug
    • Uses: fungistatic, used with amphotericin B because of synergistic effects for treatment of systemic fungal diseases
    • ADR: bone marrow suppression, hair follicles (balding), mucous membrane in GI (gastric ulcers)
  85. Terbinafine
    • MOA: inhibits squalene epoxidase
    • DOC: pityriasis versicolor
    • ADR: GI upset, hepatotoxicity
    • CYP 450 inhibitor
    • Christmas tree fungal infection -> little spots of light circles; triangle shaped on the stomach or on lower back
  86. Tissue sporozoites
    • Primaquine
    • Used: prevent the relapse of infection because it irradicates hypnozoites; vivax or ovale
  87. Blood sporozoites
    • rest of the antimalarial drugs
    • Used: clinical cure and prophylaxis
  88. TX of Chloroquine sensitive malaria
    • P. falciparum: Chloroquine alone
    • P. malariae: Chloroquine alone
    • P. Vivax and ovale: Chloroquine + Primaquine (to kill hypozoites)
  89. TX of Chloroquine resistant P. flaciparum
    • Drugs: Quinine, Mefloquine
    • Notes: serious/complicated P. falciparum is treated by IV Quinidine
  90. Prophylaxis of Malaria
    • Chloroquine sensitive regions: Chloroquine+/- Primaquine
    • Chloroquine resistant regions: Mefloquine
    • In pregnancy: all drugs can e used EXCEPT primaquine; cannot treat vivax or ovale while pt is preggers
  91. Chloroquine
    • MOA: accumulates in food vacuole of parasite. prevents conversion of heme to hemozoin. Heme accumulation leading to death
    • Other Use: amebic liver abscess
    • ADR: Pruritis, GI irritation, Retinopathy
  92. Quinine
    • Quinidine is a D-isomer of Quinine
    • Given IV - tx of severe, complicated
    • Uses: Chloroquine resistant P. falciparum malaria
    • ADR: cinchonism, arrythmia, causes hemolysis in G6PD deficient patients, intravascular hemolysis - called as black water fever
    • Note: remember sulfonamides, dapsone and isonizaid
  93. Mefloquine
    • Given only orally, long half life of 20 days
    • Use: Chloroquine resistant malaria tx and prophylaxis
    • ADR: syncope, Exra cardiac beats
    • C/I: psychosis, seizures, cardiac conduction defects
  94. Primaquine
    • Only active agent against dormant liver forms of vivax and ovale (Hypnozoites)
    • only drug used to prevent the relapse cases of vivax and ovale
    • ADR: hemolysis in G6PD def pts
  95. TX of pneumocystosis
    • MCC of pneumonia is AIDS patients/homosexual males
    • Drugs: TMP - SMZ (cotrimaxozole, pentamidine, pyrimethamine plus sulfadiazine
  96. Metronidazole
    • Orally and IV
    • MOA: unknown
    • Uses: all forms of amebiasis (colitis and hepatic), trichomoniasis, giradiasis, anerobic bacterial infections (B. fragillis, C. Diff(doc)), H. pylori associated peptic ulcers
    • Interactions: disulfram like reaction of with alcohol
  97. Praziquantel
    • MOA: increased calcium influx -> paralysis of worms
    • Uses: cestodes and trematodes
    • Org: Schistosoma, Clonorchis
  98. Ivermectin
    • Use: Round Worms
    • Org: Ochocerca volvulus (rIVER blindness)
    • MOA: increased calcium influx -> paralysis of worms
  99. HIV - Reverse Transcription
    • allow HIV's genetic code to join the host cell's DNA, a double stranded DNA replica of the original RNA template is produced
    • for HIV genes to get into the host cell's DNA, the viral RNA has first to be converted to DNA
    • Reverse transcription produces a single strand of DNA from the viral RNA
  100. Nucleoside Reverse Transcriptase Inhibitors (NRTI)
    • Drugs: Zidovudine (AZT), Didanosine (ddl), Zalcitabine (ddC), Stavudine (D4T), Lamivudine (3TC)
    • MOA: effective against retroviruses only (produce RT); integrated into the growing viral DNA and terminates chain elongation; resistance is common and occurs due to mutation in RT enzyme; always used in combination with other drugs (HAART therapy)
    • ADR: Pancytopenia, Pancreatitis, Peripheral Neuropathy
    • C/I: Alcoholics and Gall Stones
    • Uses: treatment and prophylaxis of HIV; Zidovudine used to prevent vertical transmission of HIV (mother to fetus - combination given in 2nd or 3rd trimester to mother)
  101. ADR of Drugs - NRTI
    • Zidovudine (AZT): Pancreatitis, Megaloblastic anemia, asthenia, myopathy, peripheral neuropathy
    • Didanosine (ddi): Pancreatitis, periperal neuropathy, hyperurecemia, liver tox
    • Zalcitabine (DDC): Periperhal neuropathy, GI, pancreatitis, neutropenia, rash
    • Stavudine (D4T): peripheral neuropathy, myelosuppression
    • Lamivudine (3TC): Least toxic among NRTI, GI, Neutropenia
  102. Non - nucleoside analog reverse transcriptase inhibitors (NNRTI)
    • MOA: inhibit the reverse transcription directly
    • ADR: Rash, or no adr at all
    • Drugs: NeVIRapine, DelaVIRdine, EfaVIRenz
  103. Protease Inhibitors
    • MOA: during reproduction cycle o HIV, a specific protease is needed to process polyproteins into mature HIV components; if protease is missing non - infectious HIV is produced; specific to HIV protease because it differs significantly from human protease
    • Drugs: SaquiNAVIR, IndiNAVIR, NelfiNAVIR, RitoNAVIR, AmpreNAVIR, IopiNAVIR
    • ADR: GI intolerance, parasthesia, dizziness, rash, headache, hyperglycemia, hyperlipidemia, Thrombocytopenia (Indinavir), Ritonavir is CYP450 inhibitor - coadmin increases conc. of these drugs
    • Notes: lopinavir has low oral bioav.; L+R increases the anti-retroviral effect of Lopinavir
  104. Combination therapy
    • HAART
    • restore sensitivity: lamivudine and zidovudine
    • compete for binding site: zidovudine and stavudine
    • Possible combinations: 2 NRTI+1 NNRTI; 2 NRTI+1 PI; 1 NRTI+1 NNRTI+1 PI; 3 NRTI
  105. HIV prophylaxis
    • Needle Stick: AZT+3TC for one month
    • High risk cases: AZT + 3TC+ Indinavir
    • Pregnancy: AZT full dose in trimester 2 and 3 + 6 weeks to neonate
  106. Herpes Virus
    • Drugs: Acyclovir (prototype), Valacyclovir, Famciclovir, Penciclovir, Trifluridine, Virdarabine
    • MOA (Acyclovir): acyclic gunasine derivative, phosphorylated by viral thymidine kinase, inhibits virus DNA synthesis by: competing with GTP for viral DNA polymerase, chain termination
    • MOR: lack of viral thymidine kinase; changes in the viral DNA polymerase
  107. Acyclovir
    • Clinical uses: oral, IV and topical formulations; cleared by glomerular filtration and tubular secretion
    • Uses: HSV 1 &2, VZV
    • ADR: nausea, diarrhea, headache, tremors, and delirium, seizures if overdosed, crystalluria (maintain hydration to prevent this)
  108. Anti - CMV
    • Drugs: Gancyclovir, Foscarnet, Valgancyclovir, Cidofovir, Fomivirsen
    • Ganciclovir: moa - same as acyclovir; used: HSV, VZV, CMV; prophylaxis and Rx of CMV infections; ADR: hepatotox, leukopenia, thrombocytopenia, crystalluria, seizures in overdose
    • Note: person resistant to acyclovir, also resistant to ganciclovir
  109. Foscarnet
    • MOA: acts by inhibiting the DNA and RNA polymerases
    • Uses: Rx of acyclovir - resistant strains of HSV and CMV and simplex 1 and 2 as well
    • ADR: nephrotox (acute tubular necrosis)
  110. Fomivirsen
    • MOA: binds to mRNA and inhibits protein synthesis and viral replication
    • Uses: CMV retinitis (given as an intravitreal injection)
    • Side effects: iritis and increased intraocular pressure
  111. Different types of influenza
    • Type A and B - focus of antivrial treament
    • A - global epidemics
    • B - regional outbreaks
    • Drugs: Amantadine, Rimantadine, Oseltamivir, Zanamivir
  112. Oseltamivir and Zanamivir
    • MOA: inhibitors of an enzyme called Neuraminidase - found on the outer cell membrane of viral particles; inhibits binding of virus to host cell
    • Uses: active against influenza A & B
  113. Amantadine and Rimantadine
    • MOA: act by inhibiting the uncoating of viral RNA of influenza A; both equally effective; no action against influenza B (prevents viral replication)
    • ADR: GI intolerance, CNS tox - psychosis with amantadine
    • C/I: psychotic pts
  114. Other antivirals
    • Interferon alfa - used in treatment of HBV and HCV
    • Ribavarin - oral admin for HBV; given as a nebulizer in severe RSV infections (RSV - respiratory syncytial virus)
    • Rx of hepatitis B&C - Interferon, Lamivudine, Ribavarin (B only)
  115. Two types of immunity
    • Cell mediated immunity: mediated by T lymphocytes
    • Humoral immunity: mediated by antibodies produced by B cells
  116. Abnormal immune responses
    • Hypersensitivity reactions: type 1 - IgE mediated causing urticaria, angioedema, rashes, asthma, severe anaphylactic shock; eg. Penicillin reaction/Peanut allergy/bees; treated with - epi and hydrocortisone and dopamine at high doses
    • Autoimmune disorders
    • Immune deficiencies
    • requires immunosuppressant therapy in first two incidences and immunostimulat therapy in the third
  117. Immunosuppressants
    • Specific T cell inhibitors: Cyclosporin, Tacrolimus, Sirolimus (also inhibits B cells)
    • Cytotoxic drugs: Azathioprine, Methotrexate, Cyclophosphamide, Chlorambucil
    • Newer drugs: Etanercept, Leflunamide, Thalidomide
    • Antibiotics: Muromunab - CD2, Dacizimab, Infliximab, Lymphocyte Immunoglobulin, Rh (D) immunoglobulin
  118. Cyclosporine
    • normal stimulation of T helper cells leads to activation of calcineurin, cytoplasmic phosphatase which dephosphorylates the regulatory protein NF-AT permitting its translocation and production of IL-2
    • MOA: enters the target cells, binds to protein called Cyclophyllin and forms a complex -> complex inactivates calcineurin and inhibits the IL-2 production-> eventual inhibition of T cell proliferation finally leading to immunosuppression
    • DOC: any organ transplant
  119. Tacrolimus
    MOA: same as Cyclosporine, except it binds to FK binding protein (FKBP) instead of Cyclophyllin
  120. Cyclosporin and Tacrolimus
    • Uses: prevention and treatment of graft rejection reactions in solid organs, bone marrow and skin transplantations; rheumatoid arthritis, psoriasis, asthma
    • ADR: nephrotox (75%), Infections (70% - a lot of infection due to inhibiting the immune system), HTN
    • Note: give drug to recipient or person donating? both are receiving the drug, particularly the recipient because you do not want the bodies to reject the organ, aka Graft vs. Host disease
  121. Cytotoxic cells
    • Azathioprine: prodrug; gets transformed into 6-Mercaptopurine; uses: sle and glomerulonephritis
    • Thalidomide: C/I in pregnancy, limb defects - flipper limbs
  122. Antibodies
    • Lymphocyte Immuno Globulin (LIG): aka anti thymocyte globulin (ATG); uses: prior to bone marrow transplant to prevent graft vs. host reaction
    • Rh 0 (D) Immunoglobulin: uses - prevention of Rh hemolytic disease of the new born
  123. Monoclonal antibodies
    • Muromunab - CD3: MOA - binds to CD3 antigen on surface of T cells and blocks action of T cells; uses - renal homograft rejection crisis (acute rejection crisis - works right away)
    • Daclizumab: hibly specific, binds to IL -2 on T cells; uses - with other drugs for renal transplants
    • Infliximab: TNF - alpha antagonist, used in rheumatoid arthritis, Crohns disease, inflammatory bowel disease
  124. Immunomodulators
    • Aldesleukin: Recombinant interleukin - 2; used for renal cell carcinoma
    • Interferons: interferon alpha used in hairy cell leukemia, CML, kaposi sarcoma, and hepatitis, melanoma, renal cell carcinoma; interferon beta used in MS, hep B &C
    • BCG (Bacille Calmette - Guerin): used in TB immunization (PPD skin test can show up positive due to this vaccination) and surface bladder cancer
    • Thymosin: protein hormone from thymus gland, promotes maturation of pre T cells; used in Di George's syndrome (thymic aplasia - thymus and parathyroid gland not present)
  125. Treatment of cancers
    • Cancers curable with drugs alone: testicular cancer, lymphomas, choriocarcinoma, childhood tumors - ALL, Burkitt's lymphoma, Wilms tumor
    • Malignancies curable by surgery and drugs: Ca Breast, osteogenic sarcoma, esophageal cancer, rectal cancer
    • Most of other malignancies: only used as palliative therapy (pancreatic)
    • Debulking - surgery for cancer
  126. Cell Cycle specificity (CCS)
    • MOA: kill only actively dividing cells, effective in hematological cancers (eg. leukemia, lymphoma) and solid tumors with more proliferation (eg. choriocarcinoma). Different drugs activate in different stage of cell cycle
    • Uses: fastly growing cancer; any cell in G0 phase, it will not be affected at all
  127. Cell Cycle non specific (CCNS)
    • MOA: kill both resting as well as dividing cells
    • Uses: does not work against fastly growing cancers, works against our own body tissue
  128. General principles of cancer chemotherapy
    • Combination of drugs: 2-6 drugs with diff MOA, toxicity profile and kinetic scheduling; should be effective when used alone; produced greater tumor cell killing
    • Intensive pulse courses: every 3-4 wks with max tolerable doses; allows hematological and immunological recovery between the cycles of therapy so less adverse effects
    • Kinetic scheduling: drugs should be given according to their nature of CCS
    • ADR: gastric ulcers, balding, bone marrow suppression, teratogenecity, carcinogenecity, impotence, sterility, amenorrhoea
  129. Resistance to anticancer drugs
    acquired: single drug resistance (mutation); multiple drug resistance (over expression of MDR1 (calcium atpase pump), gene for cell surface proteins acting as drug efflux pumps - verapamil can reverse it
  130. Alkylating agents
    • MOA: form reactive carbonium ion intermediates which transfers alkyl group to nucleophillic group of DNA (N-7 position of guanine); results in abnormal base pairing or cross linkage of DNA; S phase specific (DNA synthesis) - killled when it comes to the next step)
    • Drugs: bisamines - Cyclophosphamide, Chlorambucil, Mechloroethamine, Melphalan; others - Busulphan, Cisplatin, Procarbazine, Carboplatin, Dacarbazine
  131. Cyclophosphamide
    • MOA: inactive as such, transformed to active metabolite aldophosphamide by splitting off acrolein (responsible for its impt side effect)
    • ADR: hemorrahagic cystitis
    • TX: with Mesna or N - acetyl cystine
  132. Busulfan
    • ADR: pulmonary fibrosis, skin pigmentation
    • Smokers stay away from this drug!
  133. Cisplatin
    • ADR: highly emetic, ototoxic, neuro toxic and renal toxic
    • TX: Amifastine reduces nephrotoxicity
  134. Procarbazine
    • part of MOPP regimen
    • Uses: Non - hodgkins lymphoma
  135. Antimetabolites
    • MOA: Drugs that competitively inhibit untilization of normal substrate or get themselves incorproated forming non-functioning marcomolecules
    • Folate antagonists: Methotrexate
    • Purine Antagonismsts: Mercarptopurine (6-MP), Azathiprine, Thioguanine (6-TG)
    • Pyrimidine antagonists: 5-Fluorouracil, carpecitabine, Cytarabine, Gemcitabine
  136. Methotrexate
    • Oldest, highly efficacious
    • MOA: inhibits dihydrofolate reductase, leading to reduced synthesis of nucleotides. Kills cells in S phase
    • ADR: folate def -> bone marrow suppression (Leucovorin rescue - prevented by giving folinic acid)
    • DOC: horiocarcinoma and ALL; also for - other leukemia/lymphomas, rheumatoid arthritis, psoriasis, immunosuppressant for organ transplant rejections, ectopic pregnancy -> miscarriage
    • ADR: enhanced by trimethoprim and probenecid (inhibits active secretion of this drug)
  137. Mercaptopurine
    • MOA: first the drugs are activated by HGPRTase to toxic nucleotides that inhibits the inter conversion steps in purine synthesis
    • Resistance: due to reduced activity of HGPRTase enzyme in tumor cells
    • Notes: metabolized with Xanthine oxidase - to inhibit use allopurinol
    • ADR: none!
  138. 5 - Fluorouracil (5-FU)
    • MOA: first converted to 5FdUMP, which inhibits the thymidinylate synthesis -> no thymidine -> no DNA
    • Resistance: due to increased thymidinylate synthase
    • Notes: also used as antifungal agent (flucytosine, eventually converted to 5-FU in fungus); synergistic effectives with Methotrexate
    • Uses: solid tumors
    • ADR: BM suppression (not reversible with Folinic acid) - only specific for G1 phase, kill cells in S phase
  139. Vinca alkaloids
    • Drugs: Vincristine (Oncovin) and Vinblastine
    • MOA: acts primarily in M phase, bind to micro tubular protein (beta - tubulin), prevent its polymerisation and blocks the formation of mitotic spindle
    • Uses: component of MOPP and COP in HOdgkin's and non Hodgkin's respectively
    • ADR: neurotox with peripheral neuropathy, BM suppression
  140. Taxanes
    • Drugs: Paclitaxel and Docetaxel
    • MOA: binds to beta - tubulin, has opposit action of vinca alkaloids, inhibits microtubule depolymerization, prevent microtubule disassembly into tubulin monomers
    • ADR: peripheral neuropathy
    • Uses: breast and ovarian tumors
  141. Bleomycin
    • Antibiotic
    • ADR: pulmonary fibrosis
  142. Doxyrubacin
    • MOA: inhibit topoisomerase II and generate free radicals
    • ADR: dilated cardiomyopathy
    • Dexrazoxane - free radical inhibitor (an iron chelating agent) is used as 'rescue therapy' to minimize the cardiotoxicity
  143. L-Asparaginase
    • Derived from E.Coli
    • MOA: enzyme that depletes serum aspirigine. Leukemic cells cannot synthesize aspirgine - they die. Normal cells remain unaffected
    • Uses: childhood ALL
    • ADR: severe pancreatic tox
  144. Corticosteroids
    • Not cytotoxic, but modify the growth of hormone dependent tumors
    • Glucocorticoids: used in ALL mainly, but an treat other leukemias and lymphomas; Prednisone - MC
    • ADR: cushing's disease, osteoperosis, HTN, immunosuppression, peptic ulcers, hyperglycemia
  145. Hormones as treatment for cancer
    • Flutamide - testosterone receptor blocker: prostate cancer
    • Tamoxifen - estrogen receptor blocer: estrogen dependent breast cancer
    • Leuprolide - GnRH analogue: breast and prostate cancers
  146. Treat side effects of anticancerdrugs
    • Allopurinol: 6 - MP and treatment of gout (low protein diet if pt has gout; renal excretion - gets out uric acid)
    • Odancetron and dronobinol: anti-emetic
    • Erythropoetin: RBCs
    • Platelets: platelet transfusion
    • Methotrexate: Folinic acid; bone marrow
    • Amifostine: cisplatin, works only on nephrotox
    • Cyclophosphamide: hemorrhagic, use Mesna (N - acetyl cystiene)
    • Doxyrubisin: dexrazoneane
    • G-CSF: granulocytes colony stimulating factor - all WBCs
    • GM-CSF: granulocytes+monocytes
  147. Co-therapy regimens for cancers
    • MOPP: regimen in Hodgkins disease - Mechlorethamine, oncovin, procarbazine, prednizone
    • ABVD: regimen in Hodgkins disease - Adriamycin, bleomycin, vinblastine, dacarbazine
    • COP: regimen in Non -Hodgkins disease - cyclophosphamide, oncovin, prednisone
    • PVB: testicular cancer - cisplatin, vinblstine, bleomycin
    • CMF: breast cancer - cyclophosphamide, methotrexate, fluorouracil