1 / 29

DRUG INTERACTIONS

DRUG INTERACTIONS. Geriatric population Polypharmacy, multiple diseases, altered physiological response AIDS patients : antiviral drugs + antibiotics or antifungal agents for prophylaxis against opportunistic infections. Interactions during distribution and metabolism.

kreeli
Télécharger la présentation

DRUG INTERACTIONS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. DRUG INTERACTIONS • Geriatric population • Polypharmacy, multiple diseases, altered physiological response • AIDS patients • : antiviral drugs + antibiotics or antifungal agents for prophylaxis against opportunistic infections

  2. Interactions during distribution and metabolism • Interactions affecting distribution • fraction of drug is bound by plasma proteins (primarily albumin) • Binding sites of albumins e.g. are finite competition (and displacement ) takes place when 2 plasma protein- bound drugs are in the blood stream together. • Interactions increase (or inhibit) the metabolism • e.g. ethanol, antihistamines, phenytoin, barbiturates, glutethimide • e.g. phenybutazone, chloramphenical, allopurinal, cimetidine, desipramine and methylphenidate

  3. Interaction in the gastrointestinal tract • change of local pH; altering of gastric emptying or intestinal motility; complexes formation • complexes of tetracyclines formed in the presence of polyvalent mineral ions e.g. Al 3+, Ca 2+, Mg2+ • cholestyramine (a chcolesterol-lowering drug) acts as ion-exhanger resins to bind with anions, e.g. anticoagulant drug coumadin • Results: interference with absorption

  4. Interactions during excretion • Decreasing renal clearance of other drugs • e.g. probenecid, salicylates, sulfinpyrazone, phenylbutazone, thiazide diuretics • clinic use of probenecid to  [penicillin] in blood.

  5. Drug-food interactions • Some selected drug-food interactions, e.g. • Vitamin B12 (cyanocobalamin) + Vitamin C--large doses Precipitate B12 deficiency. • Thiamine + Blueberries, fish, Foods containing thiaminases + Alcohol Decreased intake, absorption, utilization • Benzodiazepines + Caffeine  Antagonism of antianxiety action • problems in combining drugs and herb medicine • tannings prevent absorption of certain drugs.

  6. Saquinavir, a protease inhibitor used in AIDS patients, low bioavailability (F = 4%) due to inactivation by cytochrome P-450 3A4 in liver and intestine, • grapefruit juiceF of Saquinavir (F  50%). • grapefruit juice also F of Triazolam, midazolam, cyclosporin, coumarin, misoldipine felodipne • Bioflavinoid naringin much less effect

  7. Summation and potentiation • effect of two drugs given at the same time may be • Additive 2+3 = 5 • Synergistic 2+3 = 8 • Potentiation 0+2 = 4 • e.g. in AIDS treatment, combining of AZT, 3TC and protease inhibitors

  8. ANTIBIOTICS: DRUGS THAT CURE • P. Ehrlich, chemotherapy, • “the use of drugs to injure an invading organism without injury to the host”, • 1904, discovered the organic dyes e.g. trypan red effective against in trypanosome-infected mice; • later studied the aromatic arsenicals against trypanosomiasis, • 1910, found arsphenamine effective in antisyphilitic; the compound was ‘606’ or Salvaran, too toxic to be used in human

  9. Antibiotics • Probably the only class of drugs that cures disease • Depends on its selective toxicity to the microbes • Bactericidal or bacteriostatic

  10. Basis of the selective toxicity of antibiotics • 1. inhibit a reaction vital only to the microbe and not the host, e.g. penicillin inhibits the cross-linking of microbial peptidoglycan. • 2. inhibit a reaction that yields a product vital to both microbe and host. However, the host has an alternative mechanism of obtaining the substance, e.g. sulfa drugs inhibit folic acid synthesis. • 3. undergo biochemical activation to a toxic form in the microbe, e.g. acyclovir to treat herpes viral infections. • 4. selectively accumulate in the microbe because of a more active cell membrane transport mechanism, e.g. quinine. • 5. have a higher affinity for a critical site of action in the microbe, e.g. chloramphenicol binds to 70s ribosome.

  11. Action mechanism of Acyclovir- must be phosphorylated to be active. • 1. Intracellularly converted to the monophosphate by viral thymidine kinases, • 2. to diphosphate by cellular guanylate kinase, • 3. finally to triphosphate by various cellular enzymes. • 4. Fully active acyclovir triphosphate competes with the natural substrate, dGTP, for a position in the DNA chain of the herpes virus. • 5. Once incorporated, it terminates DNA synthesis.

  12. Penicillin • 1928, Alexander Fleming, Staphylococcus variants contaminated with mold Penicillium notatum, lysis • 1940, Howard Florey: “enough evidence, ….., has now been assembled to show that penicillin is a new and effective type of chemotherapeutic agent, and possesses some properties unknown in any antibacterial substance hitherto described.” • Pfizer - mass production during World War II.

  13. Selective toxicity: human use of 12.5-15 g of penicillin per day without ill effects, 0.002 mg/ml may kill pneumococcus, high therapeutic index, • not always the case, e.g. antifungal drug amphotericinB (work by binding to ergosterol- the fungus membrane sterols), daily use 0.5-0.6 mg/kg, 1 mg can cause fever, chills and low blood pressure in some patients.

  14. 1930s, the discovery of sulfa drug against streptococcal infections, prontosil (prodrug of sulfanilamide) • Gerhard Domagk, administered the drug to his ill daughter to save her life. He received Nobel prize in 1939.

  15. Mechanism of action of antibiotics • Penicillins, cephalosporins are b-lactams (for containing the b-lactam ring structure), analogs of D-alanyl-d-alanine in the cell walls of gram-positive bacteria, covalently bound to penicillin-binding proteins (PBPs), cell permeability, leakage, death. (e.g. Penicillin G/V; amoxicillin; ampicillin)

  16. G (-) cocci: Gonococcus; Menigococcus G (+) cocci: Pneumococcus;Streptococcus; Staphylococcus G (-) rods: Acinetobacter; Bacteroides; Brucella; Enterobacter; E.coli; Haemophilus; Klebsiella; Legionella;Pasteurella; Proteus; Pseudomonas; Salmonella; Serratia; Providencia; Shigella; Vibrio G (+) rods: Actinomyces; Bacillus; Clostridium; Corynebacterium, Lsteria

  17. Classification of penicillins: 1. Natural: Penicillin G; Penicillin V 2. Penicillinase resistant: Methicillin 3. Broad spectrum: Amoxillin; Ampicillin 4. Anti-pseudomonas : carbenicillin; tricarcillin

  18. Vancomycinand Bacitracin, inhibitors of cell wall synthesis, but, are polypeptides. Vancomycin is only effective against G(+) microbes. • Polymyxins, amphipathic agents interacts with phopholipids microbial membrane, disruption of membrane, permeability increase, also affect mammalian's, restricted to topical application

  19. Rifampin inhibits DNA dependent RNA polymerase; prevention for patients exposed to N. meningitidis; H. influenzae • Quinolones interfere DNA gyrase ( responsible for supercoiling); the most commonly used in urinary tract infection.

  20. Protein synthesis inhibiors: • inhibit attachment of mRNA to 30s ribosome, e.g. aminoglycosides (gentamicin, neomycin) • inhibit tRNA binding to 30s ribosome, e.g. tetracycline • inhibit attachment of mRNA to 50s ribosome, e.g. chloramphenicol • inhibit translocation step peptidyl tRNA moving from acceptor to donor site, e.g. erythromycin

  21. sulfonamides, structural similar to para-amino benzoic acid (PABA), competitive inhibitor of dihydropteroate synthetase, interfere folic acid synthesis

  22. PABA Dihydropteroate synthetase

  23. Resistance to antimicrobial agents • emergence of antibacterial resistance in pathogenic strains world-wild problem • microbes develop resistance by • preventing the drug from reaching the target • increase ability to metabolize antibiotics b-lactamase, co-administer with b-lactamase inhibitor (e.g. claulanic acid and sulbactam ) • change at drug binding site

  24. Genetics of bacterial resitance • Spontaneous mutation • Plasmid mediated, extrachromosomal DNA • Transduction, phage e.g. Staphylococcus aureus penicillinase • Transformation • Conjugation, R-factor, resistance trait and RF-factor, synthesis of pillus, 1959, outbreak of bacillary dynsentery, responsible pathogen Shigella flexneri resist tetracycline, sulfonamide, streptomycin and chloramphenicol

  25. Selection of appropriate antibiotic • Ideally, identify the pathogen before use of antibiotics • In practice, therapy started immediately with a minimum expense, inappropriate use

  26. Chemotherapeutic Agents: • Inhibitors of cell wall synthesis-penicillins; cephalosporins; vacomycin • Protein synthesis inhibitors-gentamicin; tetracyclines;erythromycin; chloramphenicol; • Folate antagonists- sulfonamides • Quinolones and urinary tract antiseptics • Drugs used in tuberculosis and leprosy: isoniazid; rifampin; thalidomid • Antifungal drugs: amphotericin B; nystatin; ketoconazole • Antiviral drugs: saquinavir; acyclovir • Antiprotozoal drugs: primaquine; quinine

More Related