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 • 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
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
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.
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.
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 juiceF of Saquinavir (F 50%). • grapefruit juice also F of Triazolam, midazolam, cyclosporin, coumarin, misoldipine felodipne • Bioflavinoid naringin much less effect
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
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
Antibiotics • Probably the only class of drugs that cures disease • Depends on its selective toxicity to the microbes • Bactericidal or bacteriostatic
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.
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.
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.
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.
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.
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)
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
Classification of penicillins: 1. Natural: Penicillin G; Penicillin V 2. Penicillinase resistant: Methicillin 3. Broad spectrum: Amoxillin; Ampicillin 4. Anti-pseudomonas : carbenicillin; tricarcillin
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
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.
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
sulfonamides, structural similar to para-amino benzoic acid (PABA), competitive inhibitor of dihydropteroate synthetase, interfere folic acid synthesis
PABA Dihydropteroate synthetase
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
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
Selection of appropriate antibiotic • Ideally, identify the pathogen before use of antibiotics • In practice, therapy started immediately with a minimum expense, inappropriate use
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