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 juice F 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

– 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.

Basis of the selective toxicity of antibiotics

– 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.

Action mechanism of Acyclovir- must be phosphorylated to be active.

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 g/ml may kill pneumococcus, high therapeutic index,

– not always the case, e.g. antifungal drug amphotericin B (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 -lactams (for containing the -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; MenigococcusG (+) cocci: Pneumococcus; Streptococcus; StaphylococcusG (-) rods: Acinetobacter; Bacteroides; Brucella; Enterobacter; E.coli; Haemophilus; Klebsiella; Legionella;Pasteurella;Proteus; Pseudomonas; Salmonella; Serratia; Providencia; Shigella; VibrioG (+) rods: Actinomyces; Bacillus; Clostridium; Corynebacterium, Lsteria

Classification of penicillins:

1. Natural: Penicillin G; Penicillin V2. Penicillinase resistant: Methicillin3. Broad spectrum: Amoxillin; Ampicillin4. Anti-pseudomonas : carbenicillin; tricarcillin

• Vancomycin and 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

Dihydropteroate synthetasePABA

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 -lactamase, co-administer with -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