Transcript life.nthu.edu.tw

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 proteinbound 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
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 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 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
• 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 synthetase
PABA
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