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2015-03-22 12:46:13
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  1. risk- benefit ratio
    • Safe and effective drug therapy requires an understanding
    • of the balance between the drug’s adverse (toxic) effects
    • and its benefits
  2. targeted tissue and toxicity considerations
    • intended and unintended tissue (correct receptor on target but diff tissue)
    • on target- dose too high, chronic activation or inhibition effects
    • off target- incorrect receptor is inhibited or activated
  3. chlorpromazine
    • - antipsychotic drug controls schizophrenia
    • antagonist at D2 receptor in limbic areas
    • of brain that control the symptoms of
    • schizophrenia
    • also, an antagonist at D2 receptor in
    • striatal areas that cause motor
    • impairment
  4. simvastatin
    • is used clinically to decrease cholesterol
    • levels -its intended target tissue is the liver.
    • The drug inhibits HMG CoA reductase which is the
    • rate-limiting enzyme in cholesterol production.
    • HMG CoA reductase also regulates the
    • posttranslational modification of several muscle
    • proteins.
    • An adverse effect of simvastatin therapy is
    • muscle toxicity.
  5. Antihistamines
    • beneficial effect of stopping allergic inflammation, itching, sneezing and rhinorrhea but also have a number of adverse effects at this intended target.
    • H1 antihistamine drugs also have unintended targets (cholinergic and α –
    • adrenergic receptors) where they cause numerous adverse effects.
  6. Enantiomers
    • of the same compound can differ in their targets and toxic effects.
    • citalopram is a racemic antidepressant drug
    • its toxic effects include : diaphoresis,
    • drowsiness, fatigue, impotence, and insomnia
    • escitalopram-(S)-citalopram was developed under
    • the supposition that on-target
    • antidepressant effects are produced by (S)-
    • citalopram while off-target toxic effects
    • come from the (R)-enantiomer
  7. Non -selective β agonists
    • activate β1 receptors and β2 receptors causing
    • off-target (β1 receptor) activation – can cause tachycardia and palpitations
    • when used to treat asthma
  8. Non -selective β-blockers (antagonists)
    • block β1 receptors and β2
    • receptors causing off-target (β2 receptor) blockade – can exacerbate
    • asthma symptoms when used to treat heart disease
  9. Acetaminophen
    • 50% of hepatic necrosis cases are
    • caused by overdose
    • P450 induction (e.g. by
    • alcohol) can increase amounts of toxic
    • metabolite formation
    • The toxic product is usually removed by glutathione
    • Approximately 13g of acetamiophen intake
    • depletes glutathione
  10. therapeutic goals of acetaminophen and antidote
    • keep plasma acetaminophen levels
    • below line
    • prevent centrilobular hepatic
    • necrosis
    • n-acetylcysteine is an antidote
    • that restores glutathione levels
  11. Small molecule drugs (< 600 daltons)
    form haptens that bind to proteins
  12. Larger drugs
    (e.g., peptides, proteins) activate the immune system directly
  13. Two toxic immune responses
    • - hypersensitivity reactions and autoimmune
    • reactions
  14. Type 1
    • (IGE mediated) is most common
    • Penicillin, lidocaine cause type 1 (immediate) hypersensitivity responses in some patients.
    • Can cause anaphylaxis that may require treatment with epinephrine.
  15. Type II, III, and IV
    ciprofloxacin- type IV (delayed type hypersensitivity reaction) -can be very severe in some patients
  16. methyldopa
    • –antihypertensive agent
    • Can cause hemolytic anemia and thrombocytopenia
    • by eliciting an immune response to Rhesus antigens (Rh
    • factors)
  17. procainamide
    • –potent Class 1A antiarryththmic
    • Causes reversible Lupus-like (SLE) symptoms in 25 to 30 % of patients
    • approximately 80% show increased antinuclear antibody titers
  18. Idiosyncratic Toxicity
    • - rare adverse effect for which no obvious mechanism is apparent
    • Some idiosyncratic effects are not related to drug metabolism
  19. succinylcholine
    • -short-acting neuromuscular-blocking anesthetic
    • drug
    • IST -1 in 3000 patients have prolonged neuromuscular block due to abnormal or deficient plasma pseudocholinesterases that slows
    • metabolic degradation of the drug
  20. isoniazid
    • -is considered a first-line agent in the treatment of
    • tuberculosis. - metabolized by n-acetyltransferase 2 (NAT2) that acetylates the drug
    • IST Patients who metabolize isoniazid slowly (slow acetylators) build up high levels of toxic metabolites
    • This metabolite causes hepatitis in about 2.1% of drug recipients.
    • Differences in metabolism run in families.
  21. hemolytic anemia idiosyncratic effects not related to drug metabolism
    • 10 % of Africans and 10-20 % of Mediterraneans and
    • Southeast Asians get from:
    • anti-malarials, sulfonamide antibiotics, ibuprofen,
    • acetaminophen and aspirin
    • These patients have a deficiency in glucose-6-phosphate dehydrogenase that protects red blood cells from oxidative stress.
    • This idiosyncrasy occurs more frequently in parts of the world where malaria is present.
  22. pharmacogenetics
    • The study of genes causing variations in response to drugs is pharmacogenetics.
    • Pharmacogenetics is helping to elucidate the mechanisms that underlie idiosyncratic drug toxicity.
  23. We now know that G6PD deficiency is:
    an X-linked recessive genetic trait that is related to the sickle-cell trait that protects from malaria
  24. Effective Dose/response (ED50)
    curve describes the therapeutic effect.
  25. Toxic Dose/response (TD50)
    curve describes any adverse effects.
  26. Lethal Dose/response (LD50)
    curve describes mortality
  27. sildenafil
    inhibits phosphodiesterase type 5 (PDE5) and prolongs the action of cyclic GMP (cGMP) by partially preventing its breakdown
  28. nitroglycerin
    • stimulates guanylyl cyclase to increase cGMP levels in vascular smooth muscle that dilates blood vessels and
    • lowers blood pressure
  29. co-exposure of NG and viagra
    • additively increases cGMP levels and creates a risk of
    • severe hypotension.
  30. Drug-Food Interactions acetaminophen
    • increased risk of hepatotoxicity if echinacea tea is also consumed.
    • Some species of echinacea may contain pyrrolizidine alkaloids that deplete glutathione.
    • A reduction in glutathione levels lowers the dose at which acetaminophen causes hepatotoxity.
  31. acute toxicity
    : adverse effects of a single exposure to a drug
  32. chronic toxicity
    : adverse effects that occur with repeated exposure over time