Basic Pharmacology

DOSE-RESPONSE CURVES:

• Definitions:
  • Affinity: A measure of the propensity of the drug to bind with a given receptor.
  • Potency: A potent drug induces the same response at a lower concentration. A potent drug has a lower EC50 value.
  • Efficacy: The biologic response resulting from the binding of a drug to its receptor. An efficacious drug has a higher E_max value.
  • Partial Agonist: A compound whose maximal response (E_max) is somewhat less than the full agonist.
• GRADED-RESPONSE CURVE: A plot of efficacy (some measured value, such as blood pressure) -vs- drug concentration.
  • EC50 = The drug concentration at which 50% efficacy is attained. The lower the EC50, the more potent the drug.
  • E_max = the maximum attained biological response out of the drug.
  • 
• QUANTAL DOSE-RESPONSE CURVE: A graph of discrete (yes-or-no) values, plotting the number of subjects attaining the condition (such as death, or cure from disease) -vs- drug concentration.
  • ED50: The drug-dosage at which 50% of the population attains the desired characteristic.
  • LD50: Lethal-Dose-50. The drug-dose at which 50% of the population is killed from a drug.
• THERAPEUTIC INDEX = LD50 / ED50
  • The ratio of median lethal dose to median effective dose.
  • The higher the therapeutic index, the better. That means that a higher dose is required for lethality, compared to the dose required to be effective.
• MARGIN OF SAFETY = LD1 / ED99
  • The ratio of the dosage required to kill 1% of population, compared to the dosage that is effective in 99% of population.
  • The higher the margin of safety, the better.
• COMPETITIVE INHIBITORS: They bind to the same site as the endogenous molecule, preventing the endogenous molecule from binding.
  • The DOSE-RESPONSE CURVE SHIFTS TO THE RIGHT in the presence of a competitive inhibitor.
    • The EC50 is increased: more of a drug would be required to achieve same effect.
    • The E_max does not change: maximum efficacy is the same, as long as you have enough of the endogenous molecules around.
  • The effect of a competitive inhibitor is REVERSIBLE and can be overcome by a higher dose of the endogenous substance.
  • The intrinsic activity of a competitive inhibitor is 0. It has no activity in itself, but only prevents the endogenous substance from having activity.
  • Partial Agonist: A substance that binds to a receptor and shows less activity than the full agonist.
    • At low concentrations, it increases the overall biological response from the receptor.
    • At high concentrations, as all receptors are occupied, it acts as a competitive inhibitor and decreases the overall biological response from the receptor.
• NON-COMPETITIVE INHIBITORS: They either (1) bind to a different (allosteric) site, or (2) they bind irreversibly to the primary site.
  • The DOSE RESPONSE CURVE SHIFTS DOWN in the presence of a non-competitive inhibitor.
    • The EC50 is increased: more of a drug would be required for same effect.
    • The E_max decreases: The non-competitive inhibitor permanently occupies some of the receptors. The maximal attainable response is therefore less.
  • The intrinsic activity of the non-competitive inhibitor is actually a negative number, as the number of functional receptors, and therefore the maximum attainable biological response, is decreased.
    
     

ADVERSE EFFECTS:

• Drug Toxicity: Dose-dependent adverse response to a drug.
  • Organ-Directed Toxicity:
    • Aspirin induced GI toxicity (due to prostaglandin blockade)
    • Epinephrine induced arrhythmias (due to beta-agonist)
    • Propanolol induced heart-block (due to beta-antagonist)
    • Aminoglycoside-induced renal toxicity
    • Chloramphenicol-induced aplastic anemia.
  • Neonatal Toxicity: Drugs that are toxic to the fetus or newborn.
    • Sulfonamide-induced kernicterus.
    • Chloramphenicol-induced Grey-Baby Syndrome
    • Tetracycline-induced teeth discoloration and retardation of bone growth.
  • TERATOGENS: Drugs that adversely affect the development of the fetus
    • Thalidomide:
    • Antifolates such as Methotrexate.
    • Phenytoin: Malformation of fingers, cleft palate.
    • Warfarin: Hypoplastic nasal structures.
    • Diethylstilbestrol: Oral contraceptive is no longer used because it causes reproductive cancers in daughters born to mothers taking the drug.
    • Aminoglycosides, Chloroquine: Deafness
• Drug Allergy: An exaggerated, immune-mediated response to a drug.
  • TYPE-I: Immediate IgE-mediated anaphylaxis.
    • Example: Penicillin anaphylaxis.
  • TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attack against a specific cell type, usually blood cells (anemia, thrombocytopenia, leukopenia).
    • Hemolytic anemia: induced by Penicillin or Methyldopa
    • Thrombocytopenia: induced by Quinidine
    • SLE: Drug-induced SLE caused by Hydralazine or Procainamide.
  • TYPE-III: Immune-complex drug reaction
    • Serum Sickness: Urticaria, arthralgia, lymphadenopathy, fever.
    • Steven-Johnson Syndrome: Form of immune vasculitis induced by sulfonamides. May be fatal.
      • Symptoms: Erythema multiforme, arthritis, nephritis, CNS abnormalities, myocarditis.
  • TYPE-IV: Contact dermatitis caused by topically-applied drugs or by poison ivy.
• Drug Idiosyncrasies: An unusual response to a drug due to genetic polymorphisms, or for unexplained reasons.
  • Isoniazid: N-Acetylation affects the metabolism of isoniazid
    • Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis.
    • Fast N-Acetylation: Some evidence says that Isoniazid is more likely to cause hepatotoxicity in this group. However, other evidence says that age (above 35 yrs old) is the most important determinant of hepatotoxicity.
  • Alcohol can lead to facial flushing, or Tolbutamide can lead to cardiotoxicity, in people with an oxidation polymorphism.
  • Succinylcholine can produce apnea in people with abnormal serum cholinesterase. Their cholinesterase is incapable of degrading the succinylcholine, thus it builds up and depolarization blockade results.
  • Primaquine, Sulfonamides induce acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase deficiency.
    • They have an inability to regenerate NADPH in RBC's ------> all reductive processes that require NADPH are impaired.
    • Note that this is Acute Hemolytic Anemia, yet it is not classified as an allergic reaction -- it is an idiosyncrasy when caused by sulfonamides or primaquine. Other anemias are Type-II hypersensitivity reactions.
    • G6PD deficiency is most prevalent in blacks and semitics. It is rare in caucasians and asians.
  • Barbiturates induce porphyria (urine turns dark red on standing) in people with abnormal heme biosynthesis.
    • Psychosis, peripheral neuritis, and abdominal pain may be found.
       

      TOLERANCE

      • Pharmacokinetic Tolerance: Increase in the enzymes responsible for metabolizing the drug.
        • Warfarin doses must be increased in patients taking barbiturates or phenytoin, because these drugs induce the enzymes responsible for metabolizing warfarin.
      • Pharmacodynamic Tolerance: Cellular tolerance, due to down-regulation of receptors, or down-regulation of the intracellular response to a drug.
      • Tachyphylaxis: When using indirect agonists, which stimulate the endogenous substance, this occurs when you run out of the endogenous substance and therefore see the opposite effect, or no effect at all.
        • Tyramine can cause depletion of all NE stores if you use it long enough, resulting in tachyphylaxis.
      • Physiologic Tolerance: Two agents yield opposite physiology effects.
      • Competitixve Tolerance: Occurs when an agonist is administered with an antagonist.
        • Example: Naloxone and Morphine are chemical antagonists, and one induces tolerance to the other.