Pharmacodyn Amics

Pharmacodyn amics

Protein Receptors Receptors for endogenous regulatory ligands – hormones, growth factors, neurotransmit-ters; Enzymes of crucial metabolic or regulatory pathways – Acetylcholinesterase, Enzymes in transport processes – Na/K pump; Structural proteins – Tubulin;

Drug – Receptor Interactions  Receptor – specific macromolecule ( Proteins – 90% - membrane, cytoplasmic or extracellular enzyme, nucleic acid; Lipids; Carbohydrates) which is the site of action of most drugs: Only around 10% of drug actions & effects are NOT mediated thru receptors.  For most drugs, the magnitude of the pharmacological response increases as the dose (drug concentration) increases  Only one drug molecule occupies each receptor site, & binding is reversible

Drug – Receptor Interactions  Combination or binding of drug to receptor causes some event which leads to the response  Response to a drug is graded or dosedependent  Interactions follow simple mass-action relationships  For a given drug, the magnitude of the response is directly proportional to the number of receptor sites occupied by the drug molecules  The number of drug molecules is assumed

Definitions  Affinity – a measure of the propensity of the drug to bind with a given receptor (specificity)  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 Emax value – maximum desirable effect  Quality – bioavailability of the drug

The Dissociation Constant The Dissociation Constant – KD – drug concentration at which half maximal binding occurs: the smaller the KD, the greater the affinity of the drug to the receptor; the smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding

Log dose – Response curve characteristics:  Maximal effect (plateau)  Potency – the location of the drug response curve along the horizontal axis: drug effect with respect to dose (vs. Efficacy – maximal ceiling effect)  Slope  Standing curve – minute changes in dose result in large effects  Inclining curve – large changes in dose needed for an effect

 Variability – the curve is different from drug to drug, from patient to patient, & from time to time in the same patient. So if you want to fix the pharmacologic

Log dose – Response Curve

intensity of effect

Maximal effect variability slope

potency Log dose

Dose – Response Relationship  No drug can create a new effect: a drug only modulates a pre-existing function  Drug-receptor interaction leads to enhancement, inhibition, or blockade of molecular signals, which is then amplified thru biochemical & physiologic events to produce the pharmacological (clinical) effect  The magnitude of a response is graded, i.e. increases continuously as the concentration of unbound drug increases at the receptor site

Definitions  GRADED-RESPONSE CURVE: A plot of efficacy (some measured value, such as blood pressure) -vs- drug concentration.  EC50 = drug concentration at which 50% efficacy is attained. The lower the EC50, the more potent the drug.  Emax = 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: dosage at which 50% of the population attains the desired effect  LD50: dose at which 50% of the population is

Agonists & Antagonists  Agonists – drugs that interact with & activate receptors  Full agonists – maximal efficacy (Emax)  Partial agonists – less than maximal efficacy 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.

 Antagonists – drugs that prevent the agonists from having an effect by binding to the receptor or to part of the effector mechanism; have no effect themselves

AGONIST

ANTAGONIST

Agonist has affinity plus intrinsic activity

Antagonist has affinity but NO intrinsic activity

Partial agonist has affinity & (less) intrinsic activity

Competitive antagonists may be overcome (surmountable) Antagonists tend to

Agonists tend to desensitize receptors up-regulate receptors

Inhibition  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. EC50 is increased: more of a drug would be required to achieve same effect. Emax 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

Inhibition  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. EC50 is increased: more of a drug would be required for same effect. Emax decreases: The noncompetitive 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.

Properties of a Drug  Safety: Therapeutic Index (TI) = 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.  minimum dose that produces toxicity over the minimum dose that produces an effective therapeutic response; TI < 4 =relatively greater potential for toxicity

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.

Drug interactions  Synergism/Potentiation – concomitant administration of another drug will increase the clinical effect e.g. multiregimen TB treatment  Addition – effects of two drugs administered at the same time will be added to each other e.g. DOLCET  Inhibition – simultaneous administration of another drug will decrease the effects of the first e.g. Warfarin & vitamin K  Pharmacokinetic interaction – giving of another drug will affect the first’s absorption, distribution, metabolism, &/or excretion

Adverse Effects & Drug Interactions  Side effect - part of the pharmacologic action of the drug but not the effect the drug is being used for; may be undesirable (adverse) e.g. gastric irritation from NSAIDS  Hypersensitivity reactions / Drug Allergy: An exaggerated, immunemediated response to a drug.  TYPE-I: Immediate IgE-mediated anaphylaxis. e.g.Penicillin anaphylaxis. 

Immunologic Reactions  TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attack against a specific cell type, usually blood cells (e.g.Hemolytic anemia: induced by Penicillin or Methyldopa; Thrombocytopenia: induced by Quinidine; 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.

Drug Toxicity  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 betaagonist); 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 GreyBaby Syndrome; Tetracycline-induced teeth

Teratogens TERATOGENS: Drugs that adversely affect the development of the fetus: especially dangerous during organogenesis (3rd to 8th week) • 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

Idiosyncrasy  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.

Drug Idiosyncrasies  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

Tolerance  Pharmacokinetic Tolerance: Increase in the enzymes responsible for metabolizing the drug. e.g.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.  Physiologic Tolerance: Two agents yield opposite physiologic effects.

Tolerance  Competitive Tolerance: Occurs when an agonist is administered with an antagonist. Example: Naloxone and Morphine are chemical antagonists, and one induces tolerance to the other.  Tachyphylaxis (Refractoriness / Desensitization) – progressive reduction in drug effect due to receptor desensitization  Homologous – decrease in number of receptors  Heterologous – decreased signal transduction e.g.Tyramine can cause depletion of all NE stores if you use it long enough, resulting in

Habituation & Addiction Habituation – getting used to a drug such that one becomes emotionally dependent on the drug Addiction – true physical as well as emotional dependence on a drug; will need pharmacologic support during withdrawal