Pharmacodynamics and Pharmacogenetics PDF

Pharmacodynamics and Pharmacogenetics MEV-262214 1  Our Objective Specific Learning Outcomes ✓ By the successful completion of this presentation, you are expected to:...

Pharmacodynamics and Pharmacogenetics MEV-262214 1  Our Objective Specific Learning Outcomes ✓ By the successful completion of this presentation, you are expected to: Define Pharmacodynamics and pharmacogenetics. Discuss how pharmacodynamics focuses on what the drug do to the body and different mechanisms by means of which these effects can be produced. Describe how drugs activate specific receptors to produce a response, explaining drug-response curve. Explain how blockers of drug action work, especially chemical antagonist, physiological antagonist and pharmacological antagonist. Enumerate different types of drug adverse effects and toxic effects on human body. 2  Pharmacodynamic Body Drug Pharmacokinetic  Pharmacodynamic Action of a Drug on the Body 1- Mechanism of action (e.g. Aspirin( 2- Pharm. Actions 3- Indications (uses) 4- Adverse effects 5- Contraindications 6- Drug interactions  Mechanism of Drug Action Receptor-mediated Non-Receptor-mediated  Receptor Mediated Mechanism ❖Receptor Ligand Specific cellular structure, protein, macromolecules present on the cell surface or intracellularly, binds ligand → Response Receptor ❖Ligand Active part of drug binds Response Receptor → Response (Action)  Types of Receptors 1- Inotropic receptors; Receptors as ion channels: (for fast transmission) 2- Enzymatic Receptors; Receptor linked to Tyrosine Kinase 3. Intracellular Receptors; Receptors regulating transcription (very slow transmission) 4. Nitric oxide (NO) Receptors 5- G-Protein coupled Receptors: (for slow transmission)  Inotropic receptors Receptors as ion channels: (for fast transmission) The receptors are linked directly to ion channels in the cell membrane Binding of the agonist to the receptor → opening of channel ⎯→ change in membrane potential or intracellular ion concentration → change in cell activity Ex. Ach on nicotinic receptors, GABA on GABAA receptors Ach Na+ Na+ Na+ Depolarization Skeletal muscle Contraction Membrane Potential  Enzymatic Receptors Receptor linked to Tyrosine Kinase Receptor is formed of 2 domains: Extracellular one ⎯→ bind with the agonist ex; insulin Intracellular one ⎯→ tyrosine kinase enzyme → Action  Enzymatic Receptors Receptor linked to Tyrosine Kinase Binding of insulin ⎯→ Two single tyrosine- kinases receptors to aggregate into a dimer ⎯→ subsequent auto-phosphorylation ⎯→ activated phosphorylated dimer binds to relay proteins ⎯→ activation ⎯→ the activated relay proteins trigger the cellular response through either production of a second messenger or turning on gene expression Response Receptors Linked to Tyrosine Kinase Enzymes Insulin Response  Intracellular Receptors Receptors regulating transcription: (very slow transmission) These are intracellular receptors. Their ligands are lipophilic to cross cell membrane Ex: steroid hormones, estrogen, progesterone & vit. D Binding of ligand to R → translocation to the nucleus → gene transcription → m-RNA → protein → action The response is delayed until the specific functioning proteins are synthesized Receptors Regulating Transcription (very slow) Delay Response  Nitric oxide (NO) Receptors NO receptors are protein in nature inside the cell. Binding of NO to its receptor ⎯→ Allosteric change in the protein (commonly; guanyl cyclase) ⎯→ triggers formation of second messenger (c-GMP) within the cell. Many drugs activate NO receptors that increase NO level Ex; nitrites, nitrates as nitroglycerine, sodium nitroprusside and PDEIs as sildenafil Nitric oxide (NO) Receptors  G-Protein coupled receptors For slow transmission Examples of G proteins: - Gs (stimulatory) ⎯→ linked to - receptors ⎯→  intracellular c- AMP - Gi (inhibitory) ⎯→ linked to 2 and M 2 receptors ⎯→  intracellular c- AMP - Gq ⎯→ linked to 1 and M1, 3 receptors ⎯→ liberation DAG and IP3  Effectors 1. Adenylyl cyclase, which forms 2nd messenger cAMP → +PKA 2. Phospholipase C, which liberates 2nd messengers DAG & IP3: DAG → activates PKC IP3 → + release of Ca2+ from SR 3. Channels that are specific for calcium, potassium or sodium.  Ligand Antagonist Agonist Partial Agonist Affinity → Ability to bind with receptor (Potency) Efficacy → Ability to Activate receptor → Action  Ligand Affinity Receptor Efficacy Response (Action) Agonist Ach Affinity Nm -R & Skeletal muscle Contraction Efficacy ++++  Partial Agonist Sch Ach Affinity Nm - R & Fasciculations ++ Partial Efficacy (Agonistic) Relaxation (Antagonistic) Antagonist Agonist Antagonist Affinity Receptor No Efficacy No Response  Antagonism 1. Chemical Antagonists: Interact chemically with the agonist away from receptor, e.g –ve charge Heparin neutraliz. by +ve charge Protamine sulfate 2. Physiological Antagonists : One drug antagonizes the effect of another drug by acting on a different receptor, e.g. 2-BD effect of EP antagonizes H1-BC effect of histamine 3. Pharmacological Antagonists: (act on same receptor) 2 types Competitive antagonists ( -B) Noncompetitive antagonists (α -B) Chemical Antagonists Protamine Heparin Sulfate -ve +ve  Physiological Antagonists Anaphylaxis Histamine Histamine H1- R EP Bronchodilator & ↑ BP B2 &α1- R Pharmacological Antagonists I- Competitive Antagonist II- Noncompetitive Antagonist I- Competitive Antagonist Agonist Antagonist Antagonist Receptor No Response  I- Competitive Antagonist Agonist Antagonist Agonist Antagonist Agonist Receptor Response +++ (Action) Duration of Antagonism depends on plasma conc. of Agonist & Antagonist.  I- Competitive Antagonist 100% 50% e.g. (β-blocker) Propranolol  II- Noncompetitive Antagonist Agonist Agonist Antagonist Agonist Receptor No Response Duration of antagonism depends on rate of Turnover of the Receptor II- Noncompetitive Antagonist e.g. (α-blocker) Phenoxybenzamine  Pharmacological Antagonist Competitive Antagonist Non-competitive Antagonist 1. Antagonist competes with the against on the 1. Antagonist has very high affinity to binds same binding site of the receptor. irreversibly to a site (allosteric) other than where the agonist binds. 2. Duration of antagonism depends on the relative 2. Duration of antagonism depends on the rate of plasma concentrations of agonist and antagonist. turnover of the receptor molecules. 3. Antagonist causes parallel shift to the right in the 3. Antagonist causes downward & non-parallel dose-response curve & no change in Emax shift in the dose-response curve & decrease in (maximum response). Emax (maximum response) Example: Examples:  Blockers. Phenoxybenzamine ( blocker).  Non-Receptor-Mediated Mechanisms 1. Drugs Acting on Enzymes 2. Drugs Acting on Plasmatic Membranes 3. Drugs Acting on Subcellular Structures 4. Drugs Acting on the Genetic Apparatus 5. Drugs Acting by Physical Means 6. Drugs Acting by Chemical Action  1. Drugs Acting on Enzymes * Drugs may inhibit or activate enzyme systems. * Examples; of drugs acting via enzyme inhibition: - Monoamine oxidase inhibitors (MAOIs) ⎯→ inhibit MAO enzyme preventing destruction of biogenic amines (e.g. nor-epinephrine). - Choline esterase inhibitors (ChEIs) ⎯→ inhibit ChE preserving Ach. - Aspirin inhibits cyclooxygenase (COX) ⎯→ decreases prostaglandin synthesis.  2. Drugs Acting on Plasmatic Membranes * Drugs may affect permeability, carrier systems, transport processes or enzyme systems in the plasmatic membrane. Examples: Cardiac glycosides inhibit membrane-bound ATPase. Phenytoin activates Na + pump. Amphotericin-B increase permeability of fungal plasmatic membrane.  3. Drugs Acting on Subcellular Structures Mitochondria: Salicylates ⎯→ uncouple oxidative phosphorylation. Microtubules: Colchicine ⎯→ disrupts microtubules inhibiting mitosis.  4. Drugs Acting on the Genetic Apparatus * Antibiotics (e.g. aminoglycosides, chloramphenicol & tetracyclines) ⎯→ inhibit bacterial protein synthesis. * Anticancer drugs e.g. antimetabolites and alkylating agents ⎯→ affect DNA synthesis or function  5. Drugs Acting by Physical Means * Adsorbents: ⎯→ charcoal adsorbs gases and toxins in intestine. * Lubricants: ⎯→ liquid paraffin is used in constipation. * Osmosis: ⎯→ mannitol as osmotic diuretics.  6. Drugs Acting by Chemical Action a.Antacids ⎯→ neutralize HCL in peptic ulcer. b.Citrates ⎯→ interact with calcium to inhibit blood coagulation. a.Protamine ⎯→ neutralizes – ve heparin by its positive charge.  Chelation Is the capacity of organic compounds to form complexes with metals (chelates). The chelate becomes more water-soluble and easily excreted. It is useful in treatment of heavy metal poisoning: Examples of Chelators 1. Ethylene diamine tetra acetic acid (EDT A) chelates calcium. 2. Dimercaprol (BAL) chelates arsenic, gold & copper. 3. Penicillamine chelates copper in Wilson's disease. 4. Desferrioxamine chelates iron and is used in iron toxicity. Dose-Response Relationships  Dose-Response Relationship 2 types of curves: Graded D-R Curve All/None (Quantal) D-R Curve  Graded Dose-Response Curves % Response 100% Emax (Efficacy) (Potency) EC50 1) Efficacy (Emax): Maximal effect prod. by drug (> imp. Than Potency) 2) Potency (ED50): Dose → 50% of the Max. response. ↓ EC50 → ↑ potency Efficacy of C >D Emax or Efficacy is more important Clinically than drug Potency  All/None (Quantal) Dose-Response Curves the percentage of patients who respond to the drug is plotted against log the dose.  All/None (Quantal) Dose-Response Curves 1. ED50: dose of the drug that cures 50% of patients. 2. LD50: dose of the drug that kills 50% of patients. 3. Therapeutic index (TI): is the ratio between LD50 and ED50 Therapeutic index = LD50 / ED50  Quantal Dose-Response Curves Therapeutic index (TI)= TD50 / ED50 gives an idea about the safety of the drug: if the TI is large, i.e. the LD50 much higher than the ED50 → the drug is safe.  Receptor Cycling or Turnover Down-regulation Receptor Up-regulation ↓ No. of Receptors ↑ No. of Receptors Internaliz. Externaliz. Recycling ++ New Receptor Old Receptor ++ Agonist New Receptor Antagonist  Adverse Drug Reactions Undesired effects of a drug. ◼ Type A: Augmented “side effects and overdosage toxicity”. ◼ Type B: Bizarre “hypersensitivity, idiosyncrasy”. ◼ Type C: Continuous “Adverse effects occurring on chronic use of drugs” ◼ Type D: Delayed “Mutagenicity, Carcinogenicity, Teratogenicity” ◼ Type E: Ending of use “adverse effects following withdrawal of some drugs”  Type A (Augmented) 1. Side effect (Dose = Therapeutic) 2. Overdose (Dose > Therapeutic) 1- Side effect (Dose = Therapeutic) 1ry pharmacological action 2ry pharmacological action 2- Overdose (Dose > Therapeutic) Lidocaine → Seizure  Type B (Bizarre) 1- Hypersensitivity (Allergic reactions) Immune-based adverse reactions Not dose-related induced by prior contact with drugs 2- Idiosyncrasy Genetically-mediated adverse effects e.g. Favism……………………  Type C (Continuous) Adverse effects occurring on chronic use of drugs Examples: Analgesic nephropathy. Corticosteroids-induced osteoporosis, diabetes and hypertension. Antipsychotic induced parkinsonism.  Type D (Delayed) adverse effect may occur even after stopping the drug Examples: Mutagenicity: drug-induced gene abnormalities; with metronidazole. Carcinogenicity: drug-induced neoplasm; with radioactive drugs Teratogenesis: induction of fetal abnormalities. Caused by some drugs when given early in (1st Trimester ) pregnancy. 1st Trimester is the period of organogenesis in intrauterine life.  Teratogenesis Drug induced fetal abnormalities Examples: Thalidomide: phocomelia Tetracyclines : dental hypoplasia Anti-epileptic : cleft Lip and palate I131 : fetal goiter  Type E (Ending of use) Angina or infarction following sudden withdrawal of long term use of β- blockers Hypertension following sudden withdrawal of chronic clonidine therapy Addisonian crisis following sudden withdrawal of chronic corticosteroid therapy Abnormal drug reactions that occur due to genetic abnormality.  Pharmacogenetic disorders 1. Hemolytic Anemia due to G6PD↓↓ 2. Succinylcholine Apnea 3. Malignant Hyperthermia 4. Porphyria  1. Hemolytic Anemia due to G6PD Deficiency (Favism) Congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD) enzyme RBCs hemolyzed in presence of some oxidant drugs Aspirin, Antimalarials, Sulfonamides and Fava beans Oxidant drugs 2. Succinylcholine Apnea Succinyl choline “skeletal muscle relaxant” Metabolized by Pseudocholine esterase  Succinylcholine Apnea (cont.) Genetic defect in pseudocholine esterase enzyme Failure of succinyl choline breakdown Respiratory muscle paralysis with apnea  3. Malignant Hyperthermia Genetic disorder in which skeletal muscles fail to sequester Ca+2 in sarcoplasmic reticulum following administration of Succinylcholine and halothane marked muscle rigidity & rise of temperature Treated by Dantrolene which block Ca+2 release from sarcoplasmic reticulum  4. Porphyrias Genetic disorders of porphyrin metabolism  levels of porphyrins and their precursors severe neurological disturbances & may cause death  Porphyrias (cont.) Barbiturates and sulfonamides Increasing ALA-synthase activity with accumulation of porphyrin precursors. Severe neurological disturbances & may cause death Thank you