BMS 361 2- Principles of Pharmacodynamics Lecture 2 PDF

BMS 361 2- Principles of Pharmacodynamics Mai Ahmed Ebeid lecturer of Clinical Pharmacology Faculty of Physiotherapy Fall 2022  Lecture Objectives By the end of this lecture, the student should be able to: 1. Define basic terms in pha...

BMS 361 2- Principles of Pharmacodynamics Mai Ahmed Ebeid lecturer of Clinical Pharmacology Faculty of Physiotherapy Fall 2022  Lecture Objectives By the end of this lecture, the student should be able to: 1. Define basic terms in pharmacology: e.g., agonist, antagonist &partial agonist. 2. Describe the different signaling mechanisms for drug receptor interaction. 3. Compare efficacy & potency of 2 drugs on the basis of their dose response curves. 4. Specify the types of antagonists used in pharmacology based on their effects on the dose response curves of their agonists. 5. Predict how to treat toxicity of different types of antagonists. 6. Define basic terms in pharmacology: e.g., tolerance, tachyphylaxis. 7. Define teratogenicity 8. Calculate the dose in different age groups. 9. List the different mechanisms of tolerance. 10. Compare between tolerance and cross tolerance. 11. Describe the drawbacks of over the counter drugs 12. Differentiate between different types of prescriptions 13. Define basic terms in pharmacology: e.g., intolerance, side effect, 14. hypersensitivity idiosyncrasy, pharmacogenetics, mutagenicity, 15. carcinogenicity, iatrogenic disease, drug abuse. 16. Differentiate between different types of adverse drug reactions 17. List drugs that should not be stopped suddenly 18. Predict the type of drug interaction that may occur with different drugs. 19. Specify how to reduce risk of drug interaction  Pharmacodynamics Effects of Drug on Body Mechanism of Action Receptors Non- Receptors Pharmacological Effects Intended (Therapeutic): Unintended Uses (Indications) ( Adverse Effects) RESPONS E Agonist NO RESPONS E Antagonist  Drug Receptor Interaction  Full Agonist  Antagonist Has AFFINITY and  Partial Agonist EFFICACY  Inverse Agonist E.g. Nor adrenaline: Binds and activates beta-1 adrenergic receptor→ increases heart rate  Graded Dose Response Curve [Quantitative]: the degree of response of agonist in relation to log the dose. Efficacy (Emax): is the maximal effect produced by the drug. Emax 2. Potency of the drug is assessed by: ED50: it is dose that produces 50% of the maximal response.[dose axis] The lower the ED50 the more potent the drug is. Potency  Another Type of Dose Response Curve Determined for All Drugs Parameters obtained from the All/None curve 1. ED50: It is the dose that cures 50% of cases. 2. LD50 (Lethal Dose 50) : The dose that kills 50% of animals. Therapeutic index (TI): TI = LD50/ED50. Drug safety: if the TI is large, the drug is safer. Therapeutic Index of a drug is 2 ?? Therapeutic Index of a drug is 10 ?? Which drug you prefer to use: TI 10 or 2 ?? Which is called drug with low T.I. or Safety Margin??  Antagonists Interacts with the receptor without activation Value: inhibits action of endogenous agonist. Affinity Without Efficacy Most of drugs are antagonists Types: 1.Pharmacological 2.Chemical 3.Physiological (Functional)  Pharmacological Antagonists: bind to the same receptors of agonist Competitive Antagonist Noncompetitive Antagonist  Competes with the agonist for the same  Binds irreversibly to the recognition recognition site of the receptor. site of the receptor or allosteric site.  Duration of antagonism depends on the  Duration of antagonism depends on relative plasma concentrations of agonist the rate of turnover of the receptor and antagonist. molecules. Treatment of Toxicity: Treatment of Toxicity: High Dose of Agonist Never Say High Dose of Agonist Chemical Antagonists: Antacids and HCL in stomach Physiological antagonists [Functional]: one drug antagonizes the effect of another by acting on a different receptor to induce the opposite action 2-bronchodilator and alpha vasoconstrictor effects of epinephrine antagonize H1-bronchconstrictor and vasodilator effects of histamine.  Partial Agonist Have a variable degree of affinity. It is an agonist if used alone Alone: it activates the empty receptor, but with lower efficacy than that of a full agonist.[affinity and partial efficacy] Inverse Agonist= Antagonist Example: some anti-histamines Receptor Cycling [Turnover] and Desensitization The number of receptors is not constant, but the receptors are cycling (turnover). Chronic use of the Agonist  number of receptors [down regulation] Tolerance Chronic Use of the Antagonist   the number of receptors [up regulation] Tolerance  Non-Receptors Mediated Mechanism 1- Drugs Acting on Enzymes 2- Drugs Acting on Plasmatic Membranes 3-Drugs Acting on the Genetic Apparatus 4- Drugs Acting by Physical Means Demulcents (soothing): Adsorbents: charcoal adsorbs gases and toxins in intestine. Lubricants: liquid paraffin is used in constipation. Factors Modifying Dose-Response Relationship (Action) 1. Age 2. Sex: + Pregnancy and lactation 3. Pathological state 4. Psychological factors: placebo effect 5. Drug interaction 6. Tolerance  1. Age of Patient Various methods & formulas are used for calculating the child dose: Surface area method: The child dose = Adult dose X Surface area (m2)/ 1.73 Weight method: The child dose = Adult dose X Weight (Kgs) / 70  2. Gender Dose in female is usually less than male due to difference in drug metabolism and components of the body In pregnant female: some drugs can → teratogenicity. In lactating female: drugs can pass to the baby in milk:  3. Pathological States In patient sensitive to penicillin→ Hypersensitivity 4. Psychological Factors: Some patients may respond to a placebo the same way they respond to the active drug. 5. Drug Interactions: The response to the drug may be affected by administration of another drug  6. Tolerance: Definition: reduced responsiveness to the drug on repeated administration so that higher doses are needed to produce the same effect. A- Pharmacokinetic tolerance: due to decreased drug level at the site of action. Example: when enzyme induction increases the liver capacity to increase metabolism the other drug. Decrease drug absorption from GIT Increase drug excretion  B- Pharmacodynamic Tolerance: Without decreased drug level Decreased sensitivity of the receptors e.g. opiates Decreased number of receptors [down regulation] e.g. ß2-agonists Increased number of receptors [up regulation] e.g. ß-receptor antagonists. Counter regulatory mechanism e.g. salt &water retention with vasodilators in treatment of hypertensive.  Special Types of Tolerance Cross Tolerance: Tolerance to related drugs with same pharmacological action e.g. cross tolerance between different members of opioids. Clinical Value: treatment of addiction  ADVERSE DRUG REACTIONS (ADR) Definition: The harmful effects of a drug, which require reduction of dose, drug withdrawal or immediate treatment. Types of Adverse Reactions Type A: Augmented (side effects and overdose toxicity). Type B: Bizarre (hypersensitivity, idiosyncrasy). Type C: Continuous (reactions due to long-term use). Type D: Delayed (teratogenesis, mutagenesis and carcinogenesis). Type E: Ending of use (adverse effects following drug withdrawal). Others  Type A (Augmented): Dose Dependent Predictable A. Intolerance (at doses < therapeutic): tinnitus after a small aspirin dose due to lower threshold to a normal pharmacologic action of drug. B. Side effect (occurs at therapeutic dose): i. Sedation with 1st generation antihistamines. ii. Thrush [candida infection] with antibiotics. C. Overdose Toxicity: e.g. hepatotoxicity with acetaminophen.  Type B (Bizarre): Dose Independent (Not Dose Related): Unpredictable 1. Hypersensitivity (Allergic reactions) A.Immune-based adverse reactions: B.induced by Prior Contact with drugs. C.Treatment of anaphylaxis: epinephrine ,hydrocortisone, antihistamines. 2. Idiosyncrasy (Genetically- Mediated) Pharmacogenetics): Induced with First Exposure to the drug. Hemolytic Anemia due to G6PD Deficiency Congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD) enzyme renders RBCs readily hemolyzed in presence of some oxidant drugs as aspirin, antimalarials, sulfonamides, chloramphenicol and fava beans (favism).  Type C (Continuous) Occurring on chronic prolonged use of drugs: e.g. Analgesic nephropathy Corticosteroids-induced osteoporosis, diabetes and hypertension. Type D (Delayed): Occur even after stopping drug: 1. Teratogenesis (teratos = monster; genesis = production): fetal malformation due to drug use during pregnancy  Type E: End of Dose (ADR following withdrawal of some drugs after Chronic Use) 1. Abstinence (withdrawal syndrome) in drug-dependent persons (addicts) following withdrawal of heroin or alcohol. 2. Addisonian crisis on sudden withdrawal of corticosteroid therapy.  Other Adverse Effects 1. Drug Abuse: the use of a drug for non-therapeutic purpose. It is more common with drugs acting on CNS causing drug dependence. 2. Iatrogenic Disease (Drug-Induced Disease): Drug prescribed for a disease causes another disease, e.g. aspirin- induced peptic ulcer. Prescription Writing & Dispensing Medication (Reading) Self-medication (OTC agents): OTC (Over-the-counter) agents are drugs dispensed without a prescription as they have a high safety margin e.g. simple analgesics, antacids, laxatives, antihistaminics, antitussives & expectorants. Risks associated with the use of OTC drugs: 1. May aggravate preexisting disease e.g. nasal decongestant in hypertensives. 2. May cause drug interactions e.g. aspirin →bleeding in patients on warfarin. 3. May lead to complications e.g. peptic ulcer with NSAIDs. Prescription-only medicines: (Reading) 1. Ordinary prescription: drugs requiring prescription by specialists. 2. Special prescription: used for some drugs with low addiction liability e.g. sedative hypnotics. These drugs are called "table drugs". 3. Narcotic prescription: for highly addictive drugs e.g. morphine. Prescription forms are supplied by local health authorities. The physician writes 2 forms of prescription (one is kept by pharmacist to be dispensed only once within 5 days from its date). Dose is written both numerically & alphabetically & the patient’s & doctor’s identities are included. Thank You