Pharmacodynamics Lecture Notes PDF

Pharmacodynamics  Mechanisms of action: Drugs act through either receptor or non-receptor mechanism. I. Receptor-mediated mechanism: Receptor: specific cellular structures interact with drug to mediate pharmacological effect. Types of drugs acting on rece...

Pharmacodynamics  Mechanisms of action: Drugs act through either receptor or non-receptor mechanism. I. Receptor-mediated mechanism: Receptor: specific cellular structures interact with drug to mediate pharmacological effect. Types of drugs acting on receptors: 1- Agonist: binds to the receptor (affinity) and produce effect (efficacy). 2- Antagonist: Drug that blocks the effect of agonist.  Types of Agonists: A-Full Agonist: Produce maximal efficacy. B-Partial agonist: Produces less than maximal efficacy and blocks effect of full agonists. C-Inverse agonist: Binds to the receptor to decrease the constitutive activity (-ve efficacy).  Types of Antagonists: [A] Pharmacological antagonist: A drug that binds without activating its receptor and prevents activation by an agonist. Competitive 1. The antagonist binds reversibly to the receptor and can be displaced by increasing the concentration of the agonist. 3. Duration of antagonism depend on relative plasma concentration of agonist and antagonist. Irreversible: 1. The antagonist binds irreversibly to the receptor and could not be displaced by increasing the concentration of the agonist. 3. Duration of antagonism depend on the rate of synthesis of new receptors. [B] Physiologic antagonist A drug that counters the effects of another by binding to a different receptor and causing opposing effects. [C] Chemical antagonist A drug that counters the effects of another by binding the agonist drug.  Signal transduction system 1-Ligand-gated ion channel receptor: Binding of drug to the ionic channel receptor ➔ ion flux  Signal transduction system 2- G. Protein-Coupled receptor: The agonist binds to the receptor that activates G protein that is responsible for producing response. 3- Catalytic receptors (enzyme linked receptor): Like receptors linked to tyrosine kinase (such as insulin receptor): Insulin binding to the extracellular component ➔ stimulates the intracellular component and tyrosine Kinase enzymes. 4-Intracellular receptors: like corticosteroids receptors. The drug crosses cell membrane and binds cytoplasmic receptor.  II. Non-receptor mediated mechanism: 1- Drugs acting on enzymes: Choline esterase inhibitors: Neostigmine. 2- Drugs act on plasma membrane: Digoxin inhibits Na+-K+ ATPase. 3- Drugs acting by physical means; Lubricants: liquid paraffin in constipation. 4- Drugs acting by chemical mechanisms: Antacids neutralize HCl in peptic ulcer.  Dose-response relationship - Efficacy: ability of the drug-receptor complex to produce response. - Maximal efficacy: The maximal response produced by the drug. - Potency: the amount of the drug in relation to its effect. Example:1mg of drug (A) produces the same response of 5mg of drug (B)➔ Drug (A) is more potent than(B). - ED50: the dose that cures 50% of cases. - LD50: The dose that kill 50% of animals. The drug with low LD50is considered more toxic than the drug with higher LD50. Therapeutic Index (TI): The ratio between LD50and ED50. TI=LD50/ED50 It represents the estimate of margins of drug safety If LD50 is much higher than the ED50. The therapeutic index become large, and the drug is less toxic (large TI = wide safety margin). Drugs with small therapeutic index (narrow safety margin): aminoglycosides, theophylline, hypoglycemic agents and anticoagulants.  Therapeutic Window (TW) "the most important parameter for clinical safety": The safe dosage range between the minimum effective therapeutic dose, and the minimum toxic dose This parameter is used to determine the acceptable range of plasma level when designing a dosing regimen Therapeutic Window (TW) = (Minimum effective therapeutic dose - Minimum toxic dose) For example, if the minimum therapeutic plasma concentration of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8–18 mg/L  Adverse drug reactions: The harmful effects of drugs Type A Type B (Bizarre Type C Type D (Delayed Type E (Augmented adverse effects) (Chronic adverse effects) (End of use adverse effects) adverse effects) adverse effects) dose related non-dose related dose-related time-related withdrawal time-related Common Uncommon Uncommon Uncommon Uncommon Related to Not related to Related to Usually dose- Occurs soon pharmacological pharmacological cumulative related after action of the action of the dose Occurs or withdrawal of drug drug becomes apparent the drug Predicatable unpredicatable some time after Low mortality High mortality the use of the drug  Type A Type B (Bizarre Type C (Chronic Type D (Delayed Type E (Augmented adverse effects) adverse effects) adverse effects) (End of use adverse effects) adverse effects) Sleepiness Immunological Adverse drug Teratogenesis Opiate while taking reactions: reactions seen in Carcinogenesis withdrawal antihistamines penicillin the long-term (bladder cancer syndrome Increased hair hypersensitivity treatment with induced by growth while Idiosyncrasy Corticosteroids cyclophosphamid taking Tolerance (It is e therapy. Here minoxidil reduced response bladder cancer is to the same dose occurred after a of the drug with lag time of 1 to 10 prolonged use years of and higher doses termination of are needed to treatment. ) produce the same effect).  Drug allergy Type I allergic Type II allergic Type III allergic Type IV allergic reactions reactions reactions reactions Immediate Cytotoxic Immune complex- Delayed mediated hypersensitivity Immune system IgE antibodies IgG and IgM IgG and IgM T cells involved antibodies antibodies Onset Symptoms Symptoms Symptoms set Symptoms set in appear after a appear after in after several hours to days few seconds to minutes to hours later minutes hours Examples Anaphylactic Autoimmune Serum sickness Allergic contact reactions (difficulty hemolytic anemia (fever, arthritis, an dermatitis breathing, d rash) swelling, low blood pressure, bluish skin, and shock)