Pharmacodynamics Notes PDF

2. PHARMACODYNAMICS Dr. Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine - Ain Shams University  Pharmacokinetics What the body does to the drug ? Pharmacodynamics What the drug does to the body ?  Four processes are involved in drug ther...

2. PHARMACODYNAMICS Dr. Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine - Ain Shams University  Pharmacokinetics What the body does to the drug ? Pharmacodynamics What the drug does to the body ?  Four processes are involved in drug therapy Pharmacokinetics Pharmacodynamics  Mechanisms of Drug Action Receptor OR Non-Receptor Mediated Mediated  Specific cellular macromolecules (usually Receptors proteins) that interact with a ligand (binding) to produce a response.  Receptor Mediated Drug Action Ligand Chemical substance (endogenous or exogenous) that bind to receptors Agonist Antagonist Receptor Mediated Drug Action  Types of Ligand Full Agonist Inverse Partial Agonist Ligand Agonist Antagonist  Full Agonist Interacts with the receptor (affinity) activating it (efficacy)  pharmacologic effect (has both affinity and efficacy) Affinity Efficacy Action (maximal)  Partial Agonist (Agonist-Antagonist) ❑ In absence of the agonist, it activates the empty receptor, but with lower efficacy than that of a full agonist. ❑ In the presence of the agonist, it acts as an antagonist Affinity Action Efficacy (submaximal)  Antagonist Interacts with the receptor (affinity) without activation (no efficacy) Affinity Action No Efficacy  Types of Antagonist 1. Competitive antagonists: compete with agonists for the same recognition site of the receptors  the agonist behaves as if it were less potent.  Types of Antagonist 2. Non-competitive antagonists: prevent binding of the agonist or prevent activation of the receptor by the agonist. ❑ What is Agonist It's a drug that produces pharmacological effect when it combines with a receptor It has both affinity and Efficacy ❑ What is Antagonist Drugs bind to receptors without regulatory effects, but blocking the binding of the agonists and inhibits their actions It has affinity only but no Efficacy  Dose – response Curves 1. Graded Dose Response Curve (Quantitative) Degree of response is plotted against log (dose) 2. All/Non Dose Response Curve (Qualitative) The percentage of subjects response to the drug (Responders) is plotted against log (dose) Response I. Graded Dose Response Curve  Parameters that can be obtained from the Graded dose response curve: 1. Efficacy Measured by Emax: The maximal effect of the drug  Emax →  Efficacy 2. Potency Measured by EC50: Dose produced 50% of the maximal response (Emax) EC50 →  Potency  Example: The following log dose response curves are for 4 antihypertensive drugs (A&B&C&D) that were tested for their ability to reduce Arterial blood pressure Increasing Efficacy Emax (Efficacy) of Drug A > Drug B > Drug C > Drug D  Same Efficacy (Emax) A B C D Decreasing Potency (↑EC50) 5 15 EC50 of Drug A < Drug B < Drug C < Drug D Potency of Drug A > Drug B > Drug C > Drug D Competitive Antagonism Dose Response Relationships Competitive Antagonism ❑ Antagonist competes with the agonist for the same recognition site of the receptor. ❑ Duration of antagonism depends on the relative plasma concentrations of agonist and antagonist. ❑ Causes parallel shift to the right in the log dose-response curve with increase in the EC50 but no change in Emax (maximum response “Efficacy”). Example: ACH & Atropine Non-Competitive Antagonism Dose Response Relationships Non-Competitive Antagonism ❑ Antagonist binds irreversibly to the recognition site of the receptor or bind to an allosteric site. ❑ Duration of antagonism depends on the rate of turnover of the receptor molecules. ❑ Causes downward shift in log dose response curve with decrease in Emax (maximum response) but no change in EC50.  II. All/None dose-response Curve (Qualitative) Curve is obtained if the percentage of patients who respond to the drug is plotted against log the dose. e.g. the % of patients in whom blood pressure is improved by different doses of an anti-hypertensive drug. 1. Effective dose 50 (ED50): dose of the drug that cures 50% of patients. 2. Toxic dose (TD50)/lethal dose 50 (TD50): dose of the drug that produces toxicity in 50% of patients.  II. All/None dose-response Curve (Qualitative) ❑Parameters that can be obtained from the All/None curve: 1. ED50: It is used for comparison between drugs.  Drug with a lower ED50 is more potent than that with a higher ED50. 2. Toxic dose (TD50)/lethal dose 50 (LD50): Gives an idea about the absolute toxicity of the drug.  Drug with lower TD50 is considered more toxic than the drug with higher TD50.  II. All/None dose-response Curve (Qualitative) 3. Therapeutic index (TI): Is a ratio of the toxic dose (TD50) to the effective dose (ED50) of a medication TD50 Therapeutic index = ED50 ❑ Gives an idea about the safety of the drug: If the TI is large, i.e: TD50 much higher than the ED50 → the drug is safe.  II. All/None dose-response Curve (Qualitative) 3. Therapeutic index (TI): ❑ If TD50=500mg, ED50=50 ∴TI= 100 (large) It means that toxic dose is 100 times the effective dose ❑ If TD50=200mg, ED50=100 ∴TI= 2 (small) It means that toxic dose is 100 times the effective dose  Therapeutic window The range between the minimum toxic dose and the minimum therapeutic dose. It is practical for choosing the dose for a patient.  Drugs with narrow therapeutic index Have a narrow window between their effective doses and those at which they produce adverse toxic effects. e.g. anticoagulants, antiepileptics, lithium Low or Narrow Therapeutic index → ↑ toxicity  A large therapeutic index means there is a large therapeutic window between the effective dose and the toxic dose of a drug Signal transduction systems 1 2 3 4 Group 1, 2, and 3 are cell membrane receptors 1. Ion Channels (for fast neurotransmitters) Receptors are ion-selective channels in the plasma membrane. Binding of agonist to the receptor →opening of ion channel → alteration in membrane potential or change in intracellular ion concentration  both resulting in change in cell activity. e.g.: nicotinic Ach receptors (combined Na+/K+ channels).  Ach Na+ Na+ Na+ Depolarization Skeletal muscle Contraction 2. Receptors linked to Tyrosine Kinase The receptor consists of two domains: 1. An extracellular domain, to which the agonist (e.g. insulin) binds. 2. An intracellular domain, which is a tyrosine kinase enzyme (effector). Binding of insulin causes 2 single (monomer) tyrosine-kinases receptors to aggregate into a dimmer with subsequent autophosphorylation. Then, the activated-phosphorylated dimmer binds to relay proteins, activating them. These relay proteins trigger the cellular response through either production of a second messenger or turning on gene expression.  Insulin Response 3. G protein-Coupled Receptors (for slow neurotransmitters) Receptors are linked to G proteins. The G protein is a trimer (α, βand  ). Agonist binding → dissociation of α subunit which regulates activity of several effectors. Examples of G Proteins a. Gs (stimulatory): increased cAMP. b. Gi (inhibitory): decreased cAMP. c. Gq : liberating DAG and IP3. 4. Receptors Regulating Gene Transcription (very slow) Steroid hormones, estrogen, progesterone, thyroid hormones and vitamin D enter the target cell and combine with intracellular receptor proteins associated with nuclear chromatin (DNA) to activate or inhibit transcription of the nearby gene. This will modify protein production and cause changes in the structure or function of the target tissue. Delayed Response  Receptor Cycling or Turnover Old receptors are internalized inside the cell and the new ones are externalized to the outside) Down-regulation: ↓ No. of Receptors due to continuous use of Agonist e.g β2-agonist Up-regulation: ↑ No. of Receptors due to continuous use of Antagonist e.g β-Blockers  Receptor Cycling or Turnover Receptor Internaliz. Externaliz. Recycling ++ New Receptor Old Receptor ++ New Receptor Agonist Antagonist  Non-Receptor Mediated Drug Action 1. Drugs Acting on Enzymes: Drugs may inhibit or activate enzyme systems. Ex.: Choline esterase inhibitors (ChEIs) → inhibit ChE preserving Ach. - Aspirin inhibits cyclooxygenase → 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: Polyene antifungal drugs increase permeability of fungal plasmatic membrane. 3. Drugs Acting on Subcellular Structures - Mitochondria - Microtubules 4. Drugs Acting on the Genetic Apparatus - Antibiotics: inhibit bacterial protein synthesis. - Anticancer drugs affect DNA synthesis or function 5. Drugs Acting by Chemical Action/Antagonism - Antacids neutralize HCL in peptic ulcer. - Protamine neutralize heparin by its +ve charge in treatment of heparin overdose.  Chemical antagonism between Heparin & Protamine sulfate Protamine +ve Heparin -ve Drug interacts chemically with the agonist away from receptor, e.g. negative charges on heparin are neutralized by positive charges on protamine sulfate (heparin antidote).  6. Physiological antagonist: Epinephrine & Histamine in Anaphylactic Shock One drug antagonizes the effect of another by acting on a different receptor to induce the opposite action e.g. β2- bronchodilator and α1 vasoconstrictor effects of epinephrine antagonize H1-bronchconstrictor and vasodilator effects of histamine in allergic reactions.  Anaphylactic Shock Epinephrine EP Histamine β2-Receptor α1-Receptor H1-R Histamine Histamine H1-R H1-R Life Saving Shock Thank you