Pharmacodynamics Lecture (BAS316) - Spring 2024

Pharmacodynamics PHARMACOLOGY LECTURE (BAS316) PRESENTED BY ABEER BISHR LECTURER OF PHARMACOLOGY SPRING 2024 Pharmacodynamics Pharmacodynamics is the study of the detailed mechanism of action by which drugs produce their pharmacologic effects. This stu...

Pharmacodynamics PHARMACOLOGY LECTURE (BAS316) PRESENTED BY ABEER BISHR LECTURER OF PHARMACOLOGY SPRING 2024 Pharmacodynamics Pharmacodynamics is the study of the detailed mechanism of action by which drugs produce their pharmacologic effects. This study of a drug’s mechanism of action begins with the binding of a drug to its target receptor, enzyme, or other protein and produce its response Mechanisms of drug action A- Non receptor mediated actions 1. Physical action (example: Adsorption action: e.g. activated charcoal in treatment of diarrhea) 2. Chemical action (example: Acidity and alkalinity: e.g., antacids to neutralize gastric HCL in peptic ulcer) 3. Through enzymes (example: Neostigmine inhibits Ach esterase) B- Receptor mediated actions Receptor mediated actions What is a receptor? A macromolecule on the surface of the cell or inside the cell that specifically binds to a ligand (drug). Drugs act as signals, and their receptors act as signal detectors. Receptors transduce their recognition of a bound agonist by initiating a series of reactions that ultimately result in a specific intracellular response. Receptor mediated actions Affinity: is the ability of a drug to bind to a receptor. Intrinsic activity or efficacy: is the ability of a drug to produce a response after binding to the receptor. Ligand: is a molecule which binds selectively to a specific receptor. Any molecule (drug or hormones or neurotransmitters) which attaches selectively to particular receptors or site. Drug-receptor interaction has been considered to be similar to ‘lock and key’ relationship where the drug specifically fits into the particular receptor (lock) like a key It may cause activation or inhibition to the receptor.  Types of the receptor 1. Membrane receptors a. Transmembrane ligand-gated ion channels b. Transmembrane G protein–coupled receptors c. Enzyme-linked receptors 2. Intracellular receptors Ligand-gated ion channels They are also called Ionotropic receptors. There are several structural families, the commonest consists of five subunits, arranged around a central channel. The five subunits (2α, β, γ, δ) form a cluster surrounding a central transmembrane pore. The extracellular portion usually contains the ligand binding site.  ligand-gated ion channels This site regulates the shape of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds. Depending on the ion conducted through these channels, these receptors mediate diverse functions. Example: stimulation of the nicotinic receptor by acetylcholine results in sodium influx and potassium outflux, generating for example contraction in skeletal muscle. Nicotinic Ach receptors  G protein–coupled receptors (GPCRs) They are called metabotropic receptors. The extracellular portion usually contains the ligand binding site. The intracellular portion interacts (when activated) with G protein. G proteins consist of three subunits: α, β, γ During the resting state: G protein exists as an αβγ trimer + guanosine diphosphate (GDP) occupying the site on the α subunit. During the activation: After the agonist binding to the ligand site → cause conformational changes → GDP replaced by guanosine triphosphate (GTP) → Dissociation of the G protein trimer, releasing α– GTP and βγ subunits that can associate with various enzymes and ion channels, causing either activation or inhibition of the target Types of G- protein Gs → Activates adenyl cyclase → ↑ cAMP → ↑ protein kinase A (PKA) → ↑ protein phosphorylation → Increase heart contractions. ❑Example of receptors: β1 (heart) Gi → Inhibits adenyl cyclase → ↓cAMP → Decrease enzyme activities → ↓ protein phosphorylation ❑Example of receptors: α2 Gq → Activates phosholipase C → ↑IP3 (Inositol triphosphate) → binds to IP3 receptors on sarcoplasmic reticulum that stored calcium→ ↑ Ca2+ intracellularly → by increasing its release from Ca stores → increases contraction, enzyme activation and secretions. ↑DAG (Diacylglycerol) → activates protein kinase C (PKC) → different protein phosphorylation. ❑Example of receptors: α1 G protein Type Gs Gi Gq The Adenylyl Adenylyl Phospholipase C effector cyclase cyclase The second - Inositol 1,4,5- messenger triphosphate cAMP cAMP (IP3) - Diacylglycerol (DAG) Enzyme linked receptors These receptors are polypeptides consisting of an extracellular binding domain, and a cytoplasmic enzyme domain which may be a protein tyrosine kinase (Most enzyme- linked receptors are of this type), serine kinase, or a guanylyl cyclase. In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane. The most common enzyme-linked receptor is insulin. Intracellular receptor They are called nuclear receptors. The receptor is entirely intracellular inside the cytoplasm, and, therefore, the ligand must diffuse into the cell to interact with the receptor. The ligand should be sufficiently lipid soluble to cross the plasma membrane. Their ligand binding either induce or suppress gene expression. Example: Steroid hormone receptors Ligand Agonist: is a substance that binds to the receptor and produces a response. It has affinity and intrinsic activity. Antagonist: is a substance that binds to the receptor and prevents the action of agonist on the receptor. It has affinity but no intrinsic activity. Agonist Agonists are drugs that bind and activate receptors. Types of agonists: 1. Full Agonist: binds to a receptor and produces a maximal biologic response that mimics the response of the endogenous ligand. 2. Partial Agonist: A drug that binds to a receptor but produces a smaller effect at full dosage than a full agonist Antagonists Antagonism: a substance that stops the action or effect of another substance. Based on the mechanisms, antagonism can be: 1. Chemical antagonism 2. Physiological antagonism 3. Antagonism at the receptor level: a. Reversible (Competitive) b. Irreversible (Non-competitive antagonism) Chemical antagonism & Physiological antagonism 1- Chemical antagonism: Two substances interact chemically to result in inactivation of the effect, e.g. chelating agents inactivate heavy metals like lead and mercury to form inactive complexes. 2- Physiological antagonism: Two drugs act at different sites to produce opposing effects. For example, histamine acts on H2 receptors to produce bronchospasm and hypotension while adrenaline reverses these effects by acting on adrenergic receptors.  Antagonism at the receptor level The antagonist inhibits the binding of the agonist to the receptor. 1- Competitive antagonist: It binds to the same site of the agonist to stop the agonist action, their actions are often reversible In By increasing the concentration of the agonist, the antagonism can be overcome. Example: Acetylcholine and atropine compete for the muscarinic receptors. The antagonism can be overcome by increasing the concentration of acetylcholine at the receptor. Antagonism at the receptor level 2- Non-competitive antagonist: The antagonist binds firmly by covalent bonds to the receptor. Thus it blocks the action of the agonist and the blockade cannot be overcome by increasing the dose of the agonist and hence it is irreversible antagonism. Drug synergism and antagonism Drug synergism and antagonism 1- Additive Effect: The effect of two or more drugs get added up and the total effect is equal to the sum of their individual actions. Examples are ephedrine with theophylline in bronchial asthma. 2- Synergism: When the action of one drug is enhanced or facilitated by another drug, the combination is synergistic. Here, the total effect of the combination is greater than the sum of their independent effects. 3- Antagonism: One drug opposing or inhibiting the action of another. Dose-response relationships Dose response curve A- Quantal dose response curve: Quantal dose-response curves comparing the dose of drug on the x-axis with the cumulative percentage of subjects responding to that log dose on the y-axis, yielding an S-shaped curve. Median lethal dose (LD50) is the dose which is lethal to 50 percent of animals of the test population. Median effective dose (ED50) is the dose that produces a desired effect in 50 percent of the test population  Therapeutic index Therapeutic index (TI) is the ratio of the median lethal dose to the median effective dose. Therapeutic index = LD50 /ED50. It gives an idea about the safety of the drug Larger values → indicates a wide margin between the LD50 and ED50 and indicates that the drug is safer with increasing the taken dose. Dose response curve B- Graded dose response curve: In graded dose-response relationships, the response elicited with each dose of a drug is described in terms of a percentage of the maximal response and is plotted against the log dose of the drug. As the concentration of a drug increases, its pharmacologic effect (response) also gradually increases until all the receptors are occupied (the maximum effect). After the maximum effect has been obtained, further increase in doses does not increase the response. If the dose is plotted on a logarithmic scale, the curve becomes sigmoid. Drug Potency and Maximal Efficacy Potency: The amount of drug required to produce a response. For example, 1 mg of bumetanide produces the same diuresis as 50 mg of frusemide. Thus, bumetanide is more potent than frusemide. Efficacy: is the ability of a drug to produce a response after binding to the receptor. Emax: is the maximum effect which can be expected from this drug (i.e. when this magnitude of effect is reached, increasing the dose will not produce a greater magnitude of effect) The dose-response curves of three agonists (R, S, and T) are compared. Drugs R and S are full agonists. Both have maximal efficacy, but R is more potent than S. Drug T is a partial agonist and therefore is incapable of producing the same magnitude of effect as a full agonist. T is also less potent than R and S. Factors that modify the effects of the drug The same dose of a drug can produce different degrees of response in different patients and even in the same patient under different situations. Various factors modify the response to a drug. They are: 1- Body weight 2- Age 3- Sex 4- Species and race 5- Diet and environment 6-Dose 7- Route of administration 8- Genetic factors 9- Diseases 10. Psychological factor 11. Presence of other drugs Factors that modify the effects of the drug 11- Repeated dosing can result in: Cumulation Or Tolerance Or Tachyphylaxis 1. Cumulation: Drugs like digoxin which are slowly eliminated may cumulate resulting in toxicity. 2. Tolerance: Tolerance is the requirement of higher doses of a drug to produce a given response. Tolerance may be natural or acquired. a. Natural tolerance: The species/race shows less sensitivity to the drug, e.g. rabbits show tolerance to atropine. b. Acquired tolerance: develops on repeated administration of a drug. The patient who was initially responsive becomes tolerant, e.g. barbiturates produces tolerance. Factors that modify the effects of the drug 3. Tachyphylaxis is the rapid development of tolerance. When some drugs are administered repeatedly at short intervals, tolerance develops rapidly and is known as tachyphylaxis or acute tolerance Example: ephedrine. This is thought to be due to depletion of noradrenaline stores as the above drugs act by displacing noradrenaline from the sympathetic nerve endings. Thus ephedrine given repeatedly in bronchial asthma may not give the desired response