Pharmacodynamics Lecture Notes PDF

Pharmacodynamics Dr Arif Hashmi 1/20/2024 Dr Hashmi  What is a drug? A substance used in diagnosis, treatment and prevention of disease. 1/20/2024 Dr Hashmi  Drugs Increase body’...

Pharmacodynamics Dr Arif Hashmi 1/20/2024 Dr Hashmi  What is a drug? A substance used in diagnosis, treatment and prevention of disease. 1/20/2024 Dr Hashmi  Drugs Increase body’s innate systems e.g. Increased Inhibit body’s innate systems e.g. Beta insulin secretion from the pancreas by the blockers (Atenolol) work by blocking the Sulfonylureas (Glibenclamide) in treatement of activity of sympathetic system, are used in Diabetes mellitus treatment of Hypertension Replace of lost functions e.g. exogenous insulin administration in Type 1 Diabetes mellitus 1/20/2024 Dr Hashmi  How do drugs do all this Inhibiting, stimulating??? “Receptors”” Central concept in Pharmacology 1/20/2024 Dr Hashmi  What is a receptor? The term is most often used to describe the target molecules through which soluble physiological mediators-hormones, neurotransmitters, inflammatory mediators, etc.-produce their effects. Examples such as acetylcholine receptors, growth hormone receptors 1/20/2024 Dr Hashmi  Binding of a drug to its receptor stimulates the receptor. Receptors can be any substance to which a drug binds (R+D) Example; Enzymes, Ion channels, DNA, Proteins 1/20/2024 Dr Hashmi Certain Drugs do not need to bind to Receptors for their action. They show their responses by virtue of their physio-chemical properties. Osmotically active substances: Osmotic diuretics like mannitol are not reabsorbed by the kidney, and the osmotic load they create in the renal tubule obligates the loss of water. Laxatives like magnesium sulfate work in the intestine by the same principle. Chemical entities: Neutralization of stomach acid by antacids like Magnesium hydroxide. Also charcoal as part of universal antidote in cases of poisoning. Ions: Ammonium chloride is sometimes used to acidify the urine. When it is taken orally, the liver metabolizes ammonium ion to urea, while the chloride is excreted in the urine. The loss of Cl- obligates the loss of H+ in the urine, thus the urine pH is lowered in cases of metabolic acidosis. 1/20/2024 Dr Hashmi  Binding of a drug to a receptor Millions of types of receptors in the body, Thousands of types of drug molecules How do the drugs bind to the correct receptor? 1/20/2024 Dr Hashmi  “Affinity” – The strength of physio-chemical binding between a receptor and a drug. 1/20/2024 Dr Hashmi Potency: The potency of a drug refers to the dose (actually the molar concentration) required to produce a specific intensity of effect. We usually specify the ED 50. ED 50 (EC50): The median effective dose, or the dose which produces a response in 50% of subjects. If the response is death (lethality) we call it the LD 50. 1/20/2024 Dr Hashmi  Efficacy: Also called Maximal Efficacy or Intrinsic Activity. This is the maximum effect which the drug can produce. A potent drug may have a low efficacy, and a highly efficacious drug may have a low potency. For the clinician, efficacy is much more important than potency (within limits). 1/20/2024 Dr Hashmi Selectivity: This refers to the separation between desired and undesired effects of a drug. In the ideal case, a drug is completely specific, and an effective dose does not elicit any undesired effect. Penicillin is an example of a highly selective drug, since it works specifically by inhibiting cell wall synthesis, and (other than allergic responses) it has very little effect on human cells at normal doses. 1/20/2024 Dr Hashmi  Measure of Efficacy Measure of Potency 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi  Agonist is a drug which binds to its "receptor" and produces its characteristic effect. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. 1/20/2024 Dr Hashmi  Agents that are only partly as effective as agonists no matter the dose employed are termed partial agonists, those that stabilize the receptor in its inactive conformation are termed inverse agonists 1/20/2024 Dr Hashmi  An antagonist binds to the receptor without causing an effect, thereby preventing an active substance from gaining access. Antagonists, bind to receptors without regulatory effect, but their binding, blocks the binding of the endogenous agonist. 1/20/2024 Dr Hashmi  Dose-Response Curve ▪ The essential feature of drug effect. Simply put, as the dose of drug increases, the response should increase. Quantification of Drug – Receptor interaction. ▪ Effect may be measured as a graded variable (change in blood pressure, force of contraction) or as a quantal variable (number dead/alive). 1/20/2024 Dr Hashmi  DRUG RESPONSE CURVE (DRC)/ CONCENTRATION EFFECT CURVE SLOPE The slope of the curve is characteristic of the particular drug-receptor interaction. When two drugs act by the same receptor mechanism, we expect to see two parallel log-dose response curves. 1/20/2024 Dr Hashmi  DRC for different types of Drug + Receptor confirmations Ra - active receptor conformation, Ri - inactive receptor conformation (Also refer to notes in this slide) 1/20/2024 Dr Hashmi Agonists with the same EFFICACY but different POTENCY. Which is the most POTENT? 1/20/2024 Dr Hashmi Agonists with same POTENCY (ED50/EC50) but variable EFFICACY. Which has the maximum EFFICACY? 1/20/2024 Dr Hashmi  Receptor transduction systems (Signal Transduction Mechanisms) What happens once an Agonist binds to the receptor? Drug action So binding of the drug to its receptor brings about a change in the internal environment/working of the cell. This change is because of signals which are transmitted by the receptor to cellular machinery within the cell. 1/20/2024 Dr Hashmi Direct activation of an ion channel The drug receptor is structurally attached to an ion channel. Binding of the drug to the receptor site(s) results in a conformational change in the receptor/channel complex that typically causes the ion channel to open. This results in a flow of channel permeant ions (e.g. Na and K for nicotinic receptors) down their electrochemical gradient with a resultant change in membrane potential Examples: nicotinic cholinergic receptors (neuromuscular junction, ganglia) GABA receptors and receptors for excitatory amino acids (glycine, glutamate, aspartate 1/20/2024 Dr Hashmi G-protein activation of an ion channel The drug receptor stimulates an ion channel via activation of a G protein Example: m2 - cholinergic receptors 1/20/2024 Dr Hashmi G-protein activation of a second messenger cascade the G-protein (Gs) mediated activation of adenylyl cyclase, with subsequent formation of camp and activation of protein kinase A (PK-A) Examples: Adenylyl cyclase/ cAMP/ PK-A: β-adrenoreceptors, α2-adrenoreceptors Drug induced activation of the cAMP/PK-A pathway. Norepinephrine binding to beta1-adrenergic receptors stimulates adenylate cyclase (AC), which converts ATP to cAMP. cAMP acts as a second messenger to stimulate protein kinase A (PK-A), which in turn phosphorylates a variety of proteins, generating a biological response. (e.g. this mechanism is responsible for norepinephrine's ability to increase the force of contraction of heart muscle, which results from the phosphorylation of the L-type Ca channel by PK-A). 1/20/2024 Dr Hashmi the G-protein activation of phospholipase C (PLC), which breaks down phosphoinositide to IP3 and diacylglycerol (Figure 7). DAG acts as a second messenger to stimulate protein kinase C, and IP3 stimulates the release of Ca ions from intracellular stores. Examples: Phospholipase C /Diacylglycerol/ IP3:α1-adrenoreceptors, angiotensin, m1-cholinergic Drug induced activation of the phosphoinositide/ PK-C pathway. Angiotensin II binding to AT1 receptors activates phospholipase C (PLC). PLC breaks down phosphoinositol into diacylglycerol (DAG) and IP3. DAG acts as a second messenger to activate protein kinase C (PK-C), which phosphorylates a variety of intracellular proteins. IP3 stimulates the release of Ca from intracellular stores. These mechanisms are believed to mediate the vasoconstrictive effects of Ang II on vascular smooth muscle. 1/20/2024 Dr Hashmi Receptors linked to Cytoplasmic Enzymes (e.g. Tyrosine Kinases) These receptors contain an extracellular domain that binds to a specific ligand, and a cytoplasmic domain that typically contains a protein tyrosine kinase Examples:EGF, Insulin, various growth factors The binding of a ligand to receptors produces a change in receptor conformation that allows receptors to interact. The interaction between receptors causes the tyronsine kinases to become active, resulting in auto-phosphorylation of the enzyme domains, and phosphorylation of tyrosine residues on different downstream signaling proteins (S→S-P). The auto-phosphorylation typically results in a prolonged response to the agonist (e.g. insulin) that persists after the removal of the ligand from the receptor site. 1/20/2024 Dr Hashmi  Pharmacodynamics II 1/20/2024 Dr Hashmi An antagonist binds to the receptor without causing an effect, thereby preventing an active substance from gaining access. ▪ Antagonists, like enzyme inhibitors, may be competitive, non-competitive or irreversible. ▪ Antagonists, bind to receptors without regulatory effect, but their binding, blocks the binding of the endogenous agonist. 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi  Non-Rececptor Receptor Antagonism Antagonism Antagonism Non- Chemical Competitive Physiological Competitive Pharmacokinetic 1/20/2024 Dr Hashmi Chemical antagonism occurs when a drug reduces the concentration of an agonist by forming a chemical complex (e.g. chelating agents). Example: protamine sulfate is a positively charged substance that when given i.v. will bind to heparin, a strongly negatively charged anticoagulant drug. As a result, protamine sulfate administration is a type of “antidote” for heparin overdose, because once heparin binds to protamine sulfate, it cannot exert its anticoagulant effects. 1/20/2024 Dr Hashmi Physiological antagonism involves drug activation of two different compensatory biological mechanisms that exist to maintain homeostasis by different mechanisms. For example, the effect of norepinephrine to increase blood pressure (viastimulation of α-adrenergic receptors) can be antagonized by administration of acetylcholine, which causes vasodilation by stimulating muscarinic receptors, resulting in the release of nitric oxide from the vascular (arteriolar) endothelium. Acetylcholine and norepinephrine exert their effects through different receptors and signal transduction pathways, which when activated produced opposing effects (e.g. vasodilation vs vasoconstriction). They therefore “physiologically” antagonize each others effects without interacting with the same receptors. 1/20/2024 Dr Hashmi  Pharmacokinetic antagonism occurs when one drug accelerates the metabolism or elimination of another (e.g. phenobarbital- induced enzyme induction increases the metabolism of the anticoagulant coumadin). 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi  Antagonists: Competitive vs. Noncompetitive Competitive antagonists bind reversibly to the same receptor site as the agonist. Because they bind reversibly and compete for the same binding site, their inhibitory effects can be “surmounted” by addition of a higher concentration of agonist This effect produces a rightward parallel shift of the dose-response for the agonist (towards higher concentrations). In the presence of a competitive antagonist, agonists can still produce the same (e.g. 100%) maximal effect as in the absence of an antagonist, the only difference being that higher agonist concentrations are needed to produce the same level of effect. The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists. 1/20/2024 Dr Hashmi Noncompetitive antagonists either bind irreversibly (e.g. by covalent bonds) to the same site as the agonist, or bind to a different site which reduces the binding of the agonist by an allosteric mechanism. The primary effect of a noncompetitive antagonist is a reduction in the maximal effect produced by the agonist In contrast to a competitive antagonist, the effect of a noncompetitive antagonist cannot be reversed by simply increasing the concentration of the agonist 1/20/2024 Dr Hashmi Therapeutic Window: For every drug, there exists some concentration which is just barely effective (the Effective Concentration) and some dose which is just barely toxic(the Toxic Concentration). Between them is the therapeutic window where most safe and effective treatment will occur. 1/20/2024 Dr Hashmi Therapeutic Index: This is the ratio of toxic to effective doses at the level of 50% response (TD 50 /ED 50). In animal toxicology studies, it is usually the LD 50 /ED 50 1/20/2024 Dr Hashmi Contrast between cholinergic receptors & adrenergic receptors Cholinergic Adrenergic receptors Nicotinic: NN and NM Alpha receptors Muscarinic: M1, M2, M3, M4 & α1, α2 M5 Beta receptors β1 β2 β3 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi 1/20/2024 Dr Hashmi Concept Map 1/20/2024 Dr Hashmi