2 Principles of Drug ActionNS.pdf

Diploma in Pharmacy FFG2 Pharmacology Please do not reproduce, redistribute or share without the prior express permission of the author. Principles Of Drug Action Chapter 2 Please do not reproduce, redistribute or share without the p...

Diploma in Pharmacy FFG2 Pharmacology Please do not reproduce, redistribute or share without the prior express permission of the author. Principles Of Drug Action Chapter 2 Please do not reproduce, redistribute or share without the prior express permission of the author.  Topic/Chapter Learning Outcome/objectives 1. Define Pharmacodynamics 2. List out principles of drug action 3. List out mechanism of drug action 4. Classification of Receptors 5. Tolerance, Drug Resistance, Desensitization 6. Therapeutic Index Please do not reproduce, redistribute or share without the prior express permission of the author.  Pharmacodynamics (What the drug does to the body) Pharmacodynamics can be defined as the study of the biochemical and physiological effects of drugs ( how our body react to drugs) and their mechanisms of action(The study of the action or effects of drugs on living organisms.) An example of pharmacodynamics is someone studying how paracetamol treats a person suffering from mild pain. Pharmacodynamics concepts include affinity, efficacy, and potency, /The extend & duration of drug actions and whether the drug is an agonist or antagonist. Pharmacodynamics includes both the desired effect of the drug as well as the undesired, or side, effects. Please do not reproduce, redistribute or share without the prior express permission of the author. Absorption: Describes how the drug moves from the site of administration to the site of action. Distribution: Describes the journey of the drug through the bloodstream to various tissues of the body. Metabolism: Describes the process that breaks down the drug. Excretion: Describes the removal of the drug from the body. When the drug forms an interaction with the receptor, the pharmacodynamics phase occurs where the biological effects are observed after the drug-receptor interaction. For a drug to be considered effective, the drug must be readily absorbable in sufficient quantity. Please do not reproduce, redistribute or share without the prior express permission of the author.  Principles of drug action ❑Drugs (except those gene based ) do not impart new functions to any system, organ or cell. ❑They only alter the pace of ongoing activity. The basic types of drug action can be broadly classified in to 5 types. ❑Stimulation ❑Depression ❑Irritation ❑Replacement ❑Cytotoxic action Please do not reproduce, redistribute or share without the prior express permission of the author.  Pharmacodynamics 1. Stimulation – It is selective enhancement/increase of the level of activity of specialized cells E.g. Adrenaline stimulates heart 2. Depression – it is the selective depression of activity of specialize cells ( reduces the rate of activity) E.g. barbiturates depress CNS , general anesthetics depress the CNS Please do not reproduce, redistribute or share without the prior express permission of the author.  Pharmacodynamics 3. Irritation – This denotes a nonselective ,often noxious effect and is particularly applied to less specialized cells. Mild stimulation may stimulate associated function. e.g. Bitters increases salivary and gastric secretion Counterirritants increases blood flow to the site 4. Replacement – this refers to the use of natural metabolites , hormones or their congeners in deficiency states. e.g. Levodopa in parkinsonism, Insulin in diabetes mellitus. Please do not reproduce, redistribute or share without the prior express permission of the author.  Pharmacodynamics 5. Cytotoxic action – Selective cytotoxic action for invading parasites or cancer cells , attenuating them without significantly affecting the host cells is utilized for cure/palliation of infections and neoplasms e.g. Penicillin, chloroquine, mebendazole. Please do not reproduce, redistribute or share without the prior express permission of the author.  Mechanism of drug action 1. Physical action 2. Chemical action 3. Through enzymes (a) Stimulation (b) Inhibition 4. Through receptors Please do not reproduce, redistribute or share without the prior express permission of the author.  1. Physical property A physical property is responsible for the activity of drug. Examples: ❑Mass of the drug – Bulk laxative (Constipation) ❑Adsorptive property – charcoal, kaolin ( Diarrhea) ❑Radioactivity - Radioisotopes ( Cancer treatment) ❑Radio opacity – barium sulfate. ( Cancer Diagnosis) Please do not reproduce, redistribute or share without the prior express permission of the author.  2. Chemical action The drug reacts extra cellularly according to simple chemical reactions. e.g. ▪Antacids like Al(OH)3 which neutralizes gastric acid ▪Chelating agents sequester toxic metals (Calcium disodium edetatate, BAL) Please do not reproduce, redistribute or share without the prior express permission of the author. 3. Enzymes Please do not reproduce, redistribute or share without the prior express permission of the author.  3. Enzymes Drugs can produce their effect by modifying enzyme activities. - e.g. Anticholinesterases like neostigmine act by inhibiting the enzyme acetylcholinesterase. - ACE inhibitors Teniligliptin inhibits DPP-4 function and increases the insulin level in the blood. -Anti Diabetic action. Please do not reproduce, redistribute or share without the prior express permission of the author.  ENZYMES Enzyme stimulation is relevant to many endogenous mediators and modulators. E.g. Adrenaline stimulates adenyl cyclase. ( Energy formation) Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author. 3. Enzymes (b) Inhibition -Enzyme inhibitors are molecules that interact in some way with the enzyme to prevent it from working in the normal manner. Poisons and drugs are examples of enzyme inhibitors. ❑Inhibition of enzymes is a common mode of drug action. ❑This can be divided in to (i) Non-specific (ii) Specific (A) Competitive (B) Non-competitive Please do not reproduce, redistribute or share without the prior express permission of the author. EXAMPLES Please do not reproduce, redistribute or share without the prior express permission of the author. Enzyme Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  (i) Non-specific inhibition ❑Many chemicals and drugs are capable of denaturing proteins. ❑These chemicals causes nonspecific inhibition by destroying the enzyme. E.g. heavy metals, strong acids, strong alkalies, alcohol, formaldehyde, phenol etc. Please do not reproduce, redistribute or share without the prior express permission of the author.  (ii) Specific inhibition This means the drug inhibits particular enzyme or enzymes. Please do not reproduce, redistribute or share without the prior express permission of the author. a) COMPETETIVE Please do not reproduce, redistribute or share without the prior express permission of the author.  (A) Competitive Competitive inhibition – the drug competes with the normal substrate or coenzyme e.g. Physostigmine and Neostigmine compete with acetylcholine for cholinesterase. Carbidopa competes with levodopa for dopa decarboxylase. Warfarin competes with vit k which act as a co-enyme for clotting factor. Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  (B) Non-competitive inhibition The inhibitor reacts with the adjacent site and not with the catalytic site but alters the enzyme in such a way that it loses its catalytic property. e.g. Acetazolamide - Carbonic anhydrase Digoxin – + + Na K ATPase Aspirin – Cyclo-oxygenase. Please do not reproduce, redistribute or share without the prior express permission of the author. B. NON COMPETITIVE Please do not reproduce, redistribute or share without the prior express permission of the author.  TUTORIAL 2A 1. State the 5 basic types of drug action and briefly describe them. 2. Give a suitable term for the below: a) Selective enhancement of the level of activity of specialized cells _______________ b) Selective depression of activity of specialized cells. _______________ 3. What is the meaning of the following? Give one example a) Replacement b) Cytotoxin action c) Stimulation 4.Explain in brief what is chemical action. Give an example 5. Draw a diagram to show a competitive inhibition Please do not reproduce, redistribute or share without the prior express permission of the author.  4. Through receptors Receptor – is defined as a binding site with functional correlate. Receptors are situated on the surface or inside the effector cell, and specific agonists combine with them to initiate the characteristic response. Please do not reproduce, redistribute or share without the prior express permission of the author.  Receptor Receptors are proteins, usually cell surface receptors, which bind to a substance (eg. a cytokine) and cause responses in the immune system. Receptors can be found in various immune cells like B cells, T cells, NK cells, monocytes and stem cells, etc. Please do not reproduce, redistribute or share without the prior express permission of the author. LIGAND - something that binds with a biological molecule to form a complex and produce some effect. Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  4. Through receptors ❑Agonist – It activates a receptor to produce an effect. ❑Antagonist – It prevent the action of an agonist on a receptor or the subsequent response , but do not have any effect of its own. Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  Receptors Receptors serve two essential functions ❑Recognition of the specific ligand molecules ❑Transduction of signal into a response Because of this a receptor will have ligand binding domain and an effector domain. Please do not reproduce, redistribute or share without the prior express permission of the author.  Classification of receptors 1. G-protein coupled receptors. – Glucagon receptor 2. Receptors with intrinsic ion channel – GABA receptor 3. Enzymatic receptors- Insulin receptor 4. Receptors regulating gene expression – Steroid receptor/ thyroid hormone Please do not reproduce, redistribute or share without the prior express permission of the author.  1. G- protein coupled receptors ( GPCR) GPCR has a 7 α helical membrane spanning hydrophobic amino acid segments which run into 3 extra cellular and 3 intracellular loops. The agonist binding site is located somewhere between the helices on the extra cellular face , while another recognition site formed by cytosolic segments binds the coupling G- protein. Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  1. G- protein coupled receptors ( GPCR) ❑These are a large family of cell membrane receptors which are linked to the effector through one or more GTP activated proteins for response. ❑The effector can be enzymes or ion channels or carrier proteins. Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  G- protein coupled receptors ( GPCR) ❑The G-proteins float in the membrane with their exposed domain lying in the cytosol and are heterotrimeric in composition. ❑It consists of 3 subunits binds together α,β,γ. Please do not reproduce, redistribute or share without the prior express permission of the author.  G- protein coupled receptors ( GPCR) In the inactive state GDP is binds with αβγ unit. When a ligand binds with the receptor leads the displacement of GDP by GTP. This causes the conformational changes in the unit and α-GTP unit separates. This units will binds to different effector cells to carry out the action. The βγ unit have been shown to modulate certain effectors like receptor operated K+ channels, adenyl cyclase and phospholiase C. Please do not reproduce, redistribute or share without the prior express permission of the author.  2. Intrinsic ion channel ❑These cell surface receptors enclose ion selective channels ( for Ca 2+ , K+ or Na+ ) with in their molecule. Agonist binding opens the channel and causes depolarization / changes/ hyper polarization in cytosolic ionic composition , depending on the ion that flows through. Within the extracellular fluid, the major cation is sodium and the major anion is chloride. The cytosol or intracellular fluid consists mostly of water, dissolved ions, small molecules, and large, water-soluble molecules (such as proteins). E.g. GABA receptor, 5HT3 receptor Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  3. Enzymatic receptors ❑This class of receptors themselves are enzymatic proteins. The agonist binding site lie on the outer side and catalytic site in the inner face of the plasma membrane. ❑These two domains are inter-connected through a single transmembrane stretch of peptide chain. ❑The enzyme in most cases is a tyrosine protein kinase. Please do not reproduce, redistribute or share without the prior express permission of the author.  4. Receptors regulating gene expression (Hormone) ❑Several biologic ligands are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors. ❑Examples: All steroidal hormones, thyroid hormone, whose receptors stimulate the transcription of genes by binding to specific DNA sequences near the gene whose expression is to be regulated. Please do not reproduce, redistribute or share without the prior express permission of the author.  Functions of receptor ❑To propagate regulatory signals from outside to within the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. ❑To amplify the signal ❑To integrate various extra cellular and intracellular regulatory signals. ❑ To adapt to short term and long-term changes in the regulatory milieu and maintain homeostasis. Please do not reproduce, redistribute or share without the prior express permission of the author.  Tutorial 2B 1. State four classification of receptors. 2. What are the function of receptors? 3. Draw the G-protein coupled receptors. Please do not reproduce, redistribute or share without the prior express permission of the author. (a)Natural – inherently less sensitive to the Tolerance drug E.g. Rabbits are tolerant to atropine A decrease in the effect of a drug as a consequence of repeated (b) Acquired – by repeated use of a drug in an individual who was initially exposure responsive A continuous presence of drug in the body leads to tolerance A higher dose of a drug is needed E.g. Cocaine, morphine to produce a given response A more gradual decrease in (c) Cross tolerance – Exposure to one response of drug which takes days drug can produce tolerance to other or weeks to develop. similar acting drugs Example: morphine / pethidine Please do not reproduce, redistribute or share without the prior express permission of the author.  Some types of cells are inherently Drug Resistance resistant to certain drugs Examples: Neoplastic or cancer cells The reduction in are resistant to certain anticancer effectiveness of a medication agents by mutating, after prolonged to cure a disease or condition administration of suboptimal drug Antimicrobial resistance (AMR), or drug doses. resistance, develops when microbes, Drug resistance can be minimized by including bacteria, fungi, parasites, and short-term, intensive, intermittent viruses, no longer respond to a drug that therapy with combinations of drugs previously treated them effectively. Please do not reproduce, redistribute or share without the prior express permission of the author.  Drug Resistance Some types of cells are inherently resistant to certain drugs Examples: Neoplastic or cancer cells are resistant to certain anticancer agents by mutating, after prolonged administration of suboptimal drug doses Drug resistance can be minimized by short-term, intensive, intermittent therapy with combinations of drugs Please do not reproduce, redistribute or share without the prior express permission of the author. DRUG RESISTANCE BACTERIA Please do not reproduce, redistribute or share without the prior express permission of the author.  DESENSITIZATION What is receptor After exposure to an agonist, the initially desensitization? maximum response is seen ▪The rapid signal attenuation Now if we continue to administer agonist it in response to stimulation of shows decrease in response due to cells by agonists desensitization of receptors ▪Decrease in response of Removal of the drug for a more extended drug due to frequent period allows the cell to recover its capacity administrations to respond Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  Therapeutic Index In animal studies, the therapeutic index is defined as the ratio of the TD50 to ED50. High Therapeutic Index = Safe Toxic dose (TD) / Lethal dose: the amount of Low or Narrow Therapeutic Index = not so the drug which kills subjects when it is safe, need to monitor dose closely administered Drugs with narrow therapeutic index Effective dose: The amount of the drug which Warfarin removes sign and symptoms of subjects when Digoxin it is administered. Theophylline It shows the relationship between the efficacy Phenytoin Lithium and safety of a given drug Please do not reproduce, redistribute or share without the prior express permission of the author. Please do not reproduce, redistribute or share without the prior express permission of the author.  References 1. Rang H.P., Dale MM, Ritter JM, Moore PK, (2003).Pharmacology (5th ed). Churchill Livingstone 2. Tripathi KD, Essentials of Medical Pharmacology, 2004 ( 5th ed ) Jaypee. 3. Kaye M., Favaro, A. (2005). Introduction to Pharmacology (10th ed.). 4. WB Saunders.Holland LN, Adams MP. Core concepts in Pharmacology.2003, Prentice Hall. 5. https://www.slideshare.net/amitgajjar85/pharmacology-13882960 Please do not reproduce, redistribute or share without the prior express permission of the author.  Tutorial 2C 1. What is tolerance? 2. State the three types of tolerance and give examples of drugs for each. 3. What is the meaning of therapeutic index? Give examples of drugs that have narrow therapeutic index Please do not reproduce, redistribute or share without the prior express permission of the author. Q&A Session Please do not reproduce, redistribute or share without the prior express permission of the author. PHARMACOKINETICS Please do not reproduce, redistribute or share without the prior express permission of the author.  Thank you Address Telephone Website Lot 33-40, Blok C, Plaza Juta, +6088 431 025/35 kk.cyberjaya.edu.my KM 7.2 Off Jalan Tuaran, 88400 Likas, Kota Kinabalu, Email Sabah, Malaysia [email protected]