Lecture 1 Basic Concepts 2024 (1).pdf

Introduction: Basic Concepts in Pharmacology September 9, 2024 Josh Berlin Dept. Pharmacology, Physiology & Neuroscience [email protected] 1...

Introduction: Basic Concepts in Pharmacology September 9, 2024 Josh Berlin Dept. Pharmacology, Physiology & Neuroscience [email protected] 1 LECTURE 1. OUTLINE A. Definitions and Terminology 1. Pharmacology 2. Therapeutics 3. Pharmacodynamics & Pharmacokinetics 4. Drug Receptors B. Drug Receptor Interactions 1. Classical Receptors 2. Non-Classical Receptors 3. Non-Receptor Mediated Actions C. Pharmacokinetics Introduction to drug properties and biological membranes 1. Absorption 2. Distribution 3. Metabolism – Biotransformation 4. Excretion Aspirin as a model drug 2  A. Definitions and Terminology 1. Pharmacology: The study of the interaction of foreign chemicals with living systems. 2. Therapeutics: Treatment of disease. The goal of therapeutics with drugs is to deliver the appropriate amount of drug for the appropriate length of time to achieve a desired benefit with a minimum of adverse side effects. Pharmacology is the rational basis of therapeutics. 3 Basic Tenet of Pharmacology For most drugs, their effects are directly proportional to the concentration of their active forms at receptors. Drug-Receptor Drug Receptor complex D + R DR RESPONSE + Effect 4  3. Pharmacodynamics & Pharmacokinetics D + R DR RESPONSE + Effect Drug + Receptor Drug Receptor Complex Biological Effect P-kinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics Absorption Drug Effects Distribution Mechanism(s) of Action Biotransformation Excretion Colloquially Pharmacodynamics - drug acting on the body Pharmacokinetics - body acting on the drug 5 4. Drug Receptors Receptor: Any macromolecule that a drug interacts with to initiate a series of events that leads to a pharmacological effect. Drug-Receptor Drug Receptor complex D + R DR RESPONSE + Effect 6  B. Drug Receptor Interactions 1. Classical receptors 2. Non-classical receptors 3. Orphan receptors 4. Non-receptor mediated actions 7 1. Classical Receptors Possess structural and steric specificity Are saturable and have limited number of binding sites Typically have an endogenous ligand – a biological signaling molecule used for cellular communication Have high affinity for endogenous ligand at physiological concentrations When endogenous ligand binds, some early recognizable physiologic and chemical events occur 8  1. Classical Receptors a. Ion channels b. G Protein Coupled Receptors (GPCR) c. Transmembrane enzymes d. Intracellular receptors 9 1. Classical Receptors a. Ion Channels: e.g. Nicotinic acetylcholine receptor a ligand-gated ion channel Na+ Nicotine Extracellular Intracellular NICOTINE acts on acetylcholine-gated ion channels. K+ Excites certain neurons of brain and autonomic nervous system Copyright © motifolio.com 10  1. Classical Receptors b. G-Protein Coupled Receptors (GPCR) Ga Gai Gas Gaq Gao 12/13 GTP GTP GTP GTP GTP Functional Functional Response Response 11 1. Classical Receptors b. GPCR: e.g. Muscarinic acetylcholine receptor G-Protein Coupled Receptor MUSCARINE acts on GPCR that bind acetylcholine. Inhibits (relaxes) cardiac muscle, some neurons. Stimulates salivary glands. 12  c. Transmembrane Enzymes 13 insight review articles c. Transmembrane enzymes: e.g. insulin receptor Figure 1 The regulation of metabolism Amino Insulin by insulin. Insulin is the most potent Glucose acids receptor anabolic hormone known, and promotes F FA the synthesis and storage of carbohydrates, lipids and proteins, while inhibiting their degradation and release into the circulation. Insulin stimulates the uptake of glucose, amino acids and fatty acids into cells, and increases the Amino acids expression or activity of enzymes that Glucose catalyse glycogen, lipid and protein Protein synthesis, while inhibiting the activity or expression of those that catalyse degradation. Triglyceride F FA Glycolysis/oxidation Glycogen Saltiel & Kahn, Nature 414, 799-806, 2001 Phosphotidylinositol-3-phosphates regulate three main classes of AGC kinases that are downstream of PI(3)K include serum- and glu- signalling molecules: the AGC family of serine/threonine protein cocorticoid-regulated kinase and the atypical PKCs, PKC-! and -"42. kinases34, guanine nucleotide-exchange proteins of the Rho family of Akt and/or the atypical PKCs seem to be required for insulin- GTPases35, and the TEC family of tyrosine kinases36. PI(3)K also acti- stimulated glucose transport. vates the mTOR/FRAP pathway, 14and might be involved in regulation Activity of this pathway is also determined by phosphatidylinosi- of phospholipase D, leading to hydrolysis of phosphatidylcholine and tol-3-phosphates such as phosphatase and tensin homologue43 and increases in phosphatidic acid and diacylglycerol. The best character- the SH2 domain-containing inositol-5-phosphatase SHIP2 (ref. 44). ized of the AGC kinases is phosphoinositide-dependent kinase 1 Overexpression of these enzymes leads to decreased levels of (PDK1), one of the serine kinases that phosphorylates and activates PtdIns(3,4,5)P3. This might terminate signal transduction and/or the serine/threonine kinase Akt/PKB37. Akt possesses a PH domain change the nature of the phosphoinositides, altering the binding that also interacts directly with PtdIns(3,4,5)P3, promoting specificity to PH or phox homology domains. Disruption of these membrane targeting of the protein and catalytic activation. Akt has genes or reducing expression of these messenger RNAs yields mice 45  d. Intracellular Receptors: e.g. estrogen 15 2. Non-Classical Receptors Non-classical receptors are macromolecules that do not fit the classical receptor description Structural and steric specificity May be difficult to saturate Often have complex, non-specific physiological effects Major classes: Enzymes Transporters 16  2a. Example: Aspirin and other ‘NSAIDs’* act on intracellular enzyme (COX) that has numerous biological functions Arachidonic Acid COX = COX Cyclooxygenase enzyme Prostaglandins *NSAIDs = Non-Steroidal Anti-Inflammatory Drugs 17 2b. Example: Antibiotics Interfere with bacterial structure by inhibiting cell wall synthesis, DNA replication, etc. Do not memorize! For illustration only 18  Comparison of macromolecular receptors 1. Classical Receptors 2. Non-Classical Receptors Possess structural and steric specificity Possess structural and steric specificity Are saturable and have limited number May be difficult to saturate of binding sites Typically have an endogenous ligand Usually don’t have an endogenous ligand When endogenous ligand binds, some Often have complex, non-specific early recognizable physiologic and physiological effects chemical events occur 19 3. Non-receptor mediated actions of drugs a. Sodium bicarbonate - Neutralization of stomach acid HCl + NaHCO3 NaCl + H2CO3 H2CO3 H2O + CO2 20  b. Metal Chelators: EDTA Use: reduce heavy metal poisoning (e.g. lead (Pb), cadmium (Cd)); increase removal of a metal from body (e.g. iron (Fe)) 21 Basic tenet of pharmacology For most drugs, their effects are directly proportional to the concentration of their active forms at receptors. D + R DR RESPONSE The concentration of the active form of a drug at its receptor and therefore the time response curve is determined by the: Dose Pharmacokinetics 22  LECTURE 1. OUTLINE A. Definitions and Terminology 1. Pharmacology 2. Therapeutics 3. Pharmacodynamics & Pharmacokinetics 4. Drug Receptors B. Drug Receptor Interactions 1. Classical Receptors 2. Non-Classical Receptors 3. Non-Receptor Mediated Actions C. Pharmacokinetics Introduction to drug properties and biological membranes 1. Absorption 2. Distribution 3. Metabolism – Biotransformation 4. Excretion Aspirin as a model drug 23 C. Pharmacokinetics Time Response Curve t1- t0 = time to onset of effect t2- t0 = time to peak effect Response Intensity t3- t1 = duration of action t0 t1 t2 t3 Time 24  Introduction to drug properties and biological membranes Cells – double lipid membrane Most drugs must cross multiple biological membranes and distribute in various body compartments 25 Diffusion properties of small chemicals Small charged chemicals diffuse best in aqueous solutions – HYDROPHILIC or lipophobic Small neutral (uncharged) chemicals prefer to distribute in lipid biological membranes – LIPOPHILIC or hydrophobic 26  Passive Diffusion: uncharged (lipophilic) small molecules pass through membrane; charged (hydrophilic) small molecules do not 27 A few drugs are small and lipophilic. They cross membranes by passive diffusion Neutral e.g. Diazepam (Valium) (uncharged) Drugs e.g. Estradiol 28  A very few small hydrophilic nutrients and drugs are transported by a specialized transport system 1. Facilitated Diffusion e.g. Glucose transporters 2. Active Transport e.g. l-dopa for Parkinson’s disease 29 Most drugs are small and charged (hydrophilic). Most are weak acids or bases. Definition: Weak acids and bases exist in both charged and uncharged forms near biological pH (pH ~ 7.0) Weak Acids: R-COOH R-SH R-COOH R-COO- + H+ Weak Bases: R-NH2 R-NH2 + H+ R-NH3+ 30  Some definitions: Protonated: Form of drug (molecule) with a H+ ion Unprotonated: Form of drug (molecule) that does not have a H+ ion pKa: the pH at which a drug (molecule) is 50% protonated and 50% unprotonated Protonation vs. charge: determined by whether drug (molecule) is a weak acid or a weak base Weak Acids: R-COOH R-COO- + H+ Weak Bases: R-NH2 + H+ R-NH3+ 31 Small charged (hydrophilic) drugs cross the membrane when they are in an uncharged form Weak acids cross in protonated form RCOOH Weak bases cross in unprotonated form RNH2 32  Henderson-Hasselbach equation – Quantitative relationship between a drug’s pKa and the solution pH Henderson-Hasselbalch equation pKa = pH + log (concentration of protonated drug) (concentration of unprotonated drug) The degree of ionization depends on the chemical properties of the drug (pKa) and the pH 33 C. Pharmacokinetics 1. Absorption – The movement of drug from the site of application to the systemic bloodstream. 2. Distribution – The movement of drug between blood and tissues. 3. Metabolism / Biotransformation – Chemical reaction(s) converting drug to a metabolite(s). 4. Termination/Excretion–Ending drug action and removal of drug from the body. 34  1. Drug Absorption Absorption – The movement of drug from the site of application to the systemic bloodstream. 35 Routes of administration ‘Enteral’ route is through GI tract and includes: – Oral (bucal) Absorption through stomach and intestines Uptake into portal vein circulation that drains to liver ‘Enteral’ comes from Greek word for ‘intestine’ – *Sublingual (under the tongue) – *Rectal (suppositories) (*considered ‘parenteral’ - some authors call them ‘enteral’) 36  Drugs taken orally are exposed to range of pH Stomach pH: ~1-2 with meal (HCl); 3-5 between meals Large intestine Small intestine pH: ~ 5.5-7 pH: ~ 5.5-7 37 Enteral administration 38  Hepatic First Pass Effect – oral administration Venous circulation Liver Heart Body Small Intestines Arterial circulation 39 Routes of administration All other routes are ‘parenteral’ (bypass GI tract): – Intravenous (IV): Injection into blood stream – Intramuscular (IM): Injection into muscle – Subcutaneous: Injection below skin – Inhalation: Lungs – Transdermal / topical: Skin (patches, ointments etc) – *Sublingual – *Rectal (*Some authors call them enteral) 40  2. Drug Distribution Distribution – The movement of drug between blood and tissues. Factors controlling distribution rate of delivery to tissues (blood flow) ability of drug to pass through capillaries (capillary permeability) hepatic ‘first pass’ effect binding of drugs to proteins and tissue components 41 Routes of administration influence distribution Routes of Administration in circulatory system 42  Hepatic First Pass Effect Venous circulation Liver Liver Heart Body Heart Body Small Small Intestines Intestines Oral Intravenous 43 2. Drug Distribution binding of drugs to proteins and tissue components Albumin in plasma Free Drug 44  2. Drug Distribution Specialized fluid compartments Blood-brain barrier Placenta and fetal compartment Specialized tissue compartments Fat/Adipose tissue can be a storage depot for some drugs 45 3. Metabolism / Biotransformation: The enzymatic conversion of drug to a metabolite(s). Result of chemical reactions – change drug structure Most common sites of biotransformation: liver blood plasma Biotransformation can involve addition or deletion of a chemical group Biotransformation can cause detoxification or activation of a drug 46  3. Metabolism / Biotransformation: Example - glucuronidation Liver: “Glucuronidation,” conjugation with glucuronic acid Makes compounds less lipid soluble and therefore better excreted 47 3. Factors affecting biotransformation contribute to variability of drug response between individuals Age Genetics Nutrition Disease Exposure to other chemicals Inhibition of biotransformation enzymes – cause of many drug-drug interactions 48  4. Elimination (excretion) Renal – via the kidney Non-renal – diffusion through lungs, sweat, saliva, feces, or breast milk 49 Renal Excretion of Drugs Kidney anatomy Proximal Distal Tubule Tubule Collecting Glomerulus Duct Loop of Henle 50  Penicillin Probenecid Penicillin filters in at glomerulus Probenecid blocks or slows active penicillin transport Some drugs affect pharmacokinetics of other drugs by blocking renal excretion Penicillin is actively transported into tubule 51 Probenecid inhibits elimination of Tamiflu (oseltamivir) and increases Tamiflu’s potency 52  Pharmacokinetics is basis of ‘dosing:’ The quantity and interval at which a drug is administered to reach a desired steady-state concentration Fig. 1-4, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th edition 53 54  Aspirin: herbal medicine from willow bark (Salix) Salicylic acid 55 Aspirin as a model drug History Pharmacodynamics – Therapeutic uses and effects – Mechanism of action Pharmacokinetics – Absorption – Distribution – Metabolism – Excretion Adverse drug reaction (ADR) Toxicity 56  History of aspirin as a drug Tea made from bark of willow tree or plant meadowsweet used as analgesic and anti-pyretic in many cultures Active principle (salicylate) isolated 1826 ‘Aspirin’ synthesized by Felix Hoffmann, working at the Bayer Chemical Company in Germany (1895) – Synthesized in search for a safer form of salicylate for his father who was using it for arthritis and experiencing severe stomach problems Hoffmann added an acetyl group to the salicylic acid molecule (chemical name, acetylsalicylic acid). 57 Salicylic acid Acetylsalicylic acid Active ingredient in willow bark Aspirin 58  Commercially available since 1899 Aspirin and Bayer: birth of the modern pharmaceutical industry 59 Bayer Company advertising around the world Public consumes tons of aspirin daily aspirin found in hundreds of proprietary compounds 60  Bayer Company - 1899 61 Therapeutic uses of aspirin Pain (analgesic) – Headache – Muscle pain (sprains, over-exertion, cramps) Inflammation (anti-inflammatory) – Chronic inflammatory disease – e.g. arthritis, gout, periodontitis Fever (anti-pyretic) Other – Prophylaxis against platelet aggregation Prevention of heart attack and stroke 62  Mechanism of action: inhibition of Cox enzymes and PG synthesis Arachidonic Acid COX = COX Cyclooxygenase enzyme Prostaglandins (PG) Homeostatic Function Inflammation Gastrointestinal Function Pain Renal Function Swelling Platelet aggregation Inflammatory Cascade Temperature regulation 63 Aspirin Absorption Rapidly absorbed from stomach and small intestine Rate-limiting step is disintegration and dissolution of tablet In blood in 2 minutes Aspirin pKa = 3.5 64  Aspirin Distribution – Acetylsalicylic acid has 15-min half-life metabolized by gastric esterases and plasma esterases to salicylate (salicylic acid) Esterases Acetylsalicylic acid (Aspirin) Salicylic acid – Salicylate and remaining acetylsalicylic acid are distributed rapidly throughout most body fluids and tissues Spinal, peritoneal, and synovial (joint) fluids Saliva, breast milk and sweat 65 Aspirin Biotransformation - Metabolism Liver: “Glucuronidation” + Glucuronic acid Salicylic acid 1-salicylate glucuronide 66  Aspirin Excretion – Excreted by glomerular filtration and proximal tubular secretion in kidney – Elimination ½ life of salicylate is 2-3 hours after single analgesic dose 67 Adverse Drug Reactions (ADR) and Toxicity – An adverse drug reaction (ADR) is a harmful, unwanted consequence of taking a drug – Toxicity - damage to cell, organ, or individual 68  Aspirin has high number of ADR and toxic effects Do not memorize! For illustration only 69 Aspirin has many ADR – COX enzyme produces prostaglandins PG have numerous effects in almost all biologic processes – smooth muscle contraction and relaxation – vascular permeability – renal electrolyte and water transport – GI and pancreatic secretion – CNS and ANS (central and autonomic nervous system) – bone resorption – platelet aggregation 70  Aspirin effects on GI tract Gastrointestinal effects – dyspepsia, nausea, gastric bleeding, peptic ulcers resulting from cellular and capillary damage along GI tract – PGs normally mediate cytoprotective mechanisms in gastric mucosal cells to resist penetration by acid 71 Prostaglandins are required for production of protective mucous layer in stomach 72  Aspirin causes toxicity at high concentrations Overdose Saturation of metabolism and excretion mechanisms – Absorption slowed in stomach, so can keep increasing blood levels for several hours after last ingestion – Salicylate and acetylsalicylate accumulate in blood – Metabolism of salicylate is capacity limited – so large repeated doses or single toxic ingestion results in plasma half-lives of 5-30 hours 73 Aspirin: Acute toxicity Mild “salicylism” is symptom complex of all four – 1. Tinnitus – ringing in the ears – 2. Loss of hearing (reversible) – 3. Headache – 4. Confusion Severe “salicylism” – Respiratory stimulation and depression (dose and time dependent) – Acid-base imbalance – Coma; death 74  Overdose treatment Treatment mostly palliative and supportive – Gastric lavage – Respiratory support – Maintenance of electrolyte balance (e.g. K+ replacement if necessary) – Maintenance of plasma pH – Alkalinization of urine by intravenous bicarbonate 75 THE END 76