L3 Basic Principles of Neuropharmacology II 2024-25 PDF

Basic principles of neuropharmacology II @Arturas Volianskis Igor Morski: “Someone is making water out of your brain” Basic principles of neuropharmacology II Learning outcomes: 1. Basic concepts: define drugs & medic...

Basic principles of neuropharmacology II @Arturas Volianskis Igor Morski: “Someone is making water out of your brain” Basic principles of neuropharmacology II Learning outcomes: 1. Basic concepts: define drugs & medicines, in contrast to ligands. 2. Review actions of drugs (and ligands) in biological systems 3. Define the concepts of pharmacodynamics and pharmacokinetics. 4. Discuss bioavailability: administration, release, absorption, distribution, metabolism and excretion of drugs. 5. Discuss volume of distribution and clearance. BI2432: Fundamental neuropharmacology Basic terms: ligands, drugs and medicines Ligand is any chemical that binds to a receptor, they can be agonists or antagonists. Drug is any substance (other than food) that is used to prevent, diagnose, treat, or relieve symptoms of a disease or abnormal condition. Drugs can also affect how the brain and the rest of the body work and cause changes in mood, awareness, thoughts, feelings, or behaviour. Some types of drugs, such as opioids, may be abused or lead to addiction. (National Cancer Institute, NCI USA) Medicine refers to the practices and procedures used for the prevention, treatment, or relief of symptoms of diseases or abnormal conditions. This term may also refer to a legal drug used for the same purpose. (National Cancer Institute, NCI USA) Drugs that influence behaviour are known as psychotropic agents. But there are many other terms: chemical, compound, agent, etc… BI2432: Fundamental neuropharmacology Drugs are all around us! Antidepressant, antianxiety, anticonvulsant and antipsychotic agents are among the most widely prescribed medications. Some of these act on other organ systems and are associated with unpleasant side effects. Many people use common substances, such as caffeine, alcohol and nicotine, that also act on the central nervous system. In some people, drugs are used compulsively, in a manner that constitutes an addiction. BI2432: Fundamental neuropharmacology The action of drugs on neural targets The NMDA Receptor The initial target of a drug determines the cells and circuits on which the drug acts, and at the same time the potential efficacy and side effects. The initial binding of a drug to its target is only the beginning of a signalling cascade that affects the behaviour of cells, neural circuits and animals. BI2432: Fundamental neuropharmacology Remember - agonists, antagonists and modulators? Receptor A Agonist B B alone Competitive Antagonist C Allosteric Ligands that alter the agonist (A) response may Potentiator activate the agonist binding site, compete with the agonist (competitive inhibitors, B), or act at D separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist. Allosteric Inhibitor BI2432: Fundamental neuropharmacology Remember - agonists, antagonists and modulators? Drug Action/ + = Effect Agonist Receptor Receptor Receptor + Antagonist No Drug Action/ + = Effect Antagonist Receptor Receptor + Agonist An antagonist may bind to the receptor in a way that prevents the access for the agonist that is required for the response. BI2432: Fundamental neuropharmacology Remember - affinity, potency and efficacy? Affinity gets the ligand (agonist or antagonist) bound to the receptor, and efficacy refers to what happens with the agonist effect once agonist is bound. The term potency is used as a comparative term for distinguishing which ligand (agonist or antagonist) has a higher affinity for a given receptor. Affinity (Kd) describes the strength of the binding between a ligand and its target substrate. Efficacy is a measure of the maximum Note: It is biological effect that a drug can produce possible for as a result of receptor binding. an agonist to have low efficacy, Potency refers to the amount of whilst being ligand required to achieve or highly potent. prevent a defined biological effect. BI2432: Fundamental neuropharmacology Pharmacodynamics Pharmacodynamics (grk, medicine & power) –The time course of the effect of a drug, and the intensity (power) of the effects. –“What a drug does to the body?” Pharmacodynamics The ability of a drug to produce an effect on an organism is dependent on the Response underlying mechanisms of drug action. Drug at the site Pharmacological effect Affinity, efficacy, potency, of action concentration-response relationships, spare receptors & amplification. Pharmacokinetics (grk, medicine & movement) –The time course of a drug in the body –“What the body does to a drug” BI2432: Fundamental neuropharmacology Pharmacodynamics vs Pharmacokinetics Pharmacodynamics (grk, medicine & power) –The time course of the effect of a drug, and the intensity (power) of the effects. –“What a drug does to the body?” Pharmacodynamics The ability of a drug to produce an effect on an organism is dependent on the Response underlying mechanisms of drug action. Drug at the site Pharmacological effect Affinity, efficacy, potency, of action concentration-response relationships, spare receptors & amplification. Pharmacokinetics (grk, medicine & movement) –The time course of a drug in the body Pharmacokinetics Administration –“What the body does to a drug” Clearance Brain Circulation Kidney Liver BI2432: Fundamental neuropharmacology Pharmacokinetics and bioavailability Pharmacokinetics (grk, medicine & movement) The ability of a drug to produce an effect on an organism is dependent on many of –The time course of a drug in the body its properties (in addition to its mechanism –“What the body does to a drug” of action), from its absorption to its stability to its elimination - its bioavailability! Bioavailability, release, excretion Bioavailability, Distribution, stability Administration Bioavailability, Clearance Brain Bioavailability, metabolism, Pharmacokinetics (grk, medicine & movement) absorption excretion Circulation –The time course of a drug in the body Kidney –“What the body does to a drug” Liver BI2432: Fundamental neuropharmacology Pharmacokinetics Pharmacokinetics includes a number of stages 1. Route of administration 2. Release / liberation 3. Absorption (dosing regiments) 4. Distribution (compartments) 5. Metabolism (metabolite kinetics, clearance) 6. Excretion (clearance) Pharmacokinetics Administration Clearance Brain Circulation Kidney Liver BI2432: Fundamental neuropharmacology Getting drugs into the brain - administration Route of administration must be considered, which can determine whether or how rapidly a drug reaches its target organ and which organs it affects. Enteral (through intestine): Oral administration typically results in a relatively slow onset of action. oral Sublingual / buccal / rectal Parenteral describes all other routes of administration, including: Intravenous (into the venous system) Intramuscular (into a muscle) intravenous. Subcutaneous (under the skin) Inhalation / nasal Intraperitoneal (into the peritoneal– abdominal cavity) Intracerebroventricular (into the cerebral ventricular system) subcutaneous Intracerebral (into the brain parenchyma) delivery. BI2432: Fundamental neuropharmacology Pros and cons of the principal routes of drug administration BI2432: Fundamental neuropharmacology Oral bioavailability - tablet dissolution (release / liberation) Tablet Fragments Fine particles pH as low as 1-2 acid & pepsin food, drug formulation, surface area, etc. will affect absorption BI2432: Fundamental neuropharmacology Oral bioavailability - absorption Most drugs are absorbed within duodenum / jejunum of small intestine (first and second sections of the small intestine) Villi increase surface area Highest concentration of villi in duodenum/ jejunum Lined with epithelial cells Supportive network of capillaries draining into portal vein Drug absorption involves a variety of processes: Passive diffusion Convective absorption Active transport Facilitated transport Ion pair formation Pinocytosis BI2432: Fundamental neuropharmacology Oral bioavailability - absorption Most drugs are absorbed within duodenum / jejunum of small intestine (first and second sections of the small intestine) Villi increase surface area Highest concentration of villi in duodenum/ jejunum Lined with epithelial cells Supportive network of capillaries draining into portal vein Drug absorption depends on intestinal motility: Food Exercise Disease Drugs Time of day BI2432: Fundamental neuropharmacology Oral bioavailability - absorption Most drugs are absorbed within duodenum / jejunum of small intestine (first and second sections of the small intestine) Villi increase surface area Highest concentration of villi in duodenum/ jejunum Lined with epithelial cells Supportive network of capillaries draining into portal vein Absorption is the disappearance of drug from its site of administration and not the appearance of the drug in the general circulation. BI2432: Fundamental neuropharmacology Oral bioavailability - first pass metabolism Most venous outflow from stomach, small & large intestine enters the portal vein en route to liver. Metabolism Mainly liver (eg. cytochrome P450 enzymes) Prodrugs (inactive until metabolised) Excretion Into major Renal and faecal body fluids elimination (eg. plasma) BI2432: Fundamental neuropharmacology Bioavailability is affected by binding to plasma proteins Highly Protein Bound Drugs > 95% bound Thyroxine Warfarin Diazepam Frusemide Heparin Imipramine Many drugs bound to circulating Amitriptyline plasma proteins such as albumin. > 90% but < 95% bound Only free drug can act at receptor Glibenclamide site Phenytoin Propranolol Sodium Valproate BI2432: Fundamental neuropharmacology Bioavailability is also affected by barriers BI2432: Fundamental neuropharmacology Getting drugs into the brain - bioavailability The bioavailability of a drug determines how much of the drug that is administered actually reaches its target. Influenced by absorption of the drug (from the gut if administered orally). Affected by metabolism and excretion. Affected by binding of the drug to plasma proteins, which makes the drug unavailable to bind to its target. Influenced by a drug’s ability to penetrate the blood-brain barrier, or its ability to permeate cell membranes. BI2432: Fundamental neuropharmacology Drug pharmacokinetics decides the dosing regiment AUC - area under the curve BI2432: Fundamental neuropharmacology Pharmacokinetics & dosing - terms used BI2432: Fundamental neuropharmacology Fundamentals of pharmacokinetics Volume of distribution Clearance Elimination half-life BI2432: Fundamental neuropharmacology Pharmacokinetics - volume of distribution 20 g 286 mg / L BI2432: Fundamental neuropharmacology Pharmacokinetics - volume of distribution 20 g 286 mg / L i.e. ~ 70 L BI2432: Fundamental neuropharmacology Volume of distribution - possible physiological meaning 20 g 286 mg / L i.e. ~ 70 L BI2432: Fundamental neuropharmacology Pharmacokinetics - apparent volume of distribution Oil 20 g Volume of tank ~ 70000 L 2.86 µg / L Remember: 1 L H20 = 1 kg BI2432: Fundamental neuropharmacology Pharmacokinetics - clearance V = 70 L Dose = 100 mg 100 mg 70 L 1429 µg / L BI2432: Fundamental neuropharmacology Pharmacokinetics - clearance V = 70 L Dose = 100 mg 100 mg CL = 7 L/h 70 L Eliminating organ 7 L/h BI2432: Fundamental neuropharmacology Pharmacokinetics - clearance V = 70 L Dose = 100 mg 100 mg CL = 7 L/h Eliminating organ 7 L/h t1/2 ~ 7h BI2432: Fundamental neuropharmacology Pharmacokinetics - clearance V = 70 L Dose = 100 mg CL = 7 L/h t1/2 = 6.93h lambda = 7 L/h / 70 L = 0.1 1/h half-life = 0.693 / 0.1 1/h = 6.93 h BI2432: Fundamental neuropharmacology Case study - fate of ethanol in body BAC = blood alcohol concentration BI2432: Fundamental neuropharmacology Case study - ethanol distribution volume BI2432: Fundamental neuropharmacology Case study - ethanol distribution volume Ethanol distribution volume 20% less in women all other things being equal. But people differ in a variety of ways and also change with ageing. BI2432: Fundamental neuropharmacology Case study - ethanol distribution volume Ethanol distribution volume 20% less in women all other things being equal. But people differ in a variety of ways and also change with ageing. BI2432: Fundamental neuropharmacology Variability in drug response People vary in: appearance and philosophy physiology and biochemistry occupations and habits genetics – genotype vs phenotype BI2432: Fundamental neuropharmacology Summary: pharmacodynamics & pharmacokinetics Pharmacodynamics (grk, medicine & power) –The time course of the effect of a drug, and the intensity (power) of the effects. –“What a drug does to the body?” Pharmacodynamics The ability of a drug to produce an effect on an organism is dependent on the Response underlying mechanisms of drug action. Drug at the site Pharmacological effect Affinity, efficacy, potency, of action concentration-response relationships, spare receptors & amplification. Pharmacokinetics (grk, medicine & movement) –The time course of a drug in the body Pharmacokinetics Administration –“What the body does to a drug” Clearance Brain Circulation The ability of a drug to produce an effect on an organism is dependent on Kidney bioavailability. Time course is determined Liver by concentration, volume of distribution and the rate of clearance. BI2432: Fundamental neuropharmacology Study materials: BI2432: Fundamental neuropharmacology Example question L3: What is pharmacokinetics? (A) The time needed for a drug to dissociate from a receptor (B) The time course of drug-effects in the body (C) The time needed for a drug to bind to a receptor (D) The time course of a drug in the body (E) The time course of a drug at a receptor BI2432: Fundamental neuropharmacology Weekly schedule of the fundamental neuropharmacology Friday 29.11.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L1. Introduction to fundamental neuropharmacology Rang & Dale’s Pharmacology, L2. Basic principles of neuropharmacology I & lecture materials Friday 06.12.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L3. Basic principles of neuropharmacology II Rang & Dale’s Pharmacology L4. Techniques in neuropharmacology & lecture materials Friday 10.12.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L5. Acetylcholine and Glutamate (and a bit of Glycine) Rang & Dale’s Pharmacology L6. Pharmacological dissection of field responses The Hippocampus Book pages 27-30 & lecture materials Tuesday 07.01.2025 (13:10-14:00);C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L7. GABA and Glycine Rang & Dale’s Pharmacology & lecture materials Friday 10.01.2025 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L8. Catecholamines Rang & Dale’s Pharmacology L9. Serotonin & lecture materials Friday 27.01.2025 (13:00-13:45 & 14:00-14:45); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L10. Neuropharmacology of drug dependence and addiction I Rang & Dale’s Pharmacology L11. Neuropharmacology of drug dependence and addiction II & lecture materials Tuesday 21.01.2025 (13:10-14:00); C/-1.04 Tuesday 23.01.2025 Neuroanatomy L12. Exam preparation 2 and Neuropharmacology ICA BI2432: Fundamental neuropharmacology