Pharmacology: Pharmacokinetics And Pharmacodynamics BIO 344 PDF

PHARMACOLOGY PHARMACOKINETICS AND PHARMACODYNAMICS BIO 344 Part 1 Matthew Churchward Slides are © 2022-2025 Matthew Churchward Figures are from Meyer’s Psychopharmacology 3e – 4e © 2018-2023 S...

PHARMACOLOGY PHARMACOKINETICS AND PHARMACODYNAMICS BIO 344 Part 1 Matthew Churchward Slides are © 2022-2025 Matthew Churchward Figures are from Meyer’s Psychopharmacology 3e – 4e © 2018-2023 Sinauer/Oxford unless otherwise attributed Course content, digital or otherwise, created and/or used within the context of the course is to be used solely for personal study, and is not to be used or distributed for any other purpose without prior written consent from the content author(s). Learning objectives Describe and apply the principles of pharmacokinetics with particular emphasis on drugs affecting the brain Administration & Absorption Distribution & Depot binding Metabolism Excretion Review the basic concepts of receptor-ligand interactions Differentiate ligand-receptor, drug-receptor, and enzyme-substrate interactions Distinguish pharmacodynamics of drug-receptor interactions and the resulting drug effects Agonists vs antagonists, competitive and non-competitive binding, allosteric effects, partial and inverse agonists Describe long-term effects of drug use – tolerance, sensitization, and dependence 2 neuro- psycho pharmacology The study of the actions of drugs on the central nervous system and their subsequent effects on human behaviour 3 Drug actions Drug effects Specific molecular changes Widespread alterations in resulting from drug binding to physiology or psychology a target site or receptor resulting from drug actions 4 Pharmacokinetics The dynamic factors contributing to the bioavailability and efficacy of drugs in the human body Provides performance guidelines for efficacy and efficiency of drug use in clinical settings 5 Principal components (ADME) 1. Absorption Administration and absorption of the drug into body fluids 2. Distribution Dispersal of drug through body fluids to the target tissues of the body Depot binding in bodily fluids and non-target tissues 3. Metabolism Biotransformation or inactivation of drugs in the body into metabolites 4. Excretion Removal of substances or metabolites from the body 6 Routes of administration A Oral administration (PO) Sublingual (below the tongue) Intravenous (IV) Transdermal (e.g. nicotine patch) Intramuscular (IM) Epidural Subcutaneous (SC) Intraperitoneal (IP)* Inhalation Intracranial* Intranasal Intracerebroventricular* Topical (mucous membranes of Intracisternal* nasopharynx, conjunctiva, colon, Intrathecal* vagina, urethra) 8 Advantages and Disadvantages of Selected Routes of Drug Administration Route of administration Advantages Disadvantages Oral (PO) Safe; self-administered; economical; no needle- Slow and highly variable absorption; subject to first-pass related complications metabolism; less-predictable blood levels Intravenous (IV) Most rapid; most accurate blood concentration Overdose danger; cannot be readily reversed; requires sterile needles and medical technique Intramuscular (IM) Slow and even absorption Localized irritation at site of injection; needs sterile equipment Subcutaneous (SC) Slow and prolonged absorption Variable absorption depending on blood flow Inhalation Large absorption surface; very rapid onset; no Irritation of nasal passages; inhaled small particles may injection equipment needed damage lungs Topical Localized action and effects; easy to self- May be absorbed into general circulation administer Transdermal Controlled and prolonged absorption Local irritation; useful only for lipid-soluble drugs Epidural Bypasses blood–brain barrier; very rapid effect Not reversible; needs trained anesthesiologist; possible on CNS nerve damage Intranasal Ease of use; local or systemic effects; very Not all drugs can be atomized; potential irritation of nasal rapid; no first-pass metabolism; bypasses mucosa blood–brain barrier  First-pass metabolism PO administration passes through the liver first prior to distribution through the body – this results in high rates of drug metabolism prior to distribution 10 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  11 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Oral administration Delivery to CSF Most convenient Epidural, intrathecal, Safe self administration intracerebroventricular, or intracisternal most direct way to access the CNS First-pass effect Bypasses liver and BBB Blood flow from stomach/intestines goes directly to the liver for detox Highly invasive Oral route has greatest breakdown of drug Effectively for experimental use only Blood-brain barrier (BBB) affects Slow steady release possible with usefulness for neuropharmacology implantable shunts or osmotic minipump 12 Drug absorption A Movement of drug from the site of administration to the circulatory system Affected by: Drug concentration affected by age, sex, body size, body fat content Breakdown by metabolic or digestive processes Solubility and ionization of drug Largely dependent on passive diffusion through biological membranes 13  Semi-permeable cell membranes 14 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Polarity terminology Polar Non-polar Water soluble Lipid soluble Hydrophilic (loves water) Hydrophobic (fears water) Lipophobic (fears fat) Lipophilic (loves fat) Polar molecules are freely transported Non-polar molecules freely diffuse through aqueous compartments (e.g. across semi-permeable membranes (e.g. blood, CSF, ECF) intestinal wall, BBB, cell membranes) 15 Absorption is dependent on drug polarity Non-polar, lipid soluble drugs can freely diffuse across cell membranes Passive diffusion down concentration gradients Non-polar molecules tend to be less soluble in water Polar or charged (ionized) drugs are prevented from diffusing through membranes Many orally administered drugs are weak acids or bases – gaining or losing charges based on the pH of the external environment 16  Example: Aspirin Aspirin (acetylsalicylic acid) has a pKa of ~3.5 In the stomach (pH 2) aspirin is uncharged and can readily diffuse across cell membranes, but is less soluble In the blood aspirin becomes ionized and is readily soluble In the intestines (pH 5.5) alternates between ionized and non-ionized forms and diffuses more slowly across membranes 17 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Factors affecting absorption Intrinsic properties of the drug Polarity Solubility pKa pH of body compartments Surface area of body compartments Stomach has a relatively small surface area (slow absorption) Intestines have relatively large surface area (fast absorption) and are the site of most (oral) drug absorption 18 Drug distribution D Once in the bloodstream drugs circulate to the entire body within minutes Drug concentration is highest in tissues with greatest blood flow Heart, brain, kidneys, liver Peripheral capillaries are highly porous allowing ready distribution of drugs (lipophilic or hydrophilic) into tissues Blood-brain barrier permits passive diffusion of only lipophilic drugs 19  BBB Peripheral capillaries are porous, allowing Brain capillaries are coupled by tight junctions and lined by hydrophilic drugs to freely enter tissues astrocyte endfeet creating a highly impermeable barrier 20 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Crossing the BBB The BBB limits access to 98% of small molecule pharmaceuticals (and 100% of large molecule pharmaceuticals) Passage of solutes through the BBB often occurs at specific transporters (e.g. glucose and amino acid transporters) Some drugs are actively removed from the ECF by efflux transporters (i.e. p-glycoprotein, a.k.a. multidrug resistance protein-1) 21 Permeable sites BBB is not a complete barrier – certain sites have direct access to the circulatory system Chemoreceptor trigger zone (CTZ) of the medulla (area postrema - vomit centre) allows direct detection of toxins in the blood Hypothalamus allows direct access to capillaries for secretion of neurohormones and hormone-releasing factors 22 Depot binding D Drug depots are inactive drug binding sites with no measurable biological effect Adipose tissue (lipid-soluble drugs) Muscle tissue Albumin (plasma protein) Decreases circulating drug concentration Prolongs drug action Can function as reservoirs for drug release Protects stored drug from metabolism Can explain individual differences in drug efficacy 23 Effect of depot binding on therapeutic outcome Depot-binding characteristics Therapeutic outcome Rapid binding to depots before reaching Slower onset and reduced effects target tissue Individual differences in amount of binding Varying effects: High binding means less free drug, so some people seem to need higher doses. Low binding means more free drug, so these individuals seem more sensitive. Competition among drugs for depot- Higher-than-expected blood levels of the displaced binding sites drug, possibly causing greater side effects, even toxicity Unmetabolized bound drug Drug remaining in the body for prolonged action Redistribution of drug to less vascularized Termination of drug action tissues and inactive sites 24 Drug metabolism M Biotransformation and elimination affects bioavailability Metabolism occurs primarily in the liver under control of microsomal enzymes cytochrome P450 family (CYP ~ 57 in total) oxidize the majority of psychoactive drugs (incl. opioids, antidepressants, amphetamines, nicotine) CYP1A2 – metabolizes many antidepressants and antipsychotics – induced by smoking CYP3A4 – metabolizes many opioids, antidepressants, statins, anxiolytics – inhibited by grapefruit juice Metabolism is a non-specific detoxification process that occurs in two distinct types or phases Type I – non-synthetic modifications oxidation, reduction, and hydrolysis Type II – synthetic modifications conjugation with glucuronide, sulfate, or methyl groups 25 Biotransformation Type I metabolism during first pass can produce active metabolites of the pharmaceutical preparation of drugs Metabolic products (active and inactive) are returned to circulation from the liver and can reach target sites of action or sites for excretion (kidneys, biliary, or fecal excretion) Both steps combine to increase water solubility of drugs to aid in filtration by kidneys and eventual excretion 26 Simvastatin (Zocor) Pharmaceutical preparation is the lactone form - Simvastatin is hydrolyzed in the liver to the bioactive hydrophobic acid form 27 Factors influencing metabolism 1. Enzyme induction repeated use results in increase in liver enzymes accelerates rate of biotransformation of all drugs metabolised by a given enzyme (contributes to tolerance and cross tolerance) 2. Enzyme inhibition drugs targeting enzymes (e.g. monoamine oxidase inhibitors - MAOI) decrease their own clearance and other drugs 3. Drug competition competition for enzymes may prevent some drugs being metabolized in a safe fashion 4. Individual differences (age, sex, genetics) genetic polymorphisms have been identified in metabolic enzymes different individuals have different rates of clearance for drugs 28  Four genetic populations based on the number of normal CYP2D6 genes PM, poor metabolizers IM, intermediary metabolizers EM, extensive metabolizers UM, ultrarapid metabolizers 29 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Excretion E Routes of excretion include breath, sweat, saliva, feces, breast milk, and urine Primary means is filtration by kidney and excretion through urine Most drugs are excreted by first-order kinetics Exponential elimination – constant fraction removed in a given time Half-life (t½) describes the interval required to eliminate half of the drug from circulation Very few drugs removed by zero-order kinetics (constant rate) Alcohol excreted at ~ 10-15 ml/hr 30  First order elimination kinetics Zero order elimination kinetics 31 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Sources: Based on data in aJ. L. Zimmerman. 2012 Crit Care Clin 28: 517–526; bC. E. Inturrisi. 2002. Clin J of Pain 18: S3; cN. L. Benowitz et al. 1982. J Pharmacol Exp Ther 221: 368–372; dH. C. Kimko et al. 1999. Clin Pharmacokinet 37: 457–470; eF. Grotenhermen. 2003. Clin Pharmacokinet 42: 327–360; fR. Bushra and N. Aslam 2010. Oman Med J 25: 55–1661; and gC. L. DeVane et al. 2002. Clin Pharmacokinet 41: 1247–1266 32 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Key points: Pharmacokinetics 1. Admin & Absorption Biotransformation by Type I (non-synthetic) or Type II (synthetic) Administration affects rate & efficiency of absorption CyP450 enzymes produce active and inactive metabolites Absorption depends on diffusion across biological membranes Non-polar/lipophilic molecules are easily absorbed Drug competition (drug interaction) 2. Distribution & Depot binding Individual variation Dispersal of drug through body fluids 4. Excretion Polar/hydrophilic molecules are easily Metabolism increases water solubility – distributed increase filtration by kidneys Depot binding affects availability and Most excretion is through kidneys urine attenuates drug actions Most occur through 1st order kinetics 3. Metabolism (exponential) 33