YR1 Lecture 1H - Introduction to Pharmacokinetics - Drs Ritesh Raju & Prof Gerald Muench 2022 (1).pdf

Introduction to Pharmacokinetics MD Year 1 2022 Prof Gerald Muench School of Medicine University of Western Sydney LEARNING OBJECTIVES Explain the general principles of pharmacokinetics Describe the absorption, distribution, metabolism and elimination of drugs within the body and factors that affect...

Introduction to Pharmacokinetics MD Year 1 2022 Prof Gerald Muench School of Medicine University of Western Sydney LEARNING OBJECTIVES Explain the general principles of pharmacokinetics Describe the absorption, distribution, metabolism and elimination of drugs within the body and factors that affect them Describe the common routes of drug administration Discuss the first pass metabolism and the blood-brain barrier Explain bioavailability and bioequivalence Compare the first order kinetics and zero order kinetics Explain the one-compartment model and the twocompartment model Discuss the pharmacokinetic behavior of multipledosing Embrace the breathtaking calculations (next lecture) Life cycle of a drug Pharmaceutical phase – Manufacturing in common dosage forms - Solid forms: tablet, capsule or powder - Liquid forms: solution or suspension Pharmacokinetic phase – absorption, distribution, metabolism and elimination Pharmacodynamic phase – Drug - receptor interaction and receptor-effector interaction – drug – enzyme interaction and change of product levels Pharmacokinetics Pharmacokinetics – defined as the study of the time course of drug and metabolite levels – in different fluids, tissues, and excreta of the body, and – of the mathematical relationships required to develop models to interpret such data. Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-24, Pg 25 Four primary pharmacokinetic processes – Absorption – Distribution – Metabolism (biotransformation) – Excretion Remember: ADME In, around and 2 ways out Journey of a drug through the body MCQ: Which disease(s) / conditions would have the most influence on the elimination of a drug ? 1. 2. 3. 4. 5. Vasectomy Stomach ulcers Liver cancer Renal failure Gall stones Human Factors Affecting Pharmacokinetic Profile of Drugs Genetic impact – Inter-individual differences in metabolism due to different genetic predisposition – “ancestral heritage” Weight – Impact on volume of distribution Age – Infants: incomplete development of renal and biliary elimination – Elderly people: decreased renal and liver function Diseases – Impact on absorption, distribution, metabolism and elimination Four primary pharmacokinetic processes –Absorption – Distribution – Metabolism (biotransformation) – Excretion Routes of Administration 1 Oral – The most commonly used because of ease/convenience – Formulations: tablets/enteric coated tablets, capsules/liquid capsules and liquid preparations Sublingual – Straight into systemic circulation bypassing first pass metabolism – Not ideal due to limited absorption – Lipid-soluble drugs such as nitroglycerine can be given this way Topical – Direct application on skin and accessible mucosal surfaces (e.g. nose, eyes, respiratory system) in form of drops, sprays, creams/ointments, gels and lotions – Local effect but may produce systemic effect (e.g., nasal sprays to deliver antidiuretic hormone) Routes of Administration 2 Parenteral – Literally any mode of administration that bypasses the gut; however it generally refers to injections and infusions – Invasive techniques that can be subcutaneous, intramuscular, intravenous and intrathecal (into subarachnoid space) – Avoids potential problems with absorption – Effect is generally achieved faster than with oral administration but not necessary wider distribution Others – Rectal application – usually topical (e.g., anti-inflammatory drugs) but can be used for systemic effects after absorption (diazepam for epilepticus in children) – Transdermal – through the skin for systemic effects (only lipid soluble drugs) with skin patches (e.g., estrogen for HRT) – Inhalation (e.g., anaesthetics) Drug Absorption from the Intestine In order to produce effects drugs taken orally have to be absorbed in the GI tract Absorption involves movement of drugs through the cellular barriers of GIT lining The rate of diffusion depends on – molecular weight – lipid solubility – ionisation (lipid solubility of ions is very limited) Strong acids or strong bases are fully ionised and poorly absorbed Most drugs are chemically weak acids or weak bases that ionise incompletely (and therefore have no charge) How do drugs cross the GI lining: Movement of Drugs across Cell Barriers Four drug transport routes across cell membrane – – – – Diffusion directly through the lipid bilayer Simple diffusion through aqueous pore proteins (channels) Facilitated diffusion through specialized carrier proteins Active (energy-requiring) transport via transmembrane carrier proteins Tortora and Derrickson, 2006, Principles of Anatomy and Physiology, Figure 2.5, Pg 67 Protein Binding Many drugs bind to plasma protein such as albumin, a, band g globulins after being absorbed Free Drug + Protein Û Drug-Protein Complex The ratio of bound to unbound drug in plasma is determined by the reversible interactions between a drug and plasma protein Degree of protein binding (USP DI 1998) – – – – – Very high > 90%, e.g., warfarin 99.9% High 65 – 90% Moderate 35 – 64% Majority of drugs Low 10-34% Very Low