Human Factors Affecting Pharmacokinetic Profiles

Human factors affecting pharmacokinetic profiles • • • • Genetics: inter-individual differences in metabolism (genetic predispositions) Weight: impact on volume of distribution Age: infants have incomplete development of renal and biliary elimination while elderly people have decreased renal and liver function Diseases: impacts ADME Absorption – routes of administration • Most commonly used – ease/convenience • Formulations: tablets/enteric coated tablets (for absorption in small intestine), capsules/liquid capsules, liquid preparations Sublingual • Straight into systemic circulation, bypassing first pass metabolism • Not ideal due to limited absorption • E.g. lipid soluble drugs such as nitroglycerine Topical • Direct application on skin and accessible mucosal surfaces (e.g. nose, eyes, respiratory system) in form of drops, sprays, ointments, gels, lotions • Local effect, but may produce systemic effect e.g. nasal sprays to deliver antidiuretic hormone Parenteral • Any mode of administration that bypasses gut, generally refers to injections/infusions • Invasive techniques that can be subcutaneous, intramuscular, intravenous, intrathecal (into subarachnoid space) • Avoids potential problems with absorption • Effect is generally achieved faster than with oral, not necessary wider distribution Rectal • Usually topical (e.g. anti-inflammatory), but can be used for systemic effects after absorption application (e.g. diazepam for epilepticus in children) Transdermal • Through skin for systemic effects with skin patches • Only lipid soluble drugs e.g. estrogen for hormone replacement therapy Inhalation • E.g. Ventolin for asthma, anaesthetics Oral Drug absorption from the intestine • Drugs taken orally must be absorbed in GI → movement through cellular barriers of GIT lining • Rate of diffusion: molecular weight, lipid solubility, ionisation (limited lipid solubility of ions) • Strong acids and strong bases are fully ionised and poorly absorbed → most drugs are chemically weak acids or weak bases that ionise incompletely (have no charge) Movement of drugs across cell barriers of GIT 1. Diffusion directly through lipid bilayer 2. Simple diffusion through aqueous pore proteins (channels) 3. Facilitated diffusion through specialised carrier proteins 4. Active transport via transmembrane carrier proteins Protein binding • Many drugs bind to plasma proteins e.g. albumin, α, β and γ globulins after being absorbed o Free drug + protein ⇔ drug-protein complex • Ratio of bound to unbound drug in plasma is determined by the reversible interactions between a drug and plasma protein…degree of protein binding: o Very high >90%) e.g. warfarin (99.9%) o High 65-90% o Moderate 35-64% → majority of drugs are moderate to very low • o Low 10-34% o Very low <10% e.g. Voltaren (diclofenac sodium) Only free, unbound fraction can produce pharmacological effects → bound molecule is trapped in blood stream and pharmacologically inactive Drug plasma levels over time Distribution • Transport of drug in body fluids from bloodstream to various tissues + site of action • Factors including rate of distribution: o Blood circulation/organ perfusion o Permeability of membranes o pH difference between plasma and tissue (affects ionisation) o Molecule size (optimum= MW: 100-1000) o Plasma protein binding o Binding to other tissues e.g. fat Body fluid compartments for distribution of drugs • Total body water = 50-70% of body weight o Extracellular/interstitial fluid ▪ Plasma (4.5% body weight) ▪ Interstitial fluid (16%) ▪ Lymph (1.2%) o Intracellular fluid 30-40% o Transcellular fluid (2.5%) – CSF, intraocular, pleural fluid First Pass Metabolism: drug distribution and the liver • FPM: absorbed from gut → hepatic portal system → pass to liver • Drugs will be partially metabolised in liver before passing into systemic circulation (1st pass metab) • Drugs show different rates of this depending on chem structure → liver’s ability to metabolise • Not application to drugs given through parenteral route, party avoided by rectal route Blood-brain barrier • Cerebral circulation: lacks fenestration (pores), endothelial cells are closer together, barrier between capillaries and brain tissue formed by CT • Clinical implication of blood-brain barrier: o Useful when preventing some drugs from crossing into brain, causing unwanted effect o May be problematic e.g. penicillin cannot cross barrier Drug elimination • Elimination of drug (or its metabolites) via metabolism or excretion → ↓ drug concentration in body • Metabolism (biotransformation): process of chemical inactivation of drug by conversion into a more water-soluble compound/metabolite which can then be excreted from body • Excretion: process whereby drugs and pharmacologically active/inactive metabolites are eliminated, primarily through kidneys and guts Metabolism • Most drugs undergo enzymatic modification of their molecule prior to removal • Effects: drug’s inactivated & effect terminated or drug’s converted to water-soluble (hydrophilic) compounds • Only hydrophilic compounds are suitable for excretion via urinary or hepatobiliary system (without significant reabsorption) • Some which are readily water-soluble can be excreted largely unchanged • Drugs can be metabolised in most cells of body, but principal site is liver • Two kinds of biochemical reactions are involved: o Phase I (simple, fast): oxidation, reduction, hydrolysis, removal or addition of active group o Phase II (more complex): conjugation with a polar molecule to make more soluble for excretion e.g. glucuronic acid derived from glucose • Not all drugs go through both phases e.g. water-soluble may go through just phase I before excretion Key enzymes in Phase I: cytochromes P450 • Oxidation performed by mono-oygenases (cytochrome P450 enzymes – superfamily of ~ 20 isoforms) and dioxygenases o CYP1A2 (example substrates: caffeine, paracetamol) o CYP2A6 (methoxyflurane) o CYP2C9 (warfarin) o CYP2C19 (omeprazole) o CYP2D6 (metoprolol) o CYP2E1 (alcohol) o CYP3A4 (nifedipine) Excretion • Renal drug excretion = 3 renal processes 1. Glomerular filtration: most drugs can cross filtration membranes freely (limit is 20 kDa), drugs that are solely eliminated by glomerular filtration exhibit 1st order kinetics 2. Active tubular secretion: two relatively non-selective carrier systems to handle… a. Acid drugs e.g. penicillin, indomethacin, thiazide diuretics b. Organic bases e.g. dopamine, histamine, morphine 3. Passive diffusion across tubular epithelium: ionised drug molecules e.g. digoxin metabolites • Other excretion routes o Bile (faeces): bigger molecules, compounds can be absorbed again from small intestine o Exhalation, saliva, sweat, tears, breast milk