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Drug absorption rate at which a drug leaves its site of administration and the extent to which it occurs Factors affecting absorption affects bioavailability route of administration (oral, inhalational, intravenous) drug concentration (loading dose, concentration effect) rate of dissolution for solid formulation drug solubility drugs in aqueous medium (parenteral) drugs in oily solution or suspension (via skin) local condition at site of absorption pH, membrane characteristics, circulation area of absorbing surface Routes of administration parenteral subcutaneous intramuscular intravenous intra-arterial epidural intrathecal interpleural intraperitoneal intra-osseus inhalation enteral oral sublingual rectal topical mucous membranes (other than enteral routes) transdermal eye Drugs administered sublingually analgesics: buprenorphine drugs acting on the cardiovascular system nitroglycerin, isosorbide dinitrate, nifedipine Intravenous administration by bolus dose drug is rapidly absorbed and has a small central volume the concentration of the drug will be high initially, it will then fall as the drug is distributed to its final larger volume (Vd) by slow infusion of the drug drug is more slowly absorbed it will be distributed as it is being administered peak concentration will be lower and will occur later Drugs administered rectally anaesthetics, hypno-sedative drugs thiopentone, methohexitone, benzodiazepines, etomidate, chloral hydrate, promethazine analgesics aqueous acetylsalicylic acid, sodium salicylate, paracetamol, indomethacin, naproxen, diclofenac pentazocine (high concentrations) drugs acting on the respiratory system theophylline drugs acting on the cardiovascular system propranolol Movement of drug molecule across cell membrane Membrane transfer of drugs affected by physicochemical properties of the drug molecules physicochemical properties of the membranes that influence this transfer mechanisms by which drugs cross membranes Physicochemical properties of drug molecule molecular size and shape (fentanyl, morphine) degree of ionisation (influence of pH) the relative lipid solubility of its ionised and unionised forms at the site of absorption Unionised and ionised molecules unionised molecules are usually lipid soluble and can diffuse through cell membrane drug molecules containing primary, secondary, or tertiary amine group ionised molecules are usually unable to penetrate lipid membrane because of their low lipid solubility drug molecule containing quaternary amine group Weak electrolytes and influence of pH most drugs are weak acids or bases, present in solution as both unionised and ionised species degree of ionisation influenced by pH and pKa Henderson-Hasselbalch equation: pH = pK + log [A-]/[HA] (for weak acid) pH = pK + log [B]/[BH+] (for weak base) for a weak acid : [ionised]/[unionised] = 10 (pH-pKa) for a weak base : [unionised]/[ionised] = 10 (pH-pKa) Degree of ionisation Drug pKa % ionised at pH 7.4 Weak acid [ionised]/[unionised] = 10 (pH-pKa) Thiopentone 7.6 39% Weak base [unionised]/[ionised] = 10 (pH-pKa) Midazolam 6.5 11% Morphine 7.9 76% Fentanyl 8.4 91% Lignocaine 7.9 76% Bupivacaine 7.7 67% weak acidic drugs are most soluble in alkaline medium (pH above their pKa), usually presented as their Na+ salts (Thiopentone) basic drugs are soluble in an acid medium (pH below their pKa), commonly administered as acid salts (HCl, SO42-, Citrate, Br, I) tend to contain nitrogen as an amine, piperidine or piperazine derivative quartenary amines are intrinsically ionized, regardless of the pH of their solution. Consequently they are hydrophilic and poorly lipid soluble, and are unlikely to cross the blood brain barrier.

Movement of ions across cell membrane consider electrochemical gradient transmembrane potential hydrate ionic radius control of selective channels active transport Cell membrane lipid bilayer bilayer of amphipathic lipids the hydrocarbon chains oriented inward to form a continuous hydrophobic phase and the hydrophilic heads are oriented outward individual lipid molecules in the bilayer can move laterally endowing the membrane with fluidity, flexibility, high electrical resistance, and relative impermeability to highly polar molecules Cell membrane protein molecules globular protein molecules penetrate into either side of or entirely through a fluid phospholipid bilayer complexes of intrinsic membrane proteins and lipids can form either hydrophilic or hydrophobic channels that allow transport of molecules with different characteristics Membrane transfer passive membrane transfer passive diffusion bulk flow pinocytosis (formation of vesicles across the cell membranes) carrier-mediated membrane transfer Passive diffusion movement and rate of diffusion directly proportional to Concentration lipid:water partition coefficient of the drug (or solubility in lipid bilayer) for non-electrolyte drugs, after a steady state, concentration of free drug on both sides of membrane is equal Ficks Law of Diffusion: flux (molecules per unit time) permeability/diffusion coefficient x C x area = thickness Bulk flow movement through intercellular pores in capillaries, except in the brain (tight junctions) bulk flow of water can carry with it small water-soluble substances (m.w. < 100-200) limited by blood flow and not lipid solubility or pH gradients

Carrier-mediated membrane transport facilitated diffusion no energy input, hence cannot occur against electrochemical gradient may be highly selective for specific conformational structures of molecules (glucose and amino acids) active transport selectivity competitive inhibition by congeners energy required movement against electrochemical gradient saturability Oral route of administration rate of absorption in the intestine (larger surface) is greater than in the stomach even if the drug is predominantly ionised in the intestine and largely unionised in the stomach (aspirin) Compare and contrast drug absorption by sublingual and rectal routes Comparison pH surface area blood flow absorption systemic effect first pass effect bioavailability formulations Sublingual Rectal 6.2-7.4 7-8 200 cm2 200-400 cm2 good good rapid rapid ( dissolution) (aqueous>non-aqueous) rapid rapid avoided avoided high high, but metabolism at site, may decrease bioavailability tablet suppository (emulsion, suspension) gelatin capsule (solution, suspension) enema (solution, suspension)

Plasma concentrations after a single oral or intravenous dose

Similar with intramuscular or epidural administration of drug

First pass effect and bioavailability drugs that are absorbed from the small intestines into the portal venous system pass through the liver before entering the systemic circulation and may be subjected to metabolic or excretory capacity of the liver for the drug (first-pass effect) if the first pass effect is great, then drug bioavailability will be substantially reduced first pass metabolism of drugs can occur in the gut and the liver gut - benzylpenicillin, insulin liver - propanolol, lignocaine, chloromethiasole, GTN Plasma concentration bioavailability (after oral administration) is the AUC

Effect of variation in bioavailability a given drug may act to produce both desirable and undesirable effects at several sites in the body and the rates of distribution of the drug to these sites may not be the same the relative intensities of these different effects of a drug may vary transiently when its rate of administration is changed therapeutic concentration may be reached by oral administration of higher dose of drug, but so will the concentration of (active) metabolites Drug distribution Phases of drug distribution initial phase (first few minutes) - to well perfused organs (heart, liver, kidney, brain) second phase (next several minutes to several hours) - to less well perfused organs (muscle, viscera) third phase - slow uptake by fat Factors affecting distribution of drugs binding to plasma proteins
inhibition CYP 450 glycoprotein

Inhibition of first pass metabolism

with inhibition of first pass metabolism Plasma concentration

inhibition CYP 450

only unbound portion is in equilibrium across membranes affects measurements of plasma drug concentration if assays do not distinguish free from bound drug (phenytoin) pH between intracellular and extracellular fluids lipid solubility permeability of capillary endothelial membrane Binding to plasma proteins covalent bonding and reversible the fraction of total drug that is bound to plasma protein is determined by the drug concentration its affinity for the binding sites the number of binding sites dissociation constant at low concentration, binding number of sites and dissociation constant at high concentration, binding number of sites and drug concentration if an agent that is extensively and strongly bound to plasma proteins, a reservoir of drug forms maintains plasma concentration prolongs drug action access to cellular sites of action may be limited may be metabolised and eliminated slowly (via glomerular filtration)

Drug in intestine


Bioavailability enteral and parenteral knowing extraction ratio for a drug across the portal system and liver it is possible to predict maximum oral availability Fmax Fmax = 1 - E = 1 - (Clhepatic / Qhepatic) for oral drug that is subjected to first-pass loss F x Dosing rate = CL x Css where F is fractional bioavailability Route Bioavailability Intravenous 100 Intramuscular <100 Subcutaneous Oral Rectal Inhalation Transdermal <100 <100 <100 <100 <100 Characteristics most rapid onset large volume feasible but may be painful smaller volume than intramuscular, may be painful most convenient, first pass effect may be significant less first pass effect than oral very rapid onset very slow absorption, lack of first-pass effect effect, prolonged duration of action

drug binding to albumin acidic drugs: salicylates, warfarin, phenylbutazone, tolbutamide, diazepam, thiopentone, phenytoin, valproate, penicillin, diuretics, digoxin some basic drugs situations with hypoalbuminaemia: pregnancy neonates elderly burns hepatic disease renal disease inflammatory disease nephrotic syndrome cardiac failure drugs binding to 1-acid glycoprotein basic drugs: beta-blockers (alprenolol, oxprenolol, pindalol, propranolol, timolol); antiarrhythmics (lignocaine, quinidine, disopyramide); calcium channel blockers (verapamil, nicardipine); opiates /opioids (methadone, pethidine, alfentanil); local anaesthetics (lignocaine, bupivacaine); antidepressants and psychoactive drugs (amitriptyline, imipramine, nortriptyline, chlorpromazine, phencyclidine, triazolam); miscellaneous (dipyridamole, erythromycin, metoclopramide, prednisolone, prazosin, progesterone) albumin will still usually carry a greater fraction of the drug simply because of its higher concentration conditions with increased 1-acid glycoprotein burns Crohns disease ulcerative colitis renal transplantation trauma chronic pain myocardial infarction postoperative period malignancy infection rheumatoid arthritis conditions with decreased 1-acid glycoprotein neonates pregnancy oral contraceptives oestrogens other drug binding proteins globulin: steroids lipoprotein: vitamin K competitive displacement of drugs acidic drugs compete with endogenous substances for binding sites on albumin (sulphonamides and unconjugated bilirubin) competition between drugs for binding sites on albumin (warfarin, phenylbutazone, salicylates, tolbutamide) risk of adverse effect is great with highly protein bound drugs if the displaced drug has a limited volume of distribution if the competition extends to the drug bound in tissues if the elimination of the drug is reduced if the displaced drug is administered in high dosage by a rapid intravenous injection with drugs with narrow toxic to therapeutic ratios (e.g. warfarin free fraction increases from 1% to 5% with salicylates)

decreased binding of drugs in uraemia, due to alteration in protein structure displacement of drug from its binding sites by some metabolic product that is usually excreted by the kidneys free fraction of phenytoin increases from 7% to as much as 25%, half life of phenytoin reduced without change in clearance effect of altered drug binding Normal binding binding Drug A (highly bound) Drug B (less bound) 98% bound 2% free 70% bound 96% bound 4% free 68% bound Reduced

(free fraction doubles) 30% free 32% free (free fraction increases by 7%)

saturable protein binding as molar concentration rises, the free unbound portion may eventually increase as all binding sites become saturated saturation of the binding sites for a low extraction drug: as drug concentration increases free fraction increases Vd and Cl increase (Cl free fraction) half-life may remain constant Css will not increase linearly as the rate of drug administration is increased saturation of the binding sites for a high extraction drug: as drug concentration increases if hepatic clearance is unchanged, increase in Vd will increase the half-life of the drug by reducing the fraction of the total drug in the body that is delivered to the liver per unit time diffusion of drugs into tissues occurs rapidly due to highly permeable nature of capillary endothelial membranes (except in the brain) lipid-insoluble drugs that permeate membranes poorly are restricted in their distribution and hence their potential sites of action if the reservoir for the drug is at target organ, and has a large capacity and fills rapidly large quantities of the drug will have to be administered initially to provide an effective concentration in the target organ cumulation may occur as a result of pH gradients, binding to phospholipids, nucleoproteins, or partitioning into lipid phase

effects of pH intracellular pH: 7.0 concentration of weak bases higher in intracellular fluid extracellular pH: 7.4 concentration of weak acids higher in extracellular fluid lowering the pH of the extracellular fluid increases the concentration of weak acids in the cells, and decreases that of weak bases distribution of drugs to the CNS blood brain barrier absence of intercellular pores at endothelial cells of the brain capillaries absence of pinocytotic vesicles tight junctions, restrict aqueous bulk flow arrangement of precapillary glial cells slow diffusion of organic acids and bases into the CNS rate of diffusion of drugs is proportional to the lipid solubility of the unionised species cerebral blood flow is the only limitation to permeation of the CNS by highly lipid-soluble drugs strongly ionised agents, and quaternary amines normally unable to enter the CNS from the circulation placental transfer of drugs simple diffusion lipid-soluble, unionised drug transfer readily penetration is least with drugs possessing a high degree of dissociation or low lipid solubility implications potential for causing congenital anomalies during first trimester may have adverse effects on the neonate if administered immediately before delivery Redistribution termination of drug effect by redistribution of the drug from its site of action to other tissues or sites rate of recovery is faster than the terminal elimination half-life, even after infusions to steady state drug reservoirs plasma proteins cellular reservoirs fat: stable reservoir because of low blood flow; lipid soluble drugs are stored by physical solution in fat bone transcellular reservoirs: gastrointestinal tract, cerebrospinal fluid, aqueous humour, endolymph, joint fluids

Volume of distribution an apparent volume

Vd =

amount of drug in body plasma concentration

depends on timing of sampling for plasma concentration of drug includes all the apparent volumes of the compartments that constitute the compartmental model for a given drug
64 32 [Drug] mg/ml 16 8 4 2 0 0 2 4 6 8 10 12 Time (h) Sampling after 4h C0 [Drug] mg/ml 64 32 16 8 4 2 0 0 2 4 6 8 10 12 Time (h) Sampling before 4h

Vd may be calculated by extrapolation of the terminal (elimination) phase using the elimination rate constant back to time zero using the area under the concentration time curve (AUC) Vd calculated by extrapolation rationale for this is that the elimination rate must have been constant from the start, and the initial, highest rate of elimination must be inversely proportional to the volume of distribution
Drug concentration (mg/ml) )(log scale) distribution phase A B equilibrium phase

Time (h)

B is the y intercept after extrapolation and represents theoretical Cp0 which would have been achieved at zero time if the dose had been instantaneously distributed, and that equals Dose/Vd Vd extrapolated = Dose/B or kel = elimination rate constant Vd calculated by AUC Vd area = dose/(AUC x kel) AUC = AUC
t= Cpt.dt t=0

= dose/V.kel = Cp0/kel

Volume of some body compartments and examples of drugs in that compartment Water total body water (0.6L/kg): small water-soluble molecules (ethanol) extracellular water (0.2L/kg): large watersoluble molecules (mannitol) blood (0.08L/kg), plasma (0.04L/kg): strongly plasma protein-bound molecules and very large molecules (heparin) Fat (0.02-0.35 L/kg) highly lipid-soluble molecules: (tertiary amino compounds) Bone (0.07 L/kg) certain ions: e.g. fluoride, lead drugs that are extensively bound to plasma proteins but are not bound to tissue components, Vd approaches plasma volume Vd and clearance inversely proportional to protein binding drugs that are bound to extravascular tissue (muscle and adipose tissue) as well Vd is higher than plasma volume Factors affecting Vd pKa of the drug changes in either tissue or plasma protein binding, example, effect of decrease in skeletal mass body composition partition coefficient of the drug in fat Vd of increased in obesity (total body water 0.5 l/kg) hydrophilic drugs have Vd similar to that of total body water age effect of decrease tissue mass for drug binding generally, large in neonates, and decreased in elderly (refer to section on The Elderly Patient) disease abnormal accumulation of fluid (oedema, ascites, pleural effusion, renal disease) can markedly increase Vd of hydrophilic drugs Compartment models central compartment Drug administration volume = Vd Drug elimination Cpo = dose/Vd single

clearance is the volume of plasma from which drug is completely removed in unit time (ml/kg/min or L/min) t Vd/Cl 0.693 x Vd Cl = t elimination half-life is the time taken for any plasma concentration to fall by one half during the elimination phase dCp/dt = -kel.Cp Cp = two

kel = elimination rate constant

/v .e


central compartment Drug administration volume = V1 Drug elimination Cpo = dose/Vd k21 k12 (slowly)

peripheral compartment volume = V2 multiple Cp = Ae-t + Be-t Cp is drug concentration at time t elimination and distribution processes are both firstorder processes VE Effector site k1e keo k13 k31 V3 Slow equilibrating compartment

V1 V2 k21 Rapidly Central equilibrating k compartment 12 compartment kel Elimination

Drug concentration (mg/ml) )(log scale)
distribution phase A B

equilibrium phase

Time (h)

k1e is rate constant for delivery of drug to effector site; k1e is smaller than keo keo is rate constant for disposal of drug from effector site or rate constant for equilibration of drug between plasma concentration and effector site allows calculation of effector site concentration tkeo is the time it takes for half of the equilibration to take place between the plasma concentration (Cp) and the effector site concentration (Ce) kel is rate constant for disposal of drug from central compartment

Cp (log scale)

Cp (log scale)

Intravenous administration, one compartment, no elimination

Intravenous administration, one compartment, with elimination

Biotransformation biotransformation of drugs by enzymes to more polar and less lipid-soluble metabolites to enhance their excretion to reduce their volume of distribution site of metabolism: hepatic, non-hepatic enzyme system: microsomal, non-microsomal enzyme systems microsomal enzymes located in smooth endoplasmic reticulum of the liver (microsomal fraction isolated after centrifugation of liver homogenates) also found in kidney, lung, gastrointestinal epithelium contributes to first-pass effect

time Intravenous administration, two compartment, no elimination

time Intravenous administration, two compartment, with elimination

Cp (log scale)

time Different volumes of Vd

Cp (log scale)


Phase I reactions introduce or expose a point of attack for the conjugating system to attach a larger molecule convert parent drug to more polar metabolite includes oxidation, reduction, or hydrolysis metabolite may be pharmacologically inactive, less active, more active, or more toxic (paracetamol, halothane) than its parent molecule when the metabolite is active, its parent compound is a prodrug (enalapril) 3 types oxidation by: cytochrome P450, amine oxidases, heme peroxidases, prostaglandin H synthase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase hydrolysis reduction Phase II reactions if the drug has a reactive (hydroxyl, thiol, or amino) group, either native or because of phase I metabolism, conjugation to form (usually) water soluble products can occur conjugation or synthetic reactions coupling the drug or its polar metabolite with an endogenous substrate, usually form inactive products glucuronide, sulphate (SO4), methyl (CH3), acetyl (COCH3), glycine or glutamyl conjugation reactions with: glucuronate, acetate, glycine, glutamate, sulphate, methyl group

Vd of central compartment = dose administered / C at time zero Vdss or volume of central and peripheral compartments, V1 + V2 = dose administered / C at steady state Vd of peripheral compartment = Vdss-V1 Vds of drugs <0.3 L/kg
vecuronium warfarin frusemide salicylic acid amoxycillin

0.3-0.6 L/kg
atracurium d-tubocurare pancuronium theophylline milrinone vancomycin

0.6-1 L/kg

1 L/kg

midazolam midazolam alfentanil diazepam mepivacaine lorazepam bupivacaine bupivacaine lignocaine lignocaine thiopentone etidocaine neostigmine thiopentone acetaminophen propofol nifedipine edrophonium captopril pyridostigmine amrinone hyoscine sufentanil cimetidine

1 L/kg

2 L/kg

3 L/kg
thiopentone propofol etomidate pethidine morphine nalbuphine ketamine

4 L/kg

> 5 L/kg

thiopentone thiopentone propofol propofol diazepam etomidate midazolam midazolam hyoscine hyoscine etidocaine etidocaine bupivacaine ketamine lignocaine atropine

propofol propofol etomidate verapamil pethidine fentanyl pentazocine pentazocine propranolol labetalol

Oxydative systems cytochrome P450 the dominant oxidative system amine oxidases haem peroxidases prostaglandin H synthase xanthine oxidase alcohol and aldehyde dehydrogenases Hepatic endoplasmic reticulum oxidative enzymes known as mono-oxygenase / mixed function oxidases found on the lipid bilayer membrane of smooth endoplasmic reticulum reaction requires presence of reducing agent, nicotinamide adenine dinucleotide phosphate, NADPH, and oxygen epoxide intermediaries can covalently bond with macromolecules and may be responsible for tissue necrosis, carcinogenicity, and other toxic effects (paracetamol, isoniazid, frusemide, a-methyldopa) Cytochrome P450 isoenzymes a superfamily of haemoproteins that are the terminal oxidases of the mixed function oxidase system structure: protein + haem group spectrophotometric absorption peak at or near 450nm when bound and reduced by carbon monoxide function: catalyses metabolism of endogenous and exogenous compounds in Phase I reactions epoxidation, N-dealkylation, O-dealkylation, hydroxylation of aliphatic and aromatic residues have a distinct but overlapping substrate specificity more than one cytochrome P450 isoenzyme can be involved in the metabolism of a drug show saturable Michaelis-Menten kinetics and need co-factors for activity
Velocity of enzyme action Vmax

distribution hepatic extra-hepatic: brain, lung, small intestines, pancreas, adrenal gland, kidney, ovary, testis, skin, adipose, mast cells, and bone marrow nomenclature cytochrome P450 isoenzymes in all species family having >40% identity in amino acids CYP 2 E 1

individual enzyme subfamily consisting of > 55% identical amino acid sequence

Hepatic cytochrome P450 monooxygenase system

Drug [Fe3+] Oxidised drug + H2O Drug[Fe3+] Cytochrome P450 Drug[Fe2+] Reduced flavoprotein Cytochrome P450 reductase Oxidised flavoprotein NADPH NADP+


Drug can be a substrate (steroid, fatty acid or compound with an alkene, alkane, aromatic ring or heterocyclic ring substituent) that serves as a site for oxygenation drug substrate binds with oxidised cytochrome P450(Fe3+), to be reduced by cytochrome P450 reductase the reduced complex then binds with molecular oxygen producing oxidised metabolite and water, and regeneration of oxidised cytochrome P450 a second electron and 2 hydrogen ions are acquired from the donor system



lipid solubility property of the drug favours drug penetration into endoplasmic reticulum and binding with Cytochrome P450 may be induced or inhibited by drugs or metabolites of drugs

Inhibition of cytochrome P450 by drugs non-selective inhibition on oxidation by direct interaction with haem iron (cimetidine through one of the nitrogen atoms of its imidazole nucleus; ketoconazole) direct irreversible inactivation (disulphiram) reversible inhibition of demethylation by fluoroquinolone antimicrobials (ciprofloxacin) affecting metabolism of midazolam by metabolites compounds whose oxidative products bind to haem (troleandomycin) that irreversibly bind to enzyme (secobarbitone, cyclophosphamide, chloramphenicol) that have a high affinity for the reduced (ferrous) form of CYP so that it is not available for further oxidation (nitroso metabolite of erythromycin) hepatic blood flow reduction can also reduce biotransformation if this is the rate limiting factor effects of propranolol and cimetidine on lignocaine metabolism inhibitors allopurinol cimetidine clarithromycin erythromycin ketoconazole miconazole quinidine amiodarone chloramphenical diltiazem fluconazole metronidazole omeprazole sulphonamides androgens ciprofloxacin disulfiram isoniazid MAO inhibitors propoxephene verapamil

Activity of selected cytochrome P450 isoenzymes Isoenzyme Substrate Inducer Inhibitor CYP1A2 caffeine, phenacetin, phenytoin, quinolone TCA, R-warfarin, omeprazole, erythromycin, phenobarbitone haloperidol, polycyclic paracetamol, hydrocarbons theophylline CYP2D6 debrisoquine, codeine dextromethorphan b-blockers, SSRIs, TCA pregnancy cimetidine quinidine methadone


paracetamol, ethanol, isoniazid halothane, isoflurane, benzene enflurane, sevoflurane, Methoxyflurane nifedipine, TCA, granisetron, codeine, dextromethorphan, alfentanil, sufentanil, fentanyl, diltiazem, midazolam, erythromycin lignocaine, ropivacaine hydrocortisone rifampicin cimetidine glucocorticoid troleandomycin carbamazepine propofol phenobarbitone grapefruit juice ketoconazole


metabolism of these drugs are affected: bupivacaine cyclosporine diazepam imipramine nifedipine lignocaine phenytoin quinidine sildenafil theophylline vecuronium warfarin phenobarbitone Induction of microsomal enzymes 2 main groups aromatic hydrocarbons (tobacco smoke, benzene) agents that resemble phenobarbitone (such as ethanol, phenylbutazone) both groups increase protein synthesis phenobarbitone type of compounds increase P450 reductase as well increase the drugs own metabolism as well inducers: drugs barbiturates carbamazepine ethanol rifampicin phenylbutazone phenytoin inducers: other factors cigarette smoking dietary protein / CHO ratio dexamethasone glutethimide spironolactone charcoal broiled meat

the lesser cytochrome P450 subfamilies involvement in metabolism of a drug, the lower the risk of drug interactions Variation in drug clearance by cytochromes

clearance by CYP1A2 term

1 year



Acetylation important for compounds such as procainamide, hydralazine, isoniazid, sulphonamide population falls into 2 groups: fast and slow acetylators genetically determined: 50% Caucasians, 90% Japanese are fast acetylators implication - drug toxicity procainamide induces antinuclear antibodies and lupus erythromatosus syndrome at faster rate in slow acetylators than fast acetylators

Conjugation reactions with glucuronate - glucuronidation of ether and esters (acetaminophen, naproxen) - catalyzed by glucuronyltransferase located in the endoplasmic reticulum with acetic acid - acetylation (sulphonamides, isoniazid, hydralazine, procainamide) - catalyzed by N-acetyl transferase with glycine - (aromatic carboxylic acids, such as salicylic acid) with sulphate - (phenolic compounds, steroids) O-, S-, and N-methylation of amines and phenols (adrenaline, noradrenaline) glucuronide synthesis is a major metabolic pathway of drugs that contain phenols, alcohol, carboxylic acids compounds inactive and rapidly secreted into urine and bile by an anion transport system ester glucuronides (from carboxylic acids) are readily hydrolysed by enzymatic and spontaneous action to parent compound ether glucuronides (from phenols, alcohols) are stable chemically both groups can be hydrolysed by intestinal or bacterial bglucuronidase resulting in enterohepatic recycling conjugation with glucuronate occurs to a lesser extent in the kidney and other tissues Nonmicrosomal biotransformation occurs mainly in the liver, but also in plasma and other tissues oxidation reactions: by flavoprotein enzymes in mitochondria and cytosol of liver and other tissues alcohol and aldehyde dehydrogenase, xanthine oxidase, monoamine oxidase reduction reactions: of nitro groups and cleavage and reduction of azo linkage hydrolysis: esters (procaine), nonspecific esterases in liver, plasma, gastrointestinal tract, and tissues amides (lignocaine) primarily in the liver polypeptides by peptidases in plasma, red blood cells conjugation reactions: with acetic acid (aromatic primary amines and hydrazines) show genetic polymorphism (isoniazid and hydralazine with slow acetylators at higher risk of toxicity) with glycine (aromatic carboxylic acids e.g. salicylic acid) may exhibit saturable kinetics with glutathione (contributes to inactivation of epoxide intermediates of hydroxylation reactions with sulphate (phenolic, steroids) O-,S-, N-methylation (of amines and phenols e.g. adrenaline, noradrenaline)

Excretion of drugs via kidneys, faeces (unabsorbed oral drug or bile), lungs, saliva, tears, sweat, breast milk, hair, skin drugs can be excreted unchanged or as metabolites more readily excreted as polar compounds Biliary excretion many drug metabolites are excreted into the bile (with carrier system similar to the renal tubules) but commonly are reabsorbed to be excreted in the urine through extensive biliary cycling Renal excretion renal excretion involves 3 processes glomerular filtration active tubular secretion (passive tubular reabsorption) rate of glomerular filtration depends on the volume of fluid filtered in the glomerulus the unbound concentration of the drug in plasma (protein bound not filtered) rate of active secretion depends on rate of drug delivery to excretory sites binding to active transport proteins (carriermediated) degree of saturation of carriers rate of transfer across tubular membrane selective active secretion systems system that secretes uric acid - secretion of organic acids (penicillin, sulphonamide) and metabolites (glucuronides) system that secretes choline, histamine, endogenous bases - secretion of organic bases (tetraethylammonium, TEA) non-selective carrier system organic ions of similar charge compete for transport passive tubular reabsorption of unionised weak acids and bases occurs in the proximal and distal tubules concentration gradient for back-diffusion created by the reabsorption of water with Na+ and other inorganic ions passive tubular reabsorption of ionised forms of weak electrolytes is pH dependent with alkaline pH urine, rapid excretion of weak acids in ionised forms (barbiturates, salicylates) and less with acidic pH opposite effects on excretion of weak bases

Excretion by other routes dependent on diffusion of unionised lipid-soluble forms of drugs through epithelial cell pH dependent saliva concentrations of some drugs parallel those in plasma breast milk is more acidic than plasma so basic compounds may be more concentrated, nonelectrolytes such as ethanol and urea reach plasma concentration application: hair and skin may allow detection of toxic metals (forensic uses e.g. arsenic, mercury) Clearance the volume of plasma from which drug is completely removed in unit time (ml/kg/min or L/min) Organ clearance organ clearance depends on the organ blood flow activity of the organs drug-metabolizing enzyme system clearance by various organs of elimination (hepatic and non-hepatic) is additive Cl systemic = Cl hepatic + Cl renal + Cl (lungs,saliva,sweat,gut) plasma clearance may assume values that are not physiological, i.e. artificially very high, higher than hepatic blood flow when drug partitions readily into another compartment (labetalol partitioning into red blood cells) most drugs eliminate following first-order kinetics, when system for drug elimination not saturated zero-order kinetics, if mechanism for elimination is saturated first-order kinetics: constant fraction of drug eliminated per unit time simple exponential decay proportional to amount in the body. rate of elimination = clearance x concentration Ct = C0e-kt (t = 0.693/k) Clearance = k x Vd = Vd x 0.693/t = [urine] x urine volume / [plasma] zero-order kinetics constant amount of drug eliminated per unit time may replace first-order when saturation occurs

Capacity limited elimination follows zero-order kinetics clearance will vary depending on the concentration of the drug that is achieved (e.g. phenytoin, ethanol) capacity limited elimination is also known as saturable elimination/metabolism dose- or concentration-dependent elimination nonlinear elimination Michaelis-Menten elimination most drug elimination pathways will become saturated if the dose is high enough phenytoin, salicylate, theophylline, high dose thiopentone exhibit first-order elimination at low doses and zero-order elimination at high doses because of saturation of the process of elimination when blood flow to the organ is not a limiting factor (Vmax x C) rate of elimination = (Km + C) Km is plasma concentration at which half maximal elimination occurs (Vm/2), Vm is maximal rate of elimination, and C is plasma concentration at concentrations > Km, the elimination rate is almost independent of concentration
log drug concentration g/ml Rate of elimination




causes first-pass metabolism to be less than expected (higher F), and there is greater increase in Css than the corresponding fractional increase in the rate of administration, e.g. phenytoin as clearance decreases, the apparent half-life for elimination increases and the approach to new steady state is slow no effect on Vd

Flow dependent elimination high-extraction drugs are cleared very readily by the organ of elimination the elimination of such drugs depends primarily on blood flow through the organ of elimination most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it Extraction ratio, E, measures the ability of the liver to remove the drug from blood as it passes through the liver, which in turn must depend on the livers drugmetabolizing enzyme systems rate of elimination of a drug by an organ = Q (CaCv) but, rate of elimination also = Css Cl dividing elimination equation by Ca: Q (Ca-Cv) rate of elimination = Ca Ca Q (Ca-Cv) = Q.E Ca if a drug is efficiently removed, the extraction ratio, E is high and approaches 1 Cl = the clearance of the drug (Cl = QE) will be limited by hepatic blood flow blood concentration, g/ml minimally affected by alteration in protein binding e.g. propofol, lignocaine, fentanyl, morphine, propranolol, chlorpromazine, diltiazem, imipramine, midazolam (0.7) Hepatic drug clearance hepatic clearance of a drug is controlled by hepatic blood flow intrinsic ability of the liver to metabolize drugs rate of removal of drug from the body by the liver is Cl hepatic = QE the intrinsic ability of the liver to irreversibly remove a drug by all pathways, independent of liver blood flow, can be expressed as a clearance term, Cl intrinsic for a drug that is completely metabolised by the liver: Cl hepatic = Cl intrinsic Intrinsic clearance of the liver for drugs with low initial intrinsic clearance increasing the enzyme activity will produce an almost proportional increase in the extraction efficiency for drugs with high initial intrinsic clearance increasing the enzyme activity has almost no effect on either the extraction ratio or hepatic clearance

Doubling intrinsic clearance low extraction drug E = 0.1 high extraction drug E = 0.9


blood concentration, g/ml


intravenous drug administration


0.01 1.0

0.01 0.1


oral drug administration

0 10 20 30 time, h 0 1 2 3




E F Clint Cls

0.1 0.9 0.17 0.15

0.18 0.82 0.33 L/min 0.27 L/min

E F Clint Cls

0.9 0.1 13.5 1.35

0.95 0.05 27.0 L/min 1.42 L/min

Doubling hepatic blood flow


low extraction drug E = 0.1 intravenous drug administration

high extraction drug E = 0.9




0.01 1.0

0.01 0.1


0.01 0 10 20

oral drug administration

30 time, h 0 1 2 3



E F Q Cls

0.18 0.10 0.82 0.90 0.75 1.50 L/min 0.14 0.15 L/min

E F Q Cls
Hepatic clearance L/min

0.95 0.05 0.75 0.71

0.90 0.10 1.50 L/min 1.35 L/min

Effect of hepatic blood flow

100 % extraction E.R. 0.9 0.5

E.R. 0.9 0.5 0.1 Liver blood flow L/min


Liver blood flow L/min

drugs that decrease liver blood flow (propranolol, cimetidine) reduce clearance of drugs with high ER elderly patients have decreased hepatic blood flow

Effects of hepatic blood flow and enzyme activity Effect of hepatic blood flow low extraction drug clearance of i.v. drug no sig. change clearance of oral drug no sig. change Effect of enzyme activity clearance of i.v. drug clearance of oral drug increased increased no sig. change increased high extraction drug increased no sig. change

Half-life elimination half-life is the time taken for any plasma concentration to fall by one half during the elimination phase (0.693 Vd) (0.7 x Vd) t = Cl Cl is a derived parameter changes as a function of both clearance and volume of distribution indicates the time required to attain 50% of steady state or to decay 50% from steady state, after a change (starting or stopping) in a particular rate of drug administration (the dose regimen) 0.693 distribution half-life, t, can be defined as, t = elimination half-life, t estimated graphically, time for concentration to half in the linear part of the elimination phase calculated: 0.693 divided by the elimination rate constant for that drug () or 0.693 rate constant for elimination also represented as k renal and hepatic disease, which alter Vd and/or clearance, will alter the elimination halftime, eg. acute viral hepatitis modifies protein binding in plasma and tissue causing no change in Vd but an increase in total clearance because higher concentration of free drug are present half-life of tolbutamide decreases in such patients can lead to significant errors if administration of drug is according to t or t 2

intermediate to high-extraction drugs dependent on blood flow not affected by protein binding high first-pass effect morphine, pethidine, fentanyl, pentazocine, propoxyphene, nalorphine, naloxone, acetylsalicylic acid isoprenaline, propranolol, salbutamol, metoprolol lignocaine, nitroglycerin, chlorpromazine, TCA, diltiazem low-extraction drugs dependent on hepatic enzymes dependent on protein binding low first-pass effect diazepam, digoxin, methadone mepivacaine phenobarbitone, phenylbutazone, phenytoin, procainamide theophylline, tolbutamide, warfarin Renal clearance C x Clrenal = U CP CU is the concentration of drug in the urine, is the rate of urine flow, and Renal extraction of drugs low extraction frusemide, gentamicin, digoxin high extraction (with tubular secretion) para-aminohippuric acid, salicylic acid, probenacid, penicillin, phenylbutazone, sulphonamide, indomethacin glucuronide, sulphates histamine, procaine, procainamide, tolazoline, morphine, atropine Concentration CP is the concentration of the drug in plasma

1 2 3 4 5 6 Time (multiples of elimination half-time) Time constants 4 time constants to reach 98% () (63.22, 86.5, 95, 98.17)

Elimination half-time time required for the concentration of the drug in the central compartment to decrease by one-half, measured from the time the infusion is discontinued (Hughes et al 1992)

The neonate protein binding reduced increased Vd poorly developed blood-brain-barrier vulnerable to toxic effects of drugs immature renal function, affects elimination of aminoglycosides and penicillins acetylcholinesterase and pseudocholinesterase reduced in premature and full term newborns adult levels are not reached until 1 year of age however resistant to suxamethonium Remifentanil hepatic microsomal enzyme systems cytochrome P450 enzymes are usually near adult activities after a few months

2 Duration of infusion (hours)

hydroxylation process slow, affects degradation of diazepam, mepivacaine Phase II enzymes develop more slowly, have low activity, with reduced glucuronide transferase conjugating ability hyperbilirubinaemia and potential for encephalopathy, toxicity of chloramphenicol and some opioids The patient with renal disease dose required in patient with renal insufficiency patients drug clearance = usual dose x normal drug clearance patients drug clearance = normal ClR x The patient with liver disease altered protein binding altered drug-metabolising activity both low and high extraction drugs affected, reducing Cl, increasing F drugs such as oxazepam and lorazepam which are eliminated via conjugation pathways are eliminated normally in cirrhosis and viral hepatitis effect of porta-systemic shunting The patient with cardiac failure Vd reduced loading dose should be reduced (lignocaine) hepatic and renal blood flow affected affecting elimination and accumulation of drugs with active or toxic metabolites e.g. lignocaine monoethylglycinexylidide (MEGX) and glycinexylidide (GX) ClCr 100

Second order kinetics bi-exponential higher order kinetics implies a multi-compartment model is required Pharmacokinetics of special groups of patients The elderly patient factors affecting Vd and Css decrease in lean body mass (muscle) increase in total body fat - increases Vd for lipid soluble drugs decrease in total body water (10-15%) - decreases Vd for water soluble drugs decrease in serum albumin or decrease in binding affinity of albumin with age - increase free fractions of highly bound drugs, and both therapeutic and toxic events may occur at lower total serum concentrations increase in alpha1 glycoprotein clearance clearance of drugs reduced liver blood flow decreases renal function deteriorates impaired elimination of drugs which are excreted to a significant extent by the kidneys e.g. digoxin, cimetidine, pancuronium

Pharmacogenetics plasma cholinesterase hydrolysis of suxamethonium N-acetyltransferase N-acetylation of isoniazid, procainamide, hydrallazine cytochrome P450 oxidation of beta-blockers, tricyclic antidepressants, debrisoquine methyl-transferase methylation of thiopurines (azathioprine), aliphatic thiol containing drugs (captopril), catecholamines and possibly histamine glucose-6-phosphate dehydrogenase deficiency unable to cope with the oxidative stress imposed by some drugs resulting in drug-induced haemolysis sulphonamides, quinidine, antimalarials (chloroquine, quinine, primaquine), aspirin, probenecid, and vitamin K gene for valine-COMT or methionine-COMT and pain perception COMT metabolises dopamine, val-COMT more efficient than met-COMT too much dopamine in the brain reduces endorphin content double-val gene produces potent COMT that rapidly metabolises dopamine, triggering endorphin production Genetic polymorphism Mendalian trait at least 2 phenotypes exist in the normal population, neither of which has a frequency of less than 1% results in distinctly different rates of metabolism of drugs in a population poor or slow metabolisers possess the homozygous autosomal recessive allele (usually mutant alleles) metabolise drugs slowly, drug cumulation, more side effects extensive or rapid metabolisers have the heterozygous or homozygous dominant allele ultra rapid metabolisers are associated with enzymes with extremely high activity and result from gene amplification metabolise drugs rapidly, low drug concentration, less efficacy

clinical consequences in drug metabolism depend on whether the activity of the drug (antihypertensive agent, debrisoquine) lies with the substrate or its metabolite (codeine morphine) the extent to which the affected pathway contribute to the overall elimination of the drug (debrisoquine) Plasma cholinesterase coded for by two allelomorphic genes on an autosomal chromosome four variants are described, normal gene N dibucaine resistant gene D fluoride resistant gene F silent gene S dibucaine-related variants are the most important the most frequent atypical form, the dibucaine resistant gene, has a far lower affinity for succinylcholine at normal serum concentrations D-gene population prevalence ~ 1:53 incidence ~ 1:2800 the usual laboratory estimates of plasma cholinesterase do not differentiate between the varieties the local anaesthetic dibucaine inhibits normal plasma cholinesterase to a far greater extent than the atypical enzyme (Kalow & Genest) dibucaine number (DN): the percentage inhibition of plasma cholinesterase produced by a standard titre of dibucaine (10-5 mmol/l) under standard test conditions, dibucaine inhibits the normal enzyme by about 80% and abnormal enzyme by about 20% Genotype SCh sensitivity NN normal ND mildly increased DD greatly increased NF mildly increased NS normal DF greatly increased DS greatly increased FF greatly increased FS greatly increased SS greatly increased DN 80 50 20 80 80 50 20 60 60 0 FN Incidence(%) 60 94 (96.2) 40 4 (3.8) 20 0.036 40 0.5 60 0.5 40 0.02 20 0.02 20 0.0025 20 0.0025 0 0.0025

DN = % inhibition of plasma cholinesterase by dibucaine 10-5 mmol/l FN = % inhibition of plasma cholinesterase by fluoride 10-5 mmol/l

Acetylation 2 groups: fast and slow acetylators 50% Caucasians, 90% Japanese are fast acetylators important for compounds such as procainamide, hydralazine, isoniazid implication drug toxicity procainamide induces antinuclear antibodies and lupus erythromatosus syndrome at faster rate in slow acetylators than fast acetylators Cytochrome P450 enzymes clinical applications: markers can be used to test for enzyme polymorphism caffeine for CYP1A2 polymorphism lignocaine for CYP3A4 polymorphism sparteine, debrisoquine, dextromethorphan for CYP2D6 polymorphism