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Transcript
Pharmacokinetics Dr. S A Ziai Pharmacokinetics examines the movement of a drug over time through the body Pharmacological as well as toxicological actions of drugs are primarily related to the plasma concentrations of drugs The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects concentration-effect dose-concentration ADME The speed of onset of drug action, the intensity of the drug’s effect, and the duration of drug action are controlled by four fundamental pathways of drug movement and modification in the body The "standard" dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug Pharmacokinetic Principles • In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route • Drugs: – The active drug molecule – Prodrug ROUTES OF DRUG ADMINISTRATION • Enteral – Oral – Sublingual • Parenteral – IV – IM – SC • Other – – – – – – Inhalation Intranasal Intrathecal/Intraventricular Topical Transdermal Rectal • Oral – Simple, Reversible – First-pass metabolism • Sublingual – Enteric coated • Parentral – – – – – – – – Heparin, Insulin Unconscious patients Rapid onset of action Highest bioavailability (IV) Irreversible, Pain, Infection Rate of administration (IV) Depot and suspension (IM) Pumps, Implants (SC) Basic parameters in PK • Clearance, the measure of the ability of the body to eliminate the drug; • Volume of distribution, the measure of the apparent space in the body available to contain the drug VOLUME OF DISTRIBUTION • The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed. • Water compartments in the body 1. Plasma compartment (6%) • Size and PB (Heparin) 2. Extracellular fluid (20%) • LMW and hydrophil Aminoglycosides 3. Total body water (60%) • Ethanol 4. Other sites • Fetus Physical Volumes (in L/kg Body Weight) of Some Body Compartments into Which Drugs May Be Distributed Compartment and Volume Examples of Drugs Water Total body water (0.6 L/kg1) Small water-soluble molecules: eg, ethanol. Total body water in a young lean man might Extracellular water (0.2 Larger water-soluble be woman,eg,0.5 L/kg L/kg)0.7 L/kg; in an obesemolecules: gentamicin. Blood (0.08 L/kg); plasma Strongly plasma protein(0.04 L/kg) bound molecules and very large molecules: eg, heparin. Fat (0.2–0.35 L/kg) Highly lipid-soluble molecules: eg, DDT. Bone (0.07 L/kg) Certain ions: eg, lead, fluoride. Determination of Vd • C = D/Vd or Vd = D/C • C = the plasma concentration of the drug • D = the total amount of drug in the body. • For example, if 25 mg of a drug (D = 25 mg) are administered and the plasma concentration is 1 mg/L, then Vd = 25 mg/1 mg/L = 25 L Volume of Distribution The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug) apparent volume Clearance Clearance, like volume of distribution, may be defined with respect to blood (CLb), plasma (CLp), or unbound in water (CLu), depending on the concentration measured • Kidneys • Liver • Clearance of unchanged drug in the urine represents renal clearance • In liver, drug elimination occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both. First order kinetic • For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration Total body clearance • It is not possible to measure and sum these individual clearances. However, total clearance can be derived from the steadystate equation Clearance is calculated from the dose divided by the AUC Rate of elimination • The elimination of a drug usually follows first-order kinetics, and the concentration of drug in plasma drops exponentially with time. • The elimination rate for most drugs is first-order and shows a linear relationship with time if lnC (where lnC is the natural log of C, rather than C) is plotted versus time • This is because the elimination processes are not saturated. • This can be used to determine the half-life, t1⁄2, of the drug (the time during which the concentration of a drug at equilibrium decreases from C to 1⁄2C): • ke = the first-order rate constant for drug elimination from the total body and CL = clearance Half-Life • Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion). • Half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions— after a change in the rate of drug administration. Time required to reach the steadystate drug concentration • Disease states can affect both of the volume of distribution and clearance • Patients with chronic renal failure have decreased renal clearance of digoxin but also a decreased volume of distribution Capacity-Limited Elimination • Phenytoin, ethanol, aspirin • Other names: saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. has no real meaning for drugselimination with capacity-limited • IfClearance dosing rate exceeds capacity, elimination, and AUC cannot be used to describe the elimination of such drugs state cannot be achieved: The steady concentration will keep on rising as long as dosing continues. Flow-Dependent Elimination • Most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it • They called "high-extraction" drugs since they are almost completely extracted from the blood by the organ. • It depends on: – Blood flow to the organ – Plasma protein binding – Blood cell partitioning Drug Accumulation • In practical terms, if the dosing interval is shorter than four half-lives, accumulation will be detectable. • For a drug given once every half-life, the accumulation factor is 1/0.5, or 2. • The accumulation factor predicts the ratio of the steady-state concentration to that seen at the same time following the first dose. • Thus, the peak concentrations after intermittent doses at steady state will be equal to the peak concentration after the first dose multiplied by the accumulation factor. ABSORPTION OF DRUGS Transport of a drug from the GI tract • IV 100% • Passive diffusion – – – – Concentration gradient Lipid soluble Water soluble Facilitated diffusion (by carrier) • No energy, Saturated, Inhibited • Active transport – ATP – Saturated – Moving against concentration gradient • Endocytosis and exocytosis – Vit B12 Permeation Aqueous Diffusion • Across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000. • Concentration gradient (Fick's law) • Bound to large plasma proteins (eg, albumin) • Electrical fields Lipid Diffusion • The lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media. • In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium • A weak acid is a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). • A weak base is a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. Effect of pH on drug absorption • More of a weak acid will be in the lipid-soluble form at acid pH • More of a basic drug will be in the lipidsoluble form at alkaline pH The pKa is a measure of the strength of the interaction of a compound with a proton The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug Determination of how much drug will be found on either side of a membrane Special Carriers • Peptides, amino acids, sugars • ABC (ATP-binding cassette) family – less selective – P-glycoprotein, multidrug-resistance type 1 (MDR1) transporter, multidrug resistanceassociated protein (MRP) – the solute carrier [SLC] family, do not bind ATP but use ion gradients for transport energy Special Carriers Transporter NET SERT VMAT MDR1 MRP1 Physiologic Function Norepinephrine reuptake from synapse Serotonin reuptake from synapse Pharmacologic Significance Target of cocaine and some tricyclic antidepressants Target of selective serotonin reuptake inhibitors and some tricyclic antidepressants Target of reserpine Transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings Transport of many xenobiotics Increased expression confers out of cells resistance to certain anticancer drugs; inhibition increases blood levels of digoxin Leukotriene secretion Confers resistance to certain anticancer and antifungal drugs Physical factors influencing absorption • Blood flow to the absorption site – Blood flow to the intestine is much greater than the flow to the stomach – Shock severely reduces blood flow to cutaneous tissues • Total surface area available for absorption – Intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach • Contact time at the absorption surface – Diarrhea, Parasympathetic, Food Bioavailability • Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route • The area under the blood concentration-time curve (AUC) is a common measure of the extent of bioavailability for a drug given by a particular route Factors that influence bioavailability – – – – First-pass metabolism Solubility of the drug Chemical instability Nature of the drug formulation – Particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution Route Bioavailability (%) Characteristics Intravenous (IV) 100 (by definition) Most rapid onset Intramuscular (IM) 75 to ≤ 100 Large volumes often feasible; may be painful Subcutaneous (SC) 75 to ≤ 100 Smaller volumes than IM; may be painful Oral (PO) 5 to < 100 Most convenient; firstpass effect may be significant Rectal (PR) 30 to < 100 Less first-pass effect than oral Inhalation 5 to < 100 Often very rapid onset Transdermal 80 to ≤ 100 Usually very slow absorption; used for lack of first-pass effect; prolonged duration of action Bioequivalence • Two related drugs are bioequivalent if they show: 1. comparable bioavailability 2. similar times to achieve peak blood concentrations Therapeutic equivalence • Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety Extent of Absorption • After oral administration, a drug may be incompletely absorbed – too hydrophilic (eg, atenolol) – too lipophilic (eg, acyclovir) – P-glycoprotein – First-Pass Elimination • In the gut wall (eg, by the CYP3A4 enzyme system) • in the liver • liver can excrete the drug into the bile • The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER): • where Q is hepatic blood flow, normally about 90 L/h in a person weighing 70 kg. • The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER): Rate of Absorption • The rate of absorption is determined by the site of administration and the drug formulation • zero-order when the rate is independent of the amount of drug remaining in the gut – when it is determined by the rate of gastric emptying or by a controlled-release drug formulation. Alternative Routes of Administration & the First-Pass Effect • The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories DRUG DISTRIBUTION DRUG DISTRIBUTION • Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. • The delivery of a drug from the plasma to the interstitium primarily depends on: • Blood flow • Capillary permeability • Protein binding • Hydrophobicity of the drug Capillary permeability BINDING OF DRUGS TO PLASMA PROTEINS Albumin has the strongest affinities for anionic drugs (weak acids) and hydrophobic drugs Competition for binding between drugs Trapping Body Fluids with Potential for Drug "Trapping" through the pH-Partitioning Phenomenon. Body Fluid Range of pH Total Fluid: Blood Total Fluid: Blood Concentration Ratios for Concentration Ratios Sulfadiazine (acid, pKa 6.5) for Pyrimethamine (base, pKa 7.0) Urine Breast milk 5.0–8.0 6.4–7.6 0.12–4.65 0.2–1.77 72.24–0.79 3.56–0.89 Jejunum, ileum contents 7.5–8.0 1.23–3.54 0.94–0.79 Stomach contents 1.92–2.59 0.11 85,993–18,386 Prostatic secretions 6.45–7.4 0.21 3.25–1.0 Vaginal secretions 3.4–4.2 0.114 2848–452 DRUG METABOLISM DRUG METABOLISM • Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. • The process of metabolism transforms lipophilic drugs into more polar readily excretable products. • The liver is the major site for drug metabolism Kinetics of metabolism 1. First-order kinetics • [C], is much less than, Km • That is, the rate of drug metabolism is directly proportional to the concentration of free drug • This means that a constant fraction of drug is metabolized per unit of time Zero-order kinetics • With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large. Therefore [C] is much greater than Km • A constant amount of drug is metabolized per unit of time Reactions of drug metabolism Phase I reactions utilizing the P450 system • The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed function oxidase): Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+ Drug NADP+ CYP R-Ase CYP e- Fe+3 Drug Drug OH NADPH Fe+3 CYP Fe+2 CYP Drug Drug eO2 CYP O2 Drug Fe+2 H2O 2H+ Electron flow in microsomal drug oxidizing system OH Summary of the P450 system • Metabolism of many endogenous compounds (steroids, lipids, etc.) and biotransformation of exogenous substances (xenobiotics). • Cytochrome P450, designated as CYP • Composed of many families of hemecontaining isozymes Summary of the P450 system • There are many different genes, and many different enzymes • Six isozymes are responsible for the vast majority of P450-catalyzed reactions: CYP3A4 (60%), CYP2D6 (25%), CYP2C9/10 (15%), CYP2C19 (15%), CYP2E1 (2%), and CYP1A2 (2%). • An individual drug may be a substrate for more than one isozyme • Considerable amounts of CYP3A4 are found in intestinal mucosa Summary of the P450 system • CYP2D6, exhibit genetic polymorphism • Some individuals, for example, obtain no benefit from the opioid analgesic codeine because they lack the enzyme that O-demethylates and activates the drug • The frequency of this polymorphism is in part racially determined, with a prevalence of 5-10% in European Caucasians as compared to <2% of Southeast Asians Summary of the P450 system Inducers • Consequences of increased drug metabolism include: 1. decreased plasma drug concentrations 2. decreased drug activity if metabolite is inactive 3. increased drug activity if metabolite is active 4. decreased therapeutic drug effect • Polycyclic hydrocarbons (found as air pollutants) induce CYP4501A2, which decreases the therapeutic concentrations of amitriptyline and warfarin Inhibitors • An important source of drug interactions that leads to serious adverse events • Some drugs, however, are capable of inhibiting reactions for which they are not substrates (ketoconazole) • Omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism Inhibitors • The more important CYP inhibitors are erythromycin, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes • Cimetidine blocks the metabolism of theophylline, clozapine, and warfarin • Grapefruit juice inhibits CYP3A4 and, thus, drugs such as amlodipine, clarithromycin, and indinavir Phase I reactions not involving the P450 system • These include: – amine oxidation (for example, oxidation of catecholamines or histamine) – alcohol dehydrogenation (for example, ethanol oxidation) – esterases (for example, metabolism of pravastatin in liver) – hydrolysis (for example, of procaine) Phase II • Conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are most often therapeutically inactive • A notable exception is morphine-6-glucuronide, which is more potent than morphine • Glucuronidation is the most common and the most important conjugation reaction Phase II • Neonates are deficient in this conjugating system, making them particularly vulnerable to drugs such as chloramphenicol • Drugs already possessing an –OH, –NH2, or – COOH group may enter Phase II directly and become conjugated without prior Phase I metabolism • The highly polar drug conjugates may then be excreted by the kidney or bile Entero-hepatic Recirculation – clinical significance Oral contraceptive failure when an antibiotic is taken An antibiotic such as rifampin also induces CYP enzymes that metabolize the contraceptive hormones and thus reduces their effectiveness even more DRUG ELIMINATION DRUG ELIMINATION • The most important route is through the kidney into the urine. • Other routes include the bile, intestine, lung, or milk in nursing mothers Renal elimination of a drug • Glomerular filtration – The glomerular filtration rate (125 mL/min) is normally about twenty percent of the renal plasma flow (600 mL/min) – Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate • Proximal tubular secretion – By two energy-requiring active transport (carrier requiring) systems, one for anions and one for cations – Premature infants and neonates have an incompletely developed tubular secretory mechanism Renal elimination of a drug • Distal tubular reabsorption – As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” • For phenobarbital (weak acid) overdose we can give bicarbonate • For cocaine, acidification of the urine with NH4Cl is useful Quantitative aspects of renal drug elimination • Plasma clearance is expressed as the volume of plasma from which all drug appears to be removed in a given time—for example, as mL/min • Clearance equals the amount of renal plasma flow multiplied by the extraction ratio, and because these are normally invariant over time, clearance is constant The Time Course of Drug Effect • Immediate Effects • The effect will not usually be linearly proportional to the concentration • The half-life of enalapril is about 3 hours. After an oral dose of 10 mg, the peak plasma concentration at 3 hours is about 64 ng/mL. • Enalapril is usually given once a day • Enalapril’s EC50 is about 1 ng/mL Note that plasma concentrations of enalapril change by a factor of 16 over the first 12 hours (four half-lives) after the peak, but ACE inhibition has only decreased by 20%. • The key factor is a high initial concentration in relation to the EC50 • When concentrations are in the range between one fourth and four times the EC50, the time course of effect is essentially a linear function of time—13% of the effect is lost every half-life over this concentration range. • At concentrations below one fourth the EC50, the effect becomes almost directly proportional to concentration Delayed Effects • Changes in drug effects are often delayed in relation to changes in plasma concentration. • This delay may reflect the time required for the drug to distribute from plasma to the site of action • The delay due to distribution is a pharmacokinetic phenomenon that can account for delays of a few minutes. • Slow turnover of a physiologic substance that is involved in the expression of the drug effect take many hours or even days to occur (eg. warfarin). Maintenance Dose • Clearance is the most important pharmacokinetic term to be considered in defining a rational steady state drug dosage regimen. • At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out"). Example: Maintenance Dose Calculation • A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient • clearance is 2.8 L/h/70 kg • intravenous infusion, F = 1 • Oral theophylline every 12 hours using an extended-release formulation Loading Dose • Volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration in the plasma (Cp) • For the theophylline example given in Example: Maintenance Dose Calculation, the loading dose would be 350 mg (35 L x 10 mg/L) for a 70-kg person. • For intravenous doses of theophylline, initial injections should be given over a 20-minute period to reduce the possibility of high plasma concentrations during the distribution phase. Examples of loading dose • L = TC.Vd/ F e.g. lidocaine t1/2 = 1-2 h Post MI arrythmias –> life threatening –> can’t wait 4-8 h –> Loading dose is used • Another example: Digoxin for heart failure If only maintenance dose is given it takes 10 days t1/2 = 61 h L = 1.5 ng/ml x 580 / 0.7 = 1243 µg ~ 1 mg It can be given iv divided – 0.5 mg, after 6-8 h 0.25 mg, after 6h 0.125 mg and then 0.125 mg (to avoid overdigitalization and toxicity) Multiple IV injections Orally administered drugs D = the dose, F = the fraction absorbed (bioavailability) T = dosage interval Influence of the rate of drug infusion on the steady state • Css = the steady-state concentration of the drug, Ro = the infusion rate (for example, mg/min) • Because ke, CLt, and Vd are constant for most drugs showing first-order kinetics, Css is directly proportional to Ro Influence of the clearance on the steady state • The steady-state concentration is inversely proportional to the clearance of the drug, CLt • liver or kidney disease, increases the steadystate concentration of an infused drug • increased metabolism, decrease the steadystate concentrations of an infused drug Therapeutic Drug Monitoring Relating Pharmacokinetics & Pharmacodynamics • Diseases may modify all of the following parameters: – pharmacokinetic variables: absorption, clearance, and volume of distribution (and the derived variable, half-life) – pharmacodynamic variables: maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug The Target Concentration Strategy 1. Choose the target concentration, TC. 2. Predict volume of distribution (Vd) and clearance (CL) based on standard population values with adjustments for factors such as weight and renal function. 3. Give a loading dose or maintenance dose calculated from TC, Vd, and CL. 4. Measure the patient's response and drug concentration. 5. Revise Vd and/or CL based on the measured concentration. 6. Repeat steps 3–5, adjusting the predicted dose to achieve TC. Pharmacokinetic Variables • Absorption – Patient's compliance – Abnormalities in the small bowel • Clearance – function of the kidney, liver, & heart – Creatinine clearance is a useful quantitative indicator of renal function – hepatic disease does not always affect the hepatic intrinsic clearance – there is no reliable marker of hepatic drugmetabolizing function Pharmacokinetic Variables • Volume of Distribution – Older people have a relative decrease in skeletal muscle mass and tend to have a smaller apparent volume of distribution of digoxin (which binds to muscle proteins) – The volume of distribution may be overestimated in obese patients if based on body weight and the drug does not enter fatty tissues well, as is the case with digoxin – In contrast, theophylline has a volume of distribution similar to that of total body water even in obese patients – Abnormal accumulation of fluid—edema, ascites, pleural effusion—can markedly increase the volume of distribution of drugs such as gentamicin that are hydrophilic and have small volumes of distribution Pharmacokinetic Variables • Half-Life – For example, the half-life of diazepam increases with age. The increasing half-life for diazepam actually results from changes in the volume of distribution with age; the metabolic processes responsible for eliminating the drug are fairly constant Pharmacodynamic Variables • Maximum Effect – If increasing the dose in a particular patient does not lead to a further clinical response, it is possible that the maximum effect has been reached. • Sensitivity – The sensitivity of the target organ to drug concentration is reflected by the concentration required to produce 50% of maximum effect, the EC50. – This may be a result of abnormal physiology—eg, hyperkalemia diminishes responsiveness to digoxin— or drug antagonism—eg, calcium channel blockers impair the inotropic response to digoxin. Timing of Samples for Concentration Measurement • It is important to avoid drawing blood until absorption is complete (about 2 hours after an oral dose) – Some drugs such as digoxin and lithium take several hours to distribute to tissues. Digoxin samples should be taken at least 6 hours after the last dose and lithium just before the next dose (usually 24 hours after the last dose). Aminoglycosides distribute quite rapidly, but it is still prudent to wait 1 hour after giving the dose before taking a sample. Initial Predictions of Volume of Distribution • In patients with edema, ascites, or pleural effusions, the weight should be corrected as follows: Subtract an estimate of the weight of the excess fluid accumulation from the measured weight. Use the resultant "normal" body weight to calculate the normal volume of distribution. Finally, this normal volume should be increased by 1 L for each estimated kilogram of excess fluid. Initial Predictions of Clearance • Cockcroft-Gault equation • Because of the difficulty of obtaining complete urine collections, creatinine clearance calculated in this way is at least as reliable as estimates based on urine collections. • Fat-free mass should be used for obese patients, and correction should be made for muscle wasting in severely ill patients. Revising Individual Estimates of Volume of Distribution & Clearance • If a patient is taking 0.25 mg of digoxin a day, a clinician may expect the digoxin concentration to be about 1 ng/mL. – bioavailability of 70% and total clearance of about 7 L/h (CLrenal 4 L/h, CLnonrenal 3 L/h). • In heart failure, the nonrenal (hepatic) clearance might be halved (5.5 L/h). The concentration is then expected to be about 1.3 ng/mL. Revising Individual Estimates of Volume of Distribution & Clearance • Suppose that the concentration actually measured is 2 ng/mL. Common sense would suggest halving the daily dose to achieve a target concentration of 1 ng/mL. • This approach implies a revised clearance of 3.5 L/h, may reflect additional renal functional impairment due to heart failure. • This technique will often be misleading if steady state has not been reached. • Blog.sbmu.ac.ir/ziai