Pharmacokinetics PDF

Topic 2: Pharmacokinetics  Pharmacokinetics Pharmacokinetics refers to what the body does to a drug. Once administered through one of several available routes, four pharmacokinetic properties determine the speed of onset of drug action, the intensity of the drug’s effect, and the d...

Topic 2: Pharmacokinetics  Pharmacokinetics Pharmacokinetics refers to what the body does to a drug. Once administered through one of several available routes, four pharmacokinetic properties determine the speed of onset of drug action, the intensity of the drug’s effect, and the duration of drug action. Pharmacokinetics Absorption: First, drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into plasma. Distribution: Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intra cellular fluids. Metabolism: Third, the drug may be biotransformed by metabolism by the liver, or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Pharmacokinetics Pharmacokinetic parameters allow the clinician to design and optimize treatment regimens: Route of administration The amount and frequency of each dose Duration of treatment ABSORPTION OF DRUGS Absorption is the transfer of a drug from its site of administration to the bloodstream via one of several mechanisms. The rate and efficiency of absorption depend on: drug’s chemical characteristics route of administration (which influence its bioavailability) IV delivery, absorption is complete (100% bioavailability). Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. Mechanisms of absorption of drugs from the GI tract Passive diffusion Facilitated diffusion Active transport Endocytosis / exocytosis Passive diffusion The vast majority of drugs gain access to the body by this mechanism. concentration gradient across a membrane separating two body compartments. drug moves from a region of high concentration to one of lower concentration. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores. lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers.  Facilitated diffusion Drugs enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concentration to an area of low concentration. It does not require energy. can be saturated,and may be inhibited by compounds that compete for the carrier.  Active transport Energy-dependent active transport involves specific carrier proteins that span the membrane. Actively transports drugs that closely resemble the structure of naturally occurring metabolites across cell membranes. capable of moving drugs against a concentration gradient. selective and may be competitively inhibited by other cotransported substances. Endocytosis / exocytosis Transport drugs of exceptionally large size across the cell membrane. Endocytosis - engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Exocytosis – secretion of many substances by a similar vesicle formation process.  Factors influencing absorption I. Blood flow to the absorption site II. Total surface area available for absorption III. Contact time at the absorption surface IV. Expression of P-glycoprotein Blood flow to the absorption site Blood flow to the intestine is much greater than the flow to the stomach, absorption from the intestine is favored over that from the stomach. Total surface area available for absorption With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. Contact time at the absorption surface If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. Parasympathetic input increases the rate of gastric emptying. Sympathetic input (prompted, for example, by exercise or stressful emotions) as well as anticholinergics (for example, dicyclomine), delays gastric emptying. The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.  Expression of P-glycoprotein Organ Function Liver Transport drugs into bile for elimination Kidneys Pump drugs into urine for excretion P-glycoprotein is a multidrug Placenta Transport drugs back into maternal blood,thereby reducing fetal transmembrane transporter protein exposure to drugs responsible for transporting various Intestines Transport drugs into the intestinal molecules, across cell membranes. lumen and reducing drug absorption into the Areas of high expression, P-glycoprotein blood reduces drug absorption. Brain Pump drugs back into blood, limiting capillaries drug access to the brain  Bioavailability Bioavailability is the fraction of administered drug that reaches the systemic circulation. Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. Bioavailability are affected by route of administration, as well as the chemical and physical properties of the agent. Determination of Bioavailability Determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. This curve refl ects the extent of absorption of the drug.  Bioavailability Bioavailability of a drug administered orally - ratio of the area calculated for oral administration compared with the area calculated for IV injection if doses are equivalent Factors that influence bioavailability First-pass hepatic metabolism Solubility of the drug Chemical instability Nature of the drug formulation First-pass hepatic metabolism If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug that gains access to the systemic circulation is decreased. E.g., more than 90 percent of nitro glycerin is cleared during a single passage through the liver, which is the primary reason why this agent is administered via the sublingual route. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities. Solubility of the drug Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Extremely hydrophobic drugs are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases. Chemical instability Low pH or presence of degradative enzymes. E.g., penicillin G are unstable in the pH of the gastric contents. insulin, are destroyed in the GI tract by degradative enzymes. Nature of the drug formulation The following can influence the ease of dissolution and, therefore, alter the rate of drug absorption; particle size salt form crystal polymorphism enteric coatings presence of excipients (such as binders and dispersing agents) DRUG DISTRIBUTION General Principles Related to Drug Distribution The process of distribution refers to the movement of a drug between the intravascular (blood/plasma) and extravascular (interstitium/ extracellular fluid) and cells of the tissues) compartments of the body. Within each compartment of the body, a drug exists in equilibrium between a protein- bound or free form. Over time, drugs within the circulation will then be metabolized and excreted from the body by the liver & kidneys.  For a drug administered IV, when absorption is not a factor, the initial phase represents the distribution phase  The amount of drug Understanding The amount of drug distribution to nontarget available to the target organs that could drug organ to produce action. potentially result in an adverse drug reaction. distribution is important in establishing: The loading dose of drugs.  Initial Phase Second Phase The drug is distributed to: highly The muscle, skin, and fat Phases of vascular organs; liver, kidney, and brain receive most of the receive drug slowly during the second phase. Drug drug. It accounts for most of the In the brain, drug distribution is extravascular drug Distribution determined by the permeability of the blood-brain barrier (BBB) to the drug molecules. distribution. It is responsible for the phenomenon of This phase is responsible for the redistribution seen with some acute onset of action of abused drugs. drugs and anesthetic drugs. Redistribution Movement of a drug from an area of high regional blood flow to an area of medium or low regional blood flow. If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action. The greater the lipid solubility of the drug, the faster its redistribution will be. For example, the anaesthetic action of thiopentone is terminated in a few minutes due to redistribution. However, when the same drug is given repeatedly or continuously over long periods, the low-perfusion and high-capacity sites are progressively filled up and the drug becomes longer-acting. Factors Affecting Drug Distribution Cardiac output and blood flow Capillary permeability Plasma protein binding Tissue binding Cardiac output and blood flow Rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Brain Skeletal Muscles heart More Adipose tissue Liver than Skin kidney viscera High blood flow permits rapid distribution  Capillary permeability determined by capillary structure and by the chemical nature of the drug. Certain organs have highly specialized inter- endothelial junctions that prevent drug movement into the organs reducing the exposure to potentially toxic substances. For example, the BBB is a continuous tight junction. Drugs that overcome this barrier require high lipid solubility, should be unionized, must be of a smaller molecular size, and should not be bound to plasma proteins. Other organs can have barriers to drug uptake as well (blood-testis barrier). Diseases such as meningitis or encephalitis can disrupt the barriers and might increase the influx of the drug and might result in enhanced therapeutic effect or toxicity. Plasma Protein Binding Some drugs bind avidly to plasma proteins and exist in two forms: bound form unbound form. The unbound drug is the active form. The ratio of the bound form and the unbound form alters drug distribution. Only unbound (free) drug molecules can leave the vascular system. Bound molecules are too large to fit through the pores in the capillary wall. Plasma Protein Binding Drugs commonly bind to the following plasma proteins: Albumin binds acidic drugs. Alpha-1 acid glycoprotein binds basic drugs. Hormone carrier proteins (e.g., thyroid binding globulin, sex hormone-binding globulin).  The bound-unbound fraction is affected by: Drug concentrations. Affinity to the binding protein. Disease-induced alteration of protein levels like hypoalbuminemia decreases the bound fraction of drugs, while inflammatory conditions increase acute phase proteins resulting in an increase of the bound fraction. Physiological alterations in the protein levels, e.g., during pregnancy. Presence of other drugs that compete with the binding sites. Plasma Protein Binding Drugs that bind to plasma proteins have a lower aVd than drugs that do not. Binding to plasma proteins might limit their glomerular filtration and slow down drug metabolism pathways.  Similar to how drugs bind to plasma proteins, drugs also reversibly bind to proteins and phospholipids in tissues. The tissues to which drugs bind act as a reservoir of these drugs. Tissue Binding They keep releasing the drug into the central compartment slowly and increase the elimination half-life of the drug. prolong half-life on the other hand, can cause tissue toxicity. e.g., nephrotoxicity/ototoxicity by aminoglycosides and cardiotoxicity by digoxin. Volume of distribution Once a drug enters the body, from whatever route of administration, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site.  Apparent Volume of Distribution (aVd) Relative size of various distribution volumes within a 70-kg individual. The following equation can represent Vd: Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L) Since the volume of distribution represents a ratio, it doesn't correspond directly to a physical volume in the body. Instead, it indicates how the drug behaves in terms of distribution within the body relative to its concentration in the plasma. Apparent Volume of Distribution (aVd) A drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma concentration. (High Vd More distribution to other tissue). Note: factor that increases Vd can lead to an increase in the half-life and extend the duration of action of the drug. Conversely, a drug with a low Vd has a propensity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma concentration. (Low Vd Less distribution to other tissue) Factors Affecting the Volume of Distribution Drug Patient Factors Factors  Molecular size smaller molecules have a high aVd. Molecular charge uncharged molecules have a high aVd. Drug pKa alters the ionization of drugs. non-ionized molecules can penetrate tissues more easily than ionized molecules. When the pH of the surrounding environment is equal to the Factors drug's pKa, the drug is 50% ionized and 50% unionized. As the pH deviates from the pKa, the degree of ionization changes. For acidic drugs, at a pH below the pKa, more molecules will exist in their non-ionized form (protonated form), while at a pH above the pKa, more molecules will exist in their ionized form (deprotonated form). The opposite is true for basic drugs. Affinity to tissue proteins binding to tissue proteins decreases the amount of drug in the central compartment resulting in an increase in aVd. Lipid solubility Lipid-soluble drugs have high volumes of distribution. Aqueous solubility water-soluble drugs tend to be ionic and have lesser volumes of distribution.  Age With increasing age, the water content of the body decreases. The muscle mass also decreases resulting in lower tissue binding for some of the drugs. Often, the aVd is found to decrease for many drugs. Patient The loading doses must be calculated with caution in the elderly. Gender Females tend to have a larger volume of distribution. Factors pH Protein levels Alters ionization of drugs. Lower protein levels result in larger than expected volumes of distribution for drugs with significant plasma protein binding. Displacement Presence of other drugs that compete for protein binding sites will alter the distribution of drugs. Pregnancy Increases the aVd for many drugs. Edema, ascites, and Increases the aVd for many drugs as the excess effusions fluid can act as reservoirs of the drug. Effect of Vd on drug half-life A large Vd has an important influence on the half-life of a drug, because drug elimination depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow, but also on the fraction of the drug in the plasma. If the Vd for a drug is large, most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases Vd can lead to an increase in the half-life and extend the duration of action of the drug.  Knowing the apparent volume of distribution can help us Estimating estimate the loading dose of drugs. the Loading Dose Drugs with larger volumes of distribution need to have larger loading doses.  Drug Distribution to the Fetus or Newborn The drug distribution to the fetus is determined by: Lipid solubility Plasma protein binding pKa of the drug and ion trapping The fetal pH (7.0–7.2) is slightly more acidic than the maternal plasma (7.4). Weak bases which cross the placenta will ionize, and the ionic form will not be able to diffuse back freely into the maternal plasma resulting in increased fetal exposure. Drug Distribution to the Fetus or Newborn The mother’s milk has a lower pH as well and has a higher concentration of lipids. The composition of milk changes postpartum and also within a feeding cycle (foremilk and hindmilk). These changes contribute to the time- and phase-dependent variation in drug movement into maternal milk. Drug distribution into the mother’s milk is determined by: pKa and ionization Low plasma protein binding Low molecular weight High lipophilicity Metabolism  Most drugs undergo chemical alteration by various bodily systems to create compounds that are more easily excreted from the body. These processes allow for the chemical Metabolism modification of drugs into their metabolites and are known as drug metabolism or metabolic biotransformation. Drug Metabolism: Biochemical changes that involve the modification of a drug via by endogenous metabolic enzymes. Types of metabolites These metabolites are the byproducts of drug metabolism and can be characterized by: active Inactive toxic metabolites Types of metabolites Metabolite Description Active metabolites biochemically active compounds with therapeutic effects inactive metabolites biochemically inactive compounds with neither a therapeutic nor toxic effect. Toxic metabolites biochemically active compounds similar to active metabolites but have various harmful effects Drug metabolism takes place: mainly in the liver hepatocytes in kidney, lungs, gastrointestinal tract and skin. Phases of metabolism Phase I and Phase II Reactions Phase I – lipophilic drug → hydrophilic (more polar) drug by inserting a polar functional group. E.g.: OH, COOH, SH, NH2 Phase II – Further ↑ water solubility of a drug by conjugation with a polar moiety, e.g.: glucuronate or sulfate.  3 main types: - Oxidation (most important) Phase I Metabolism - Reduction - Hydrolysis Phase I Metabolism Phase I Metabolism Phase I Metabolism Carried out by cytochrome P450 (CYP450) family in the liver and gastrointestinal tract. But found throughout the body. The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids) and for the biotransformation of exogenous substances (xenobiotics). Phase I Metabolism Phase 1 Reactions Drugs can either induce or inhibit the CYP450. Inducer: Drugs ↑ the production of CYP isozymes, thereby ↑ the metabolism of drugs by these enzymes. Consequences: - ↓ plasma drug concentrations Phase I Metabolism Inhibitors : Drugs ↓ P450 enzyme, ↓ metabolism of other drugs which rely on this enzyme :Important source of drug interactions that lead to serious adverse events. : E.g.: Omeprazole-warfarin interaction Omeprazole ↓ CYP isozymes, plasma warfarin ↑, RISK OF BLEEDING ↑!! Grapefruit juice inhibits CYP3A4, ↑ toxic effect of drugs nifedipine, clarithromycin, and simvastatin  Substrates, inducers, and inhibitors of CYP450 enzymes  Many Phase I metabolites are still lipophilic, Phase II conjugation with large polar molecules (glucuronic acid, sulfuric acid, acetic acid, or an Metabolism amino acid) by transferase enzymes producing more hydrophilic and inactive metabolites (ready to be excreted via kidney). In some cases, Phase II reaction occurs before Phase I. E.g. isoniazid (anti-tuberculosis drug) undergoes acetylation first (Phase II conjugation of the drug with Acetyl CoA) and then hydrolysis (Phase I). Examples of enzymes in Phase II Metabolism Phase II Metabolism Metabolism of phenytoin Metabolism of phenytoin by phase 1 cytochrome P450 (CYP) and phase 2 uridine diphosphate-glucuronosyltransferase (UGT). CYP facilitates 4-hydroxylation of phenytoin. The hydroxy group serves as a substrate for UGT that conjugates a molecule of glucuronic acid (in green) using UDP-glucuronic acid (UDP- GA) as a cofactor. This converts a very hydrophobic molecule to a larger hydrophilic derivative that is eliminated via the bile. Phase I Vs Phase II Reactions Phase I reactions Phase II reactions Convert a parent drug to a more polar Increase water solubility of a drug by (water soluble) molecule conjugation. Function: To introduce a polar Function: To attach polar & ionizable group (e.g. OH, COOH, NH2, SH) into components of the body to the Phase a lipophilic drug to increase its I metabolites to form more hydrophilic aqueous solubility (hydrophilic). metabolites. Most oxidation reactions are carried Glucuronidation is the most common out by cytochrome P450. & important conjugation reaction. Primary at endoplasmic reticulum in Enzyme located in cytosol, EXCEPT liver cells, aka microsomal enzyme. glucuronidation (microsomal enzyme)  Age: Pediatric and geriatric populations are slow metabolizers when compared to adults due to immature and loss of enzyme activity in the respective populations. Factors Gender: Males metabolize drugs faster than females. Drugs like ethanol, propranolol, and Influencing estrogens are metabolized faster in males than Drug females. Liver size and liver function capacity: Metabolism Metabolism of drugs is significantly affected in active liver diseases leading to toxic reactions and failure of therapy. Males and adults with bigger liver size metabolize the drugs faster than females and children.  Body temperature: Hyperthermia increases blood flow to the organs Factors including the liver and kidney, and one can expect drug clearance by metabolism at a faster rate. Influencing However, on the contrary, the metabolism of majority of drugs is reduced due to decreased Drug function of CYP450, FMOs, and other enzymes. Interleukins (IL 1, IL 4, and IL6), INF-y, and TNF-α Metabolism secreted during fever decrease the activity of drug- metabolizing enzymes. Drugs like α-methyldopa, salicylamide, antipyrine, and sulfonamides are proven to undergo decreased metabolism during fever.  Diet: Since CYP450 enzymes, especially CYP3A4, can be induced or Factors inhibited by various dietary compounds, type of food intake has a potential role in drug metabolism. Grapefruit juice inhibits CYP3A4, and hence midazolam, Influencing cyclosporine, and diazepam toxicity occur. Cruciferous vegetables (cabbage, cauliflower, and others) induce Drug CYP1A1 and CYP1A2 leading to therapeutic failure of warfarin, carbamazepine, and theophylline therapy. Metabolism Ethanol induces CYP2E1 and hence increases carcinogen generation by oxidative reaction in alcoholics. Polycyclic aromatic hydrocarbons in barbecued meat induce CYP1A2 and significantly affect the theophylline metabolism.  Environmental factors: Insecticides and aromatic hydrocarbons are known to induce or inhibit CYP enzymes. Factors Cigarette smoke and other plastic burnt smoke contain benzopyrene which induces CYP1A1 and Influencing CYP1A2. Heavy metal exposure like mercury, cobalt, nickel, Drug and arsenic results in inhibition of drug-metabolizing Metabolism enzymes directly by forming protein adducts. Various animal studies have proven that high-altitude hypoxia upregulates CYP2D6 activity and downregulates CYP1A2.  Genetic polymorphisms: presence of two or more variant forms of a Factors specific DNA sequence that can occur among Influencing different individuals or populations. CYP2C9 polymorphism: CYP2C9 metabolizes S- Drug warfarin, phenytoin, and various NSAIDs. CYP2C9*2 and CYP2C9*3 alleles have reduced Metabolism enzyme activity that can cause bleeding disorder when S-warfarin is administered. DRUG CLEARANCE THROUGH METABOLISM Drug elimination Drug elimination is not the same as drug excretion: A drug may be eliminated by metabolism long before the modified molecules are excreted from the body. For drugs that are not metabolized, excretion is the mode of elimination. 74 Drug Once a drug enters the body, the process of elimination begins. elimination The three major routes involved are: Hepatic Pulmonary Renal These elimination processes cause the plasma concentration of a drug to decrease exponentially. DRUG CLEARANCE BY THE KIDNEY Elimination of drugs from the body requires the agents to be sufficiently polar for efficient excretion. Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs.  Renal elimination of a drug Elimination of drugs via the kidneys into urine involves the three processes of: glomerular filtration active tubular secretion Passive tubular reabsorption  Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Allow drugs (MW < 20000) and unbound drug to flow through the capillary slits into Bowman’s space as part of the glomerular filtrate. Glomerular The glomerular filtration rate - 125 mL/min. filtration Lipid solubility and pH do not influence the passage of drugs. However, varying the glomerular filtration rate and plasma binding of the drugs may affect this process. Proximal tubular secretion: Drugs that were not transferred into the glomerular filtrate (protein bound drug) leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier requiring) systems: one for anions (for example, deprotonated forms of weak acids) one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate. Distal tubular reabsorption As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be done to minimize the amount of back-diffusion and, hence, increase the clearance of an undesirable drug. 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 example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate , which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If overdose is with a weak base, such as amphetamine, acidification of the urine with NH4Cl leads to protonation of the drug (that is, it becomes charged) and an enhancement of its renal excretion. Hepatobiliary elimination Excretion Process in The Liver Compounds molecular weight > 300 may be actively secreted in bile. Glucoruronidation facilitate excretion of drug via bile. Some drugs undergo enterohepatic recycling (i.e. enzymes in intestinal flora hydrolyze conjugated-drugs into free drug, then reabsorbed from small intestine). The enterohepatic cycle may repeat several times but can be interrupted by agents that bind drugs in the intestine (e.g. charcoal, cholestyramine). CLEARANCE BY OTHER ROUTES Other routes of drug clearance include via intestines, the bile, the lungs, and milk in nursing mothers, among others. The feces are primarily involved in elimination of unabsorbed orally ingested drugs or drugs that are secreted directly into the intestines or in bile. The lungs are primarily involved in the elimination of anesthetic gases (for example, halothane and isoflurane).  Elimination of drugs in breast milk is clinically relevant as a potential source of undesirable CLEARANCE side effects to the infant. BY OTHER ROUTES A suckling baby will be exposed, to some extent, to medications and/or its metabolites being taken by the mother.  Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small CLEARANCE extent. BY OTHER ROUTES Deposition of drugs in hair and skin has been used as a forensic tool in many criminal cases.  To achieve a desired therapeutic level of a medication, a clinician must understand the elimination order and utilize the information in subsequent dosing to maintain the therapeutic concentration Kinetics of over a set period. Elimination Misunderstanding of kinetic elimination may lead to patients experiencing toxic symptoms and could lead to other iatrogenic adverse effects up to and including death.  Most drugs are eliminated according to first-order kinetics, although some, such as aspirin in high doses, are eliminated according to zero- Kinetics of order or non-linear kinetics. Elimination Metabolism leads to products with increased polarity, which will allow the drug to be eliminated. Formulas of elimination rate constant Kel = ln (Cp1/Cp2) t Kel = 0.693 T1/2 First-Order Elimination The term first-order elimination implies that the rate of elimination is proportional to the concentration (ie, the higher the concentration, the greater the amount of drug eliminated per unit time). The result is that the drug's concentration in plasma decreases exponentially with time. Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every half- life. Most drugs in clinical use demonstrate first-order kinetics. 88 Zero-Order Elimination The term zero-order elimination implies that the rate of elimination is constant regardless of concentration. As a result, the concentrations of these drugs in plasma decrease in a linear fashion over time. 89  Comparison of first-order and zero-order elimination For drugs with first-order kinetics, rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination, the rate is constant and independent of concentration. 90 *Half-life = time for the concentration of drug in the plasma to decrease by half Drug Clearance Clearance (CL) estimates the amount of drug cleared from the body per unit of time. where t1/2 is the drug’s elimination half-life, Vd is the apparent volume of distribution, and 0.693 is the natural log constant. Drug half-life is often used as a measure of drug CL, because, for many drugs, Vd is a constant. Clearance is NOT an indicator of how much drug is being removed; it only represents the theoretical volume of blood which is totally cleared of drug per unit time. Drug Clearance Creatinine is a waste product of creatine metabolism, produced in muscle when creatine is metabolised to generate energy. Creatinine is not reabsorbed or secreted, but is exclusively filtered through the kidneys, so its rate of excretion from your bloodstream is directly related to how efficiently your kidneys are filtering. Amount of creatinine in a BLOOD used to estimate glomerular filtration rate (GFR).  Drug Clearance Cockcroft & Gault Formula (creatinine clearance estimate) - The most frequently-calculated estimates of Glomerular filtration Rate (GFR) Question: Calculate creatinine clearance of a 45-year-old 70 kg man with serum creatinine concentration of 2 mg/dL. eCcr = (140 – 45) x 70 72 x 2 = 46.2 mL/min 94 Drug Clearance Important measures of drug clearance calculated to prevent drug toxicity: Total body clearance drug half-life. Total body clearance The total body (systemic) clearance, CL total or CLt, is the sum of the clearances from the various drug-metabolizing and drug-eliminating organs. The kidney is often the major organ of excretion; however, the liver also contributes to drug loss through metabolism and/or excretion into the bile. A patient in renal failure may sometimes benefit from a drug that is excreted by this pathway, into the intestine and feces, rather than through the kidney. Total body clearance Some drugs may also be reabsorbed through the enterohepatic circulation, thus prolonging their half-lives. Total clearance can be calculated by using the following equation: Clinical situations resulting in changes in drug half-life When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. It is important to be able to predict in which patients a drug is likely to have a change in half-life. The half life of a drug is increased by: I. diminished renal plasma flow or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage. II. decreased ability to extract drug from plasma, for example, as seen in renal disease. III. decreased metabolism, for example, when another drug inhibits its biotransformation or in hepatic insuffi ciency, as with cirrhosis. On the other hand, the half-life of a drug may decrease by: I. increased hepatic blood flow II. decreased protein binding III. increased metabolism Half-Life Half-life (t 1/2) is a derived parameter, completely determined by Vd and CL. Like clearance, half-life is a constant for drugs that follow first-order kinetics. Half-life can be determined graphically from a plot of the blood level versus time, or from the following relationship: 99