Pharmacokinetics PDF

Pharmacokinetics Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. It is a branch of Pharmacology dedicated to determining the fate of drug administered to living organism from the moment it is administered up to the point at which it is completely eliminat...

Pharmacokinetics Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. It is a branch of Pharmacology dedicated to determining the fate of drug administered to living organism from the moment it is administered up to the point at which it is completely eliminated from the body. It is the description of the time course of a drug in the body. This refers to movement of the drug in and alteration of the drug by the body. It can be described as what the body does to the drug. It describes how the body affects a specific drug after administration through the mechanism of absorption and distribution as well as the chemical changes of the substances in the body and the effects and routes of excretion of the metabolites of the drug (absorption, distribution, metabolism and excretion). Pharmacokinetics of a drug depends on patient-related factors (renal function, genetic makeup, sex, age etc) as well as on the drug chemical properties. Importance of Pharmacokinetics in Therapeutics 1. It is useful in selecting and adjusting drug dosage schedules. 2. It is useful in monitoring drug levels (therapeutics and toxic concentrations). The principal factors that determine the plasma concentration of drugs are: Absorption, distribution, metabolism and excretion. Absorption This can be defined as the movement of drug from its site of administration into the systemic circulation. It is the process of a drug moving from its site of delivery into the bloodstream. Before drugs can be clinically effective, they must be absorbed. The chemical composition of a drug and the environment into which a drug is placed determine the rate and extent of drug absorption. For solid dosage, absorption of drugs first requires dissolution of the tablet or capsule. Factors affecting the absorption of a drug into the body. 1. Physicochemical properties (e.g. solubility) Drugs with higher lipid solubility are more absorbed at a greater rate. 2. Drug formulation (e.g. tablets, capsules, solutions) Drugs given in aqueous solution are more rapidly absorbed than those given in oily solution, suspension or solid form. 3. The route of administration (e.g. oral, buccal, sublingual, rectal, parenteral, topical, or inhaled). Absorption from intramuscular route is rapid than from subcutaneous route. Absorption from parenteral route is rapid than oral route. Orally administered drugs have incomplete absorption and result in less drug delivery to the site of action. For example, many orally administered drugs are metabolized within the gut wall or the liver before reaching the systemic circulation. This is referred to as first-pass metabolism, this reduces drug absorption. 4. The rate of gastric emptying 5. Degree of Ionization The greater the degree of ionization, the lesser the absorption. Drugs which are lipid soluble are in unionized form and are readily absorbed while the water soluble drugs are in ionized form and can be absorbed only if they have very small molecular size. 6. Surface area The greater the surface area, the larger will be the amount of drug absorbed e.g small intestine has a greater surface area than the buccal or gastric mucosa, thus providing large surface area for absorption. 7. Concentration of drug The greater the concentration of the drug, the greater will be the concentration gradient across the cell membrane and thus the higher the rate of absorption. 8. Local blood flow Rate of absorption is directly proportional to the local blood circulation. Distribution Drug distribution refers to the movement of a drug from systemic circulation to various tissues of the body especially the tissues where its actions are needed. Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into interstitial and intracellular fluids to get to the target cells. Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues. Factors Affecting the Distribution of Drugs Factors affecting distribution of drugs include those related to the drug and those related to the body: Factors related to the Drug: 1. Lipid solubility: the greater the lipid solubility, the more is the distribution and vice versa. 2. Molecular size: the larger the size, the less is the distribution. Smaller sized drugs are more extensively distributed. 3. Degree of ionization: drugs exist as weak acids or weak bases when being distributed. Drugs are trapped when present in the ionized form depending upon the pH of the medium. This fact can be used to make the drug concentrated in specific compartments. 5. Duration of Action: the duration of action of drugs is prolonged by the presence of bound form while the free form is released. This leads to a longer half-life and duration of action of drug. Factors Related to the Body: 1. Vascularity Most of the blood passes through the highly profused organs (75 %) while the remaining (25 %) passes through the less profused areas. Most of the drugs go first to the highly profused areas. They are then redistributed to the less profused areas like the skin and the skeletal muscles. Example includes thiopentone sodium, a general anesthetic. When given, it goes to the brain producing its effects. It is then redistributed to the less profused organs. Because of high lipid solubility, it is accumulated in the fatty tissue for longer duration. Clearance of the drug is slow, producing prolonged period of drowsiness (up to 24 hours). 2. Blood Barriers Different blood barriers exist. Blood brain barrier is present because of the delicacy of nervous tissue to avoid chemical insult to the brain. The transfer of drugs into the brain is regulated by the blood brain barrier. To gain access to the brain from the capillary circulation, drugs must pass through cells rather than between them. Only drugs that have a high lipid water partition coefficient can penetrate the tightly apposed capillary endothelial cells. Drugs that are partially ionized and only moderately lipid soluble will penetrate at considerably slower rates. 3. Placental Barriers The blood vessels of the fetus and mother are separated by the placental barrier. Drugs that traverse this barrier will reach the fetal circulation. The placental barrier, like the blood-brain barrier, does not prevent transport of all drugs but is selective. Substances that are lipid soluble cross the placenta with relative ease in accordance with their lipid-water partition coefficient and degree of ionization. Highly polar or ionized drugs do not cross the placenta readily. 4. Plasma Binding Proteins Most drugs found in the vascular compartment are bound reversibly with one or more of the macromolecules in plasma. Some drugs are dissolve in plasma water, most are associated with plasma components such as albumin, globulins, transferrin, ceruloplasmin, glycoproteins and lipoproteins. Many acidic drugs bind principally to albumin, basic drugs frequently bind to other plasma proteins, such as lipoproteins and acid glycoprotein, in addition to albumin. The extent of this binding will influence the drug's distribution and rate of elimination because only the unbound drug can diffuse through the capillary wall, produce its systemic effects, be metabolized and be excreted. Drug Metabolism (Biotransformation) Drug metabolism is the chemical alteration of drugs in the body. This is needed to render lipophilic (non-polar) compounds to hydrophilic (polar) metabolites for their elimination from the body and for termination of their pharmacological and biological activity. The major site of metabolism is liver, other organs involved are: kidney, gastrointestinal tract, skin, lungs. Phases of Metabolism There are two (2) phases of drug metabolism. These include: Phase I reaction (functionalization, pre-conjugation, asynthetic reaction) Phase II reaction (conjugation, synthetic reaction) Majority of drugs undergo phase I first and then phase II (benzene, phenacetin), but some drugs pass through phase II and then phase I (e.g isoniazid). Some drugs directly undergo phase II without phase I metabolism (meprobamate) while some may involve only phase I if phase I metabolite is sufficiently polar to be excreted (pethidine). Phase I Reaction This convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (OH, NH2, SH). It produces a more water soluble and less active metabolites which are generated by a common hydroxylating enzyme system known as cytochrome P50. If phase I metabolites are sufficiently polar, they may be readily excreted. Many phase I products are not eliminated rapidly and undergo a subsequent reaction. Phase I reactions include: oxidation, reduction and hydrolysis. Example of drugs that undergo phase I and phase II reactions: benzene, phenacetin. Phase II Reaction This is the type of reaction in which parent drugs or their phase I metabolites that contain suitable chemical groups undergo coupling or conjugation reactions with an endogenous substance (glucuronic acid, sulfuric acid, acetic acid or amino acids) to yield drug conjugates. These conjugates are polar molecules that are readily excreted and often inactive. Phase II reactions include: glucuronidation, acetylation, glutathione conjugation, sulfate conjugation and methylation. Example of drug that undergo phase II reaction only: Meprobamate (already has a functional group, no need for phase I). Factors Affecting Drug Metabolism 1. Individual differences Different people have different level of metabolism. 2. Diet and Environmental factors Certain vegetables and fruits induce or inhibit enzymes necessary for drug metabolism. Cigarette smokers metabolize some drugs more rapidly than non- smokers do. 3. Age and Sex Drugs have more effect and more toxicity in very young and old patients due to decreased drug metabolism. Males have more rapid drug metabolism than female. 4. Drug-Drug interaction Some drugs induce and some inhibit enzymes required for metabolism thus resulting in decrease or increase metabolism of the same or other drugs. 5. Disease state Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. 6. Pharmacokinetic factors As long as drug is bound to plasma protein, it will not be metabolized. Drugs which are localized in tissues are protected from metabolism e.g chloroquine in liver. NB: Drug metabolism  Phase I reactions involve oxidation, reduction and hydrolysis: o usually form more chemically reactive products, sometimes pharmacologically active, toxic or carcinogenic o often involve monooxygenase system in which cytochrome P450 plays a key role.  Phase II reactions are conjugation (e.g. glucuronidation) of a reactive group (often inserted during phase I reaction) and usually form inactive and readily excretable products.  Some conjugated products are excreted via bile, are reactivated in the intestine and then reabsorbed.  Induction of enzymes by other drugs and chemicals can greatly accelerate hepatic drug metabolism.  Some drugs show rapid 'first-pass' hepatic metabolism, and thus poor oral bioavailability. Examples of common drugs that are substrates for P450 isoenzymes Isoenzyme Drug P450 CYP1A1 Theophylline CYP1A2 Caffeine, paracetamol, tacrine, theophylline CYP2A6 Methoxyflurane CYP2C8 Taxol CYP2C9 Ibuprofen , phenytoin , tolbutamide , warfarin CYP2C19 Omeprazole CYP2D6 Clozapine , codeine, debrisoquine, metoprolol CYP2E1 Alcohol, enflurane , halothane CYP3A4/5 Ciclosporin, losartan, nifedipine , terfenadine Excretion Excretion is the process whereby the drug and its metabolites are removed from the body. It leads to termination of drug action and actually complete the job initiated by drug metabolism. The kidney (urine) is the main excretory organ, other organs such as the liver, the skin, the lungs and glandular structures, such as the salivary glands and the lacrimal glands bile are also involved in excretion. Drugs are excreted from the kidney by glomerular filtration and by active tubular secretion. Urine pH, which varies from 4.5 to 8.0, may markedly affect drug reabsorption and excretion because urine pH determines the ionization state of a weak acid or base. Acidification of urine increases reabsorption and decreases excretion of weak acids, and, in contrast, decreases reabsorption of weak bases. Alkalinization of urine has the opposite effect. In some cases of overdose, these principles are used to enhance the excretion of weak bases or acids; eg, urine is alkalinized to enhance excretion of acetylsalicylic acid. Pharmacokinetic Parameters These are parameters used to make decisions in pharmacokinetic studies. Plasma Concentration This consist of free drug and drug bounds to plasma protein. It is the unbound or free drugs that exert pharmacological activity. Factors determining degree of plasma protein binding. Two factors are involved. (a) Binding affinity (b) Number of binding sites available or concentration of plasma protein. Acidic drugs such as salicylates, phenytoin bind to Albumin and Basic drugs e.g. lidocaine bind to globulins. Fraction of drug that is free(∞ ) = free drug conc. total drug conc. Assuming instantaneous distribution after an iv injection of a drug , the concentration in the plasma Cp immediately after injection is Cp = Dose/Vd Bioavailability Bioavailability refers the measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form. Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion because (a) the drug may be incompletely absorbed. (b) the absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile. Incomplete bioavailability after s.c. or i.m. injection is less common, but may occur due to local binding of the drug. Bioavailability refers to the rate and extent of absorption of a drug from a dosage form as determined by its concentration-time curve in blood or by its excretion in urine. Factors affecting bioavailability includes 1. Solubility: A drug must be both lipid and water soluble in other to be absorbed from GIT. Drugs which have intermediate lipid-water solubility are more likely to be completely bioavailable orally e.g. theophylline. 2. Salt form Theophylline is the parent compound. It has bioavailability(F) = 1.0. Aminophylline a salt containing 80 to 85% theophylline, has bioavailability of 0.8- 0.85. 3. Dosage form and Route of administration> These affect bioavailability. Examples. Bioavailability(F) for digoxin tablets is 0.7, elixir is 0.8 and iv is 1.0. All drugs given iv, has F = 1. 4.First pass- effect: Decreases oral bioavailability This is a process whereby a drug which is absorbed from GIT is metabolised by the liver to great extent before it reaches the systemsic circulation. E.g. lidocaine and propranolol. Half Life (T1/2) Half life (t1/2) is the time required for the plasma concentration (Cp) of a drug or the total amount of drug in the body to decline by one half through excretion or metabolism or both. It provides a good indication of the time required to reach steady state after a dosage regimen is initiated, the time for a drug to be removed from the body and means to estimate the appropriate dosing interval. Half life = 0.693 × volume of distribution Clearance of drug T1/2 = 0.693Vd Cl t1/2 is dependent on its Vd and its Cl if clearance is decreased, t1/2 will increase. t1/2 = 0.693 β A large value for β corresponds to a short t 1/2 and is a reflection of the rate at which the drug leaves the body Factors Affecting Half life 1. As the clearance decreases due to some disease process the half life increases as in Renal failure. 2. If the volume of distribution is increased, half life is increased e.g half life of diagram increases in old age due to increased volume of distribution. 3. Increased protein binding increases half life. Apparent Volume Of Distribution Vd: This is defined as the volume in which the amount of the drug in the body would need to be uniformly distributed to produce the observed plasma concentration. It accounts for uniform distribution of drugs in the body. It also accounts for all of the drug in the body. It is influenced by the physicochemical properties of the drug. Vd = Ab Cp Ab = amount of drug in the body, Cp = plasma concentration , Vd = apparent vol. of distribution. Plasma Clearance (Cl) This is the volume of blood which is completely and irreversibly removed of drug per unit of time. It is a direct index of drug elimination. Drugs are removed from the body at a rate which is proportional to their Cp. Clearance is also thought of as a proportionality constant that makes the rate of drug elimination equals the rate of drug administration at steady state. Cl = FD or Cl = β × Vd AUC F= fraction absorbed, (bioavailability), AUC =area under the concentration- time curve D=dose β= elimination rate constant Vd = apparent volume of distribution The rate of drug removal is proportional to plasma concentration. Drugs that behave this way are said to follow 1 st order kinetics. However a few drugs like phenytoin and salicylates do not behave this way. Drug clearance and vol. of distribution are not fixed parameters hence equations for Cl and Vd are not applicable. Their metabolisms are liable to saturation. Elimination Rate Constant (β) This is the fraction of the volume which is cleared of drug per unit time β = 0.693 t1/2 or  β = Cl Vd β is used to predicts how plasma concentration varies with time Area under Concentration – Time curve (AUC) AUC is a measure of the amount of the drug that is available in systemic circulation (i.e. bioavailable) which is a measure of therapeutic efficacy. It is important for calculating such important pharmacokinetic parameters such as relative oral bioavailability, plasma clearance and apparent volume of distribution. It can be determined by the trapezoidal rule and is independently of any model used. Lag Time It is the time interval between the administration of a drug and absorption into the body circulation. It is affected by both lipid and water solubility properties of the drug. It affects absorption rate constant. Also affects time taken to attain maximum concentration in the blood and hence onset of action