Pharmacokinetics PDF

Pharmacokinetics Dr. Romany H Thabet, PhD Enjoy pharmacology with positive vibes what the body does to a drug  Pharmacokinetics (PK) The study of the disposition of a drug The disposition of a drug includes the processes of ADME § Absorption § Distribu...

Pharmacokinetics Dr. Romany H Thabet, PhD Enjoy pharmacology with positive vibes what the body does to a drug  Pharmacokinetics (PK) The study of the disposition of a drug The disposition of a drug includes the processes of ADME § Absorption § Distribution § Metabolism Elimination § Excretion § Toxicity ADMET  Absorption Is the transfer of a drug from its site of administration to the bloodstream via one of several mechanisms Transmembrane movement of drugs Passive transfer specialized  The Process n Absorption relies on n Passage through membranes to reach the blood n passive diffusion of lipid soluble species. Absorption & Ionization Non-ionised drug More lipid soluble drug Diffuse across cell membranes more easily  Passive transfer Passive diffusion: small molecules+concent. Gradient (no carrier, no saturation, most of the drugs) Filtration: through pores important in glomerulus. Ø Diffusion: the most important, depends on the drug being: 1- lipid soluble Ø Unionized drug is: lipid soluble and diffusible. Ø N.b.: ionization is dependent on : P.H and pKa of the drug.  Specialized transport 1. Active transport: against electrochemical gradient. Involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Primary active secondary active 2. Facilitated diffusion: doesn’t move against concentration gradient and need a carrier.e.g: glucose. (does not require energy, can be saturated and may be inhibited by compounds that compete for the carrier)  3. Endocytosis (phagocytosis) and exocytosis : engulf large droplets (as; Vitamin B12).  First Pass Metabolism Destroyed Not Destroyed Destroyed in gut absorbed by gut wall by liver to Dose systemic circulation n Bioavailability: the fraction of the administered dose reaching the systemic circulation  Factors influencing absorption 1. Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. A drug passes through membranes more readily if it is uncharged. The effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms.  The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. The lower the pKa of a drug, the more acidic it is. 2. Blood flow to the absorption site: Because 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. [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing the absorption from SC administration.] 3. 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. 4. 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. Note: Parasympathetic input increases the rate of gastric emptying, whereas sympathetic input (prompted, for example, by exercise or stressful emotions) as well as anticholinergics delays gastric emptying.  Also, 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.] 5. Expression of P-glycoprotein: P-glycoprotein is a multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed throughout the body,  Its functions include: A. In the liver: transporting drugs into bile for elimination B. In kidneys: pumping drugs into urine for excretion C. In the placenta: transporting drugs back into maternal blood, thereby reducing fetal exposure to drugs D. In the intestines: transporting drugs into the intestinal lumen and reducing drug absorption into the blood E. In the brain capillaries: pumping drugs back into blood, limiting drug access to the brain. Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance.  parameters Most important pharmacokinetic Bioavailability Volume of distribution clearance  Bioavailability Is the percentage (fraction) of drug released from a formulation that becomes available for biological effect. Factors affecting it: 1. First pass metabolism: definition?????? When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. 2. Solubility of the drug: 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. 3. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. 4. Nature of the drug formulation: For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients can influence the ease of dissolution and, therefore, alter the rate of absorption.  Bioequivalence Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent.  Therapeutic equivalence Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety. Two drugs that are bioequivalent may not be therapeutically equivalent  Distribution n The movement of drug from the blood to and from the tissues  DISTRIBUTION n Determined by: n partitioning across various membranes n binding to tissue components n binding to blood components (RBC, plasma protein) n physiological volumes  DISTRIBUTION n All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: Ø intravascular (blood plasma found within blood vessels) Ø interstitial/tissue (fluid surrounding cells) Ø intracellular (fluid within cells, i.e. cytosol) n The distribution of a drug into these compartments is dictated by it's physical and chemical properties  TOTAL BODY WATER Vascular Extravascular Intracellular 3L 9L 28 L 4% BW 13% BW 41% BW  Distribution After a drug is absorbed, it will distribute between blood and tissues. Is interpretted mathematically as-----Vd (=volume of distribution). Volume of distribution; The apparent (hypothetical) volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). Vd = Amount of drug in the body C0  Importance of Vd 1. Is an estimate of the extent of extravascular tissue uptake of drugs 2. Is important to calculate the size of a loading dose 3. Drugs with high Vd cannot be removed by dialysis 4. Any factor that increases the volume of distribution can lead to an increase in the half- life  Factors affecting Vd 1. Physicochemical properties of the drug 2. Size of tissue and amount of bl. Flow 3. Capillary permeability: the brain, where the capillary structure is continuous, and there are no slit junctions. 4. Binding to plasma proteins (class I and II) 5. Binding to tissue constituents Blood Brain Barrier  Metabolism The process of metabolism transforms lipophilic drugs into more polar readily excretable products. Occurs mainly in --------- liver but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines Types of biotransformation: Phase I phase II Oxidation, conjugation reduction, hydrolysis  METABOLISM From 1898 through to 1910 heroin was marketed as a non- addictive morphine substitute and cough medicine for children. Bayer marketed heroin as a cure for morphine addiction Heroin is converted to morphine when metabolized in the liver  Phases of Drug Metabolism n Phase I Reactions n Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, - COOH, etc.) eg. oxidation n Often these metabolites are inactive n May be sufficiently polar to be excreted readily  Drug Metabolism n The chemical modification of drugs with the overall goal of getting rid of the drug n Enzymes are typically involved in metabolism Metabolism Excretion More polar Drug (water soluble) Drug  Phases of metabolism n Phase II Reactions n Conjugation with endogenous substrate to further increase aqueous solubility n Conjugation with glucoronide, sulfate, acetate, amino acid  Mostly occurs in the liver because all of the blood in the body passes through the liver  The Most Important Enzymes n Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs n Act on structurally unrelated drugs n Metabolize the widest range of drugs.  CYP family of enzymes n Found in liver, small intestine, lungs, kidneys, placenta n Consists of > 50 isoforms n Major source of catalytic activity for drug oxidation n It’s been estimated that 90% or more of human drug oxidation can be attributed to 6 main enzymes: n CYP1A2 CYP2D6 n CYP2C9 CYP2E1 n CYP2C19 CYP3A4 nIndifferent people and different populations, activity of CYP oxidases differs.  Inhibitors and inducers of microsomal enzymes nInhibitors:cimetidine prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs) nInducers:barbiturates, carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents nBlockers: acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)  Important definitions Enzyme inducers; phenobarbital, rifampin, and carbamazepine. Enzyme inhibitors; ketoconazole, omeprazole, erythromycin, cimetidine and grapefruit juice.  Phase II n Main function of phase I reactions is to prepare chemicals for phase II metabolism and subsequent excretion n Phase II is the true “detoxification” step in the metabolism process.  Phase II reactions n Conjugation reactions n Glucuronidation (on -OH, -COOH, -NH2, -SH groups) n Sulfation (on -NH2, -SO2NH2, -OH groups) n Acetylation (on -NH2, -SO2NH2, -OH groups) n Amino acid conjugation (on -COOH groups) n Glutathione conjugation (to epoxides or organic halides) n Fatty acid conjugation (on -OH groups) n Condensation reactions  Phase I and II - Summary n Products are generally more water soluble n These reactions products are ready for (renal) excretion n There are many complementary, sequential and competing pathways n Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathways  Excretion n The main process that body eliminates "unwanted" substances. n Most common route - biliary or renal n Other routes - lung (through exhalation), skin (through perspiration) etc. n Lipophilic drugs may require several metabolism steps before they are excreted ADME - Summary  Kinetics of metabolism 1. First-order kinetics: 2. Zero-order kinetics:  Drug Elimination Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers.  clearance First order kinetics: clearance is directly proportional to the conc.of the drug in the plasma. Zero order kinetics: drug elimination occurs at a constant rate independent of the amount of the drug to be eliminated. E.g; aspirin, ethanol. Saturable kinetics: as theophylline. The drug at first is first order then become zero order.