Pharmacokinetics - Chapter 1 PDF

‫كلية الصيدلة‬ Pharmacokinetics Chapter 1 ▪ Reference(s): Pharmacology I : ‫اسم المادة‬ Msc. Samar Khater : ‫مدرس المادة‬  Intended Learning Outcomes List the stages of pharmacokinetics List th...

‫كلية الصيدلة‬ Pharmacokinetics Chapter 1 ▪ Reference(s): Pharmacology I : ‫اسم المادة‬ Msc. Samar Khater : ‫مدرس المادة‬  Intended Learning Outcomes List the stages of pharmacokinetics List the major routes of drug administration with their advantages and disadvantages. Describe the factors affecting pharmacokinetic stages and their influence on drug action  Pharmacokinetics refers to? Pharmacokinetic parameters allow the clinician to design and optimize treatment regimens: Route, dose, frequency and duration of treatment  Routes of Drug Administration It is determined primarily by: the properties of the drug and by the therapeutic objectives.  Enteral(by mouth) Oral: Advantages: Disadvantages: Enteric-coated preparations: It is useful for certain groups of drugs, which are these drugs? Extended-release preparations: Extended-release medications (ER) have special coatings or ingredients that control how fast the drug is released from the pill into the body. vs immediate release preparations. It may improve what??  Absorption of Drugs Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and extent of absorption depend on which factors? Which route full absorption , 100% bioavailability ? Mechanism of absorption of a drug from the GI tract The vast majority of drugs gain access to the body by this mechanism Facilitated diffusion: Which chemicals may use this method? ( size of molecule)? Is energy needed? Why is ATP needed in this method? Endocytosis and exocytosis: ❖Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. ❖What kind of drugs are transported by Endocytosis? ❖Exocytosis?  Factors Influencing Absorption 1) Effect of pH on drug absorption Most drugs are either weak acids or weak bases.  The effective concentration is determined by the relative concentrations of the charged and uncharged forms This depends on pH and pka A weak acid is mainly uncharged at which pH? A weak base is mainly uncharged at which pH? 2) Blood flow to the absorption site: Compare Blood flow to the intestine to that of the stomach? absorption from which site is better? 3) Total surface area available for absorption: The intestine has a surface area about 1000-fold that of the stomach So making absorption of the drug across which site more efficient? 4) Contact time at the absorption surface: Why in severe diarrhea, drugs are not well absorbed? What factors may slow gastric emptying time? Drugs, food, stress 5) Expression of P-glycoprotein: What is the location of P-glycoprotein? What is its function in cells? Which tissues It is expressed in? What is its effect on drug absorption? multidrug resistance?  Bioavailability What is bioavailability? How it is determined? Determination of bioavailability  Factors that influence bioavailability 1) First-pass hepatic metabolism: If the drug is rapidly metabolized by the liver or gut wall, what happens to the the amount of unchanged drug entering the systemic circulation? E.g. nitroglycerin by sublingual route? What if drug should be given orally? 2) Solubility of the drug: Very hydrophilic drugs are poorly absorbed, Why? Drugs that are extremely hydrophobic are also poorly absorbed, why? For a drug to be readily absorbed, what is supposed to be? 3) Chemical instability: why Some drugs, such as penicillin G, can not be given orally? such as insulin, can not be given orally? 4) Nature of the drug formulation: 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 vs Therapeutic equivalence When any Two drug formulations are considered bioequivalent? Therapeutic equivalence When any Two drug formulations are considered therapeutically equivalent ? Drug Distribution What is the Drug distribution process? The distribution of a drug depends on the following factors?  1) Blood flow Compare the Blood flow to the brain, liver, and kidney to that of: skeletal muscles. Adipose tissue, skin Viscera Which tissues or organs of the above will receive a higher amount of the drug? 2) Capillary permeability Capillary permeability is determined by: capillary structure and by the chemical nature of the drug. So which drugs readily penetrate into the CNS ? Lipid-soluble drugs or Ionized, polar drugs? Why? 3) Binding of drugs to plasma proteins and tissues Binding to plasma proteins: How does Reversible binding of a drug to plasma proteins affect the diffusion of a dug and its transfer out of the vascular compartment to tissues ? Which plasma protein is the major drug-binding protein ? This binding may act as a drug reservoir. How? Binding to tissue proteins: Why Numerous drugs accumulate in tissues? What is the effect of this on concentrations of drug in tissues compared to the extracellular fluids and blood? Drugs may accumulate as a result of binding to lipids, proteins or nucleic acids. 4) Lipophoilicity: Lipophilic drugs distribute to tissue more than Hydrophilic drugs? Why? Volume of Distribution The apparent volume of distribution, Vd,: is the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.  Distribution into the water compartments in the body Plasma compartment: 1) M.wt ? 2) binding to plasma proteins, ? is effectively trapped within the plasma (vascular) compartment (e.g., Heparin). It has a low Vd that approximates the plasma volume (4 L in a 70-kg individual). Extracellular fluid: If a drug has M.wt ? Hydrophilic or lipophilic? it can move through the endothelial slit junctions of the capillaries into the interstitial fluid (e.g., Aminoglycosides). Therefore, these drugs distribute into a volume that is the sum of the plasma and the interstitial fluid, which together constitute the extracellular fluid (14 L in a 70-kg individual). Total body water: If a drug has a M.wt? is lipophilic or Hydrophilic? it move through the slit junctions, & pass through the cell membranes into the intracellular fluid (e.g., Ethanol). These drugs distribute into a volume of about 42 L in a 70-kg individual Drug Clearance Through Metabolism The three major routes involved for elimination are: 1) hepatic metabolism 2) biliary elimination 3) urinary elimination How do these elimination processes affect the plasma concentration of a drug?  Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic drugs, why? So what must occur to Lipid-soluble agents to become into more polar (hydrophilic) substances? Reactions of Metabolism for drugs occurs mainly in which organ? Phase I and Phase II reactions  Phase I reactions convert lipophilic molecules into more polar molecules how? How does Phase I metabolism affect the drug's pharmacologic activity ? Phase I reactions utilizing the P450 system: Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system.  The P450 system is important for the metabolism of many endogenous compounds (steroids, lipids) and for the biotransformation of xenobiotics. (chemicals not normally produced or expected to be present in the body as a drug, pesticide, or carcinogen that is foreign to a living organism Cytochrome P450 (CYP) is a superfamily of heme- containing iso-enzymes that are located primarily in which organs ??? Genetic variability Variations in P450 activity may alter drug efficacy and the risk of adverse events. examples? Some individuals obtain no benefit from the opioid analgesic codeine? Why? Clopidogrel antiplatelet drug carries a warning that patients who are poor CYP2C19 metabolizers have a higher incidence of CV events when taking it. Explain?  Inducers: Xenobiotics may induce the activity of CYP450– dependent enzymes by inducing the expression of the genes encoding the enzyme or by stabilizing the enzyme. Certain drugs (e.g., phenobarbital, rifampin, and carbamazepine) are capable of increasing the synthesis of one or more CYP isoenzymes. Rifampin, significantly decreases the plasma concentrations of HIV protease inhibitors, thereby diminishing their ability to suppress HIV replication.  Consequences of increased drug metabolism include: 1. plasma drug concentrations? 2. drug activity if metabolite is inactive? 3. drug activity if metabolite is active? 4. therapeutic drug effect? Inhibitors: Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. Omeprazole is a potent inhibitor of three of the CYP isoenzymes responsible for warfarin metabolism. If the two drugs are taken together, what happens to the plasma concentrations of warfarin increase? There is increased risk of what adverse effect? ❑ Natural substances such as grapefruit juice: ❑ inhibits CYP3A4 and lead to higher levels &/or greater potential for toxic effects with drugs ❑ such as nifedipine, clarithromycin & simvastatin, that are metabolized by this system. Phase II: consists of conjugation reactions. ❑If the metabolite from Phase I metabolism is sufficiently polar, how it is excreted? ❑However, many Phase I metabolites are too lipophilic to be retained in the kidney tubules. ❑A subsequent conjugation reaction with an endogenous substrate, such as? ❑What is the result of these conjugations on: ❑ the polarity of compounds ❑ its water-solubility? ❑therapeutic activity? Drug Clearance by The Kidney Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being through the kidney into the urine. Renal elimination of a drug Glomerular filtration: Drugs enter the kidney through renal arteries. Free drug flows through the capillary slits into Bowman space as part of the glomerular filtrate. Proximal tubular secretion: Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions and one for cations. 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. Distal tubular reabsorption: Manipulating the pH of the urine may be used to minimize the amount of back diffusion and increase the clearance of an undesirable drug. Weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. “ion trapping.” 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. Clearance by Other Routes Drug clearance may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed orally or drugs that are secreted directly into the intestines or in bile are eliminated in the feces. The lungs are primarily involved in the elimination of anesthetic gases. Elimination of drugs in breast milk , what is the risk of this route? Excretion of most drugs into sweat, saliva, tears, hair, and skin, are these significant routes of excretion?  Total body clearance The total body clearance, CLtotal or CLt, is the sum of all clearances from the drug-metabolizing and drug- eliminating organs. Half life of a drug (t1/2) The time that is needed to eliminate half (50%) of the drug. When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required.  Clinical situations resulting in changes in drug half-life Patients who may have an increase in drug half-life include those with: 1. diminished renal or hepatic blood flow e.g., heart failure, or hemorrhage; 2. decreased ability to extract drug from plasma e.g., renal disease; and 3. decreased metabolism e.g., in hepatic insufficiency, as with cirrhosis.  The half-life of a drug may be decreased by 1) increased hepatic blood flow, 2) decreased protein binding, 3) increased metabolism.