Pharmacokinetics Presentation PDF

Pharmacokinetics Overview What is Pharmacokinetics? Pharmacokinetics refers to the study of drug movement through the body. Includes the processes of: - Absorption - Distribution - Metabolism - Excretion (ADME)  Absorption The process of a drug entering the bloodstream from its site of adminis...

Pharmacokinetics Overview What is Pharmacokinetics? Pharmacokinetics refers to the study of drug movement through the body. Includes the processes of: - Absorption - Distribution - Metabolism - Excretion (ADME)  Absorption The process of a drug entering the bloodstream from its site of administration. Key factors influencing absorption: 1. Drug properties (e.g., ionization, polarity, lipid solubility) 2. Route of administration 3. Blood flow to absorption site 4. Surface area for absorption 5. Contact time at the absorption surface Note: Intravenous administration bypasses absorption. Mechanisms of Absorption A drug passes through membranes more readily if it is uncharged. For a weak acid, the uncharged, protonated HA can permeate through membranes, and A − cannot. For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Bioavailability Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. The importance of Bioavailability The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect.  Bioavailability measures how much of a drug actually reaches the bloodstream and is available for use by the body after it’s given. It’s compared to the ideal case, which is IV (intravenous) administration Determination of because IV delivers 100% of the drug directly into the blood. To determine bioavailability: Drug levels in the blood are measured over time after giving it by a certain bioavailability: route (like oral). A graph of these levels is plotted, and the area under the curve (AUC) is calculated. AUC shows how much of the drug is absorbed. The bioavailability of an orally given drug is calculated by comparing its AUC to the AUC of the same drug given through IV. Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration with levels achieved by IV administration. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. AUC reflects the extent of absorption of the drug. Bioavailability of a drug given orally is the ratio of the AUC following oral administration to the AUC following IV administration Therapeutic range: minimum effective concentrations (MEC) to the minimum toxic concentration (MTC) Distribution The reversible transfer of a drug from the bloodstream to tissues and organs. Key factors: - Blood flow - Capillary permeability - Binding to plasma proteins and tissues - Lipophilicity of the drug - Volume of distribution (Vd) Blood Flow: The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of Propofol. High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained. Capillary permeability Binding of drugs to plasma proteins and tissues 1. Binding to plasma proteins Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows transfer out of the vascular compartment. Albumin is the major drug-binding protein, and it may act as a drug reservoir. 2. Binding to tissue proteins Lipophilicity The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions. Volume of distribution The apparent volume of distribution, Vd, is defined 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). Metabolism The chemical alteration of drugs to aid in elimination. Occurs primarily in the liver and involves: - Phase I: Oxidation, reduction, or hydrolysis to introduce or unmask functional groups. - Phase II: Conjugation with endogenous molecules (e.g., glucuronic acid) to enhance solubility. CYP450 enzymes play a major role in Phase I metabolism. Phase I Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually involve reduction, oxidation, or hydrolysis. Phase metabolism may increase, decrease, or have no effect on pharmacologic activity. Phase II This phase consists of conjugation reactions. If the metabolite from phase I is sufficiently polar, it can be excreted by the kidneys. many phase I metabolites are still too lipophilic to be excreted. A subsequent 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 often therapeutically inactive. A notable exception is morphine-6-glucuronide Excretion The removal of drugs and their metabolites from the body. Main routes of excretion: - Renal (urine) - Hepatic (bile, feces) - Other (sweat, breast milk, exhalation) Processes include filtration, secretion, and reabsorption in the kidneys. Half-Life and Kinetics Half-life (t1/2): Time required to reduce the drug concentration by half. Kinetics: - First-order: Constant fraction metabolized per unit time. - Zero-order: Constant amount metabolized per unit time. Dosing adjustments may be required for patients with liver or kidney dysfunction.