Pharmacokinetics PDF

Pharmacology The science that deals with drugs. Pharmacokinetics of Drugs: Absorption, distribution, metabolism, and excretion. Pharmacodynamics of Drugs: Drug actions, mechanism of action, and adverse effects of drugs. Pharmacokinetics of Drugs  First, drug absorption from the site o...

Pharmacology The science that deals with drugs. Pharmacokinetics of Drugs: Absorption, distribution, metabolism, and excretion. Pharmacodynamics of Drugs: Drug actions, mechanism of action, and adverse effects of drugs. Pharmacokinetics of Drugs  First, drug absorption from the site of administration (Absorption) permits entry of the therapeutic agent into plasma. Second, the drug may then reversibly leave the blood stream and distribute into the interstitial and intracellular fluids (Distribution). Third, the drug may be metabolized by the liver, kidney, or other tissues (Metabolism). Finally, the drug and its metabolites are removed from the body in urine, bile, or feces (Elimination). Schematic representation of drug absorption, distribution, metabolism, and elimination.  Absorption of Drugs Absorption is the transfer of a drug from its site of administration to the blood stream. Mechanisms of transport of drugs across cell membranes: 1. Passive diffusion: The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments; the drug moves from a region of high concentration to one of lower concentration. The vast majority of drugs gain access to the body by this mechanism. Lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane bilayers. 2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells, moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. This type of diffusion does not require energy, can be saturated.  Schematic representation of drugs crossing a cell membrane of an epithelial cell of the gastrointestinal tract. ATP = adenosine triphosphate; ADP = adenosine diphosphate. 3. Active transport: This mode of drug entry also 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. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, that is, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier. 4. Endocytosis: This type of drug delivery transports drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. For example, vitamin B is transported across the gut wall by endocytosis. Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release an H + causing a charged anion (A). However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B). Passage of an uncharged drug through a membrane. A drug passes through membranes more readily if it is uncharged Thus, for a weak acid, the uncharged HA can permeate through membranes, and A cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH does not. Therefore, 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 pka. (Henderson-Hasselbalch equation) A. Diffusion of the non-ionized form of a weak acid through a lipid membrane. B. Diffusion of the nonionized form of a weak base through a lipid membrane. This equation is useful in determining how much drug will be found on either side of a membrane that separates two compartments that differ in pH—for example, stomach (pH 1.0- 1.5) and blood plasma (pH 7.4). [Note: The lipid solubility of the non-ionized drug directly determines its rate of equilibration.]