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Pharmacokinetics
BMS263
| Term | Definition |
|---|---|
| Pharmacokinetics | How the body acts on (processes) the drug. 4 phases: Absorption, Distribution & storage, Metabolism, and Excretion |
| Absorption and Distribution of Drug | Drug needs to achieve adequate concentration in target tissue to work & can be determined by drug translocation & chemical transformation. Drug concentration depends on bulk flow transfer & diffusion. Requires movement across cell membrane |
| Movement Across Cell Mmebrane | Required for absorption, distribution, & storage. Movement influenced by molecule size, lipid solubility, ionisation. 4 main ways small molecules cross: Direct & facilitated (through channels) diffusion, combine with solute carrier molecules & pinocytosis |
| Carrier-Mediated Transport | Specialised transport mechanisms that regulate transport of sugars, amino acids, neurotransmitters & metal ions either by: Facilitated diffusion or Active Transport. # of available pumps can limit movement of specific substances eg. saturation kinetics |
| Diffusion through Lipid Bilayer | Determined by diffusion gradient and physiochemical properties of drug. For efficient translocation across cell membranes drugs must mix well with lipid & move easily within the bilayer |
| Partition Coefficient | Ratio of drug in lipid versus aqueous phase |
| Diffusivity | Measure of the mobility of molecules within the lipid expressed as diffusion coefficient. Doesn’t tend to vary much between different drugs |
| Lipid Solubility | Important determinant of drug pharmacokinetics, expressed as partition coefficient. Largely determines the rate of drug absorption from the gut, penetration into the brain, and rate of renal elimination |
| Permeability Coefficient | A measure of how well drugs diffuse through the lipid bilayer (number of molecules crossing certain area of membrane in a given time) |
| pH & Ionisation | Most drugs are considered weak acid/ bases & partially dissociate. Depends on pH of solution. Most drugs ionised at physiological pH. Ionisation affects steady-state distribution of drug molecules between aqueous compartments of differing pH |
| Digestive Tract Absorption | Small intestine remains the main site of absorption for drugs, due to the relatively large surface area of the small intestines compared to the stomach |
| Urinary Acidification | Inhibits renal absorption and accelerates elimination of weak bases. Allows renal absorption and retard elimination of weak acids |
| Urinary Alkalinisation | Inhibit renal re absorption and accelerates elimination of weak acids. Allows re absorption of weak bases and retard elimination of weak bases |
| Drugs Bound to Plasma Protein | Many drugs exist mainly in bound form. Binding to plasma proteins renders drug inactive. Albumin important plasma protein often binds to drugs. Binding depends on: Drug concentration, Affinity for binding sites, Plasma protein concentration |
| Drug Storage in Body Fat | Fat represents a large, non-polar compartment. Important for few drugs. Low blood flow in fat tissue. E.g. Morphine has F:W ratio of 0.4 while thiopentol has 10 ratio. So thiopental accumulates in body fat limiting its effect as IV anaesthetic |
| Absorption | Passage of drug from site of administration into plasma. Depends on route of administration. Influenced by: rate of dissolution (How fast the drug dissolves) & surface area of membrane (e.g. small intestine) |
| First Pass Metabolism | Involves GI & hepatic metabolism. Enzymes in GIT wall. After a drug is absorbed from GIT, it is delivered to the liver via the portal circulation. Orally administered drugs metabolised in the liver therefore undergo this process |
| Bioavailability | The amount of the drug that actually reaches systemic circulation as a % of the administered dose. IV administration = 100%, whereas oral and other routes vary |
| Distribution | Influenced by 3 factors: Blood flow (how much drug actually reaches target site), Ability to leave blood (only free i.e. unbound drug can leave blood + blood-CSF barrier is only permeable to lipid soluble drugs) & Ability to enter target organ |
| Equilibrium Distribution | The equilibrium pattern of distribution between the various compartments depend on: Permeability across tissue barriers, Binding within compartments, pH partition, & Fat:water partition |
| Drug Elimination | Elimination is the irreversible loss of active drug, it occurs by metabolism and excretion. Most importantly occurs via urinary system, but can also occur via hepatobiliary system, lungs or milk |
| Metabolism | Enzymatic conversion of one chemical into another |
| Excretion | Removal of chemically unchanged drug &/or its metabolites |
| Drug Metabolism | Predominately in liver. 2 phases: 1. Chemical reaction. Drugs sometimes more active than original drug. Mainly in liver using P450 enzymes; 2. Synthetic or anabolic reactions- inactivates drug. Both reduce lipid solubility & increase urinary excretion |
| Body Fluid Compartments | Body water varies from 50-70% (less in women). ECF (21.7% approx), ICF (30-40%) & Transcellular (2.5% includes CSF, cellular barriers between ICF & ECF, free & bound forms of drugs, dissociation of weak acid/base into charged & uncharged forms) |
| Consequences of Metabolism | Drug inactivation; Increase or change in drug action; Activation of a prodrug; Alteration of drug toxicity |
| Drug Recycling | Occurs in Enterohepatic circulation. Hydrophilic drugs conjugate with glucouoronides & secret via bile in GIT. Hydrolysis occurs releasing active drug AGAIN. Then reabsorbed from GIT. Cycle repeats. Prolongs drug action. 20% drug reservoir. E.g. morphine |
| Renal Excretion | Depends on glomerular filtration, tubular secretion and reabsorption. pH dependent ionization(weak acids & basic drugs change ionization with changing pH) OR Competition for active tubular reabsorption, & Age |
| Renal Clearance | Vol of plasma containing amount of substance that is removed from body by the kidneys in unit of time. Formula = Urinary Vol x Urinary Concentration / Plasma Concentration |
| Time Course of Responses | Drug enters blood, reaches peak concentration. Then decreases as its cleared. Faster the clearance, less time it remains in body (determines frequency of admin of drug) |
| Half-Life | Term used to express clearance rate of a drug. Time taken to reduce concentration of drug by 50%. Important for dosages and measuring intervals for repeat doses. Different drugs in therapeutic classes may differ |
| 1st Order Kinetics | Rate of clearance is determined by the concentration of the drug e.g. plasma drug concentration peaks quickly and clears quickly |
| Zero Order Kinetics | The clearance is dependent on the availability of enzymes to breakdown the drug. E.g. Alcohol |
| ED50 | Effective dose for half the population |
| LD50 | Lethal dose for half the population |
| Therapeutic Index | The higher it is, the safer it is. Therefore, Lower = toxic |
Created by:
Mandyrox300
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