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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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