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CP4 Clinical Pharmacology
Pharmacokinetics Toronto Notes 2019
Volume of Distribution
• Vd:theapparentvolumeoffluidintowhichadrugdistributes
• maximum actual Vd (anatomic fluid volume accessible to drug) = TBW (TBW~40 L for average adult)
■ a calculated value (Vd) = amount of drug in body ÷ plasma drug concentration
■ a theoretical value that does not correspond to an anatomical space (i.e. can exceed TBW)
■ small Vd corresponds to a drug that concentrates in plasma and/or binds plasma proteins to a high
degree
■ large Vd corresponds to a drug that distributes into tissues (fat, muscle, etc.); most is not in blood
(measured) space, and it therefore “appears” to distribute in a large volume ■ Vd of plasma protein bound drugs can be altered by liver and kidney disease ■ Vd of drugs change with age
◆ in geriatric populations, there is a reduction in total body water and total muscle mass, but an increase in total body fat resulting in an increase in the Vd of lipophillic drugs
◆ Vd of drugs will change in the geriatric population based on the drug Po/w
• example: amiodarone distributes into TBW (actual Vd ~40 L), but it concentrates in fat tissues yielding an apparent Vd of 400 L; therefore, to achieve a given plasma concentration of amiodarone, we dose as
though the drug distributes into 400 L of body fluid
Plasma Protein Binding
• drugmoleculesinthebloodexistinanequilibriumoftwoforms:
1. bound to plasma protein: acidic drugs bind to albumin, basic drugs bind to α1-acid glycoprotein 2. free or unbound: can leave the circulation to distribute into tissues and exert an effect, subject to
metabolism and elimination
• boundfractionisdeterminedbydrugconcentration,bindingaffinity,andplasmaproteinconcentration
(number of binding sites)
• reducednumberofbindingsites(e.g.hypoalbuminemia)orsaturationofbindingsites(e.g.
competition/displacement) may result in increased concentration of free drug, which is often metabolized with no harmful effects, although toxicity is possible
Depots
• abodycompartmentinwhichdrugmoleculestendtobestoredandreleasedslowlyoveralongperiod of time
• fatisadepotforverylipidsolubledrugs(e.g.diazepam)
• someoil-basedmedicationsareinjectedIMforslowrelease(e.g.depotmedroxyprogesteroneacetate
q3mo; depot risperidone q2wk)
Barriers (relative)
• bodystructuresthatlimitorpreventdiffusionofdrugmolecules,suchastheplacentaorBBB(abarrier composed of tight junctions between capillary endothelial cells and astrocytes)
• manyofthesebarriersresult,inpart,fromtheactivityofmultidrugeffluxpumps(e.g.Pgp),which serve as a natural defense mechanism against drugs and xenobiotics
• needtoconsiderdosingrouteifdrugsaremeanttocrossthesebarriers
• barriersareimportantindeterminingsiteofactionandsideeffectsprofileofdrugs(e.g.CNS
depression if drug crosses BBB, risk of harm to a fetus if drug crosses placental barrier)
Metabolism (Biotransformation)
• definition:chemicaltransformationofadruginvivo
• sitesofbiotransformationincludeliver(main),GItract,lung,plasma,kidney
• asaresultoftheprocessofbiotransformation:
■ an inactive prodrug may be activated (e.g. tamoxifen to endoxifen; codeine to morphine)
■ a drug may be changed to another active metabolite (e.g. diazepam to oxazepam and others) ■ a drug may be changed to a toxic metabolite (e.g. meperidine to normeperidine)
■ a drug may be inactivated (most drugs)
Drug Metabolizing Pathways
• phaseI(P450)reactions
■ minor molecular changes introduce or unmask polar groups on a parent compound to increase
water solubility (e.g. oxidation-reduction, hydrolysis, hydroxylation, demethylation); the change in Po/w is typically minimal compared to phase II, and often phase I places a polar ‘handle’ on a lipophilic drug to allow for phase II
■ mediated by CYPs found in the endoplasmic reticulum (primarily in hepatocytes)
■ product of the reaction can be excreted or undergo further phase II reactions • phaseII(conjugation)reactions
■ conjugation with large polar endogenous substrates (e.g. glucuronidation, glutathione conjugation, sulfation)
■ dramatically increases water solubility and renal elimination
■ can result in biologically active metabolites (e.g. glucuronides of morphine)
■ can occur independently of phase I reactions
Multiple drugs and endogenous substances can compete for the same protein binding sites. For example, ASA displaces highly protein-bound acidic drugs such as phenytoin, thus increasing risk of toxicity, and sulfonamide displaces bilirubin, which could potentially lead to jaundice and kernicterus
in neonates
Special consideration must be given in dosing patients in hypoalbuminemic states (e.g. liver failure or nephrotic syndrome) to prevent drug toxicity. Highly protein-bound drugs (e.g. warfarin, digoxin, diazepam, furosemide, amitriptyline) will exert a greater effect in these patients than in healthy individuals because of higher levels of free drug
Main Factors Governing Penetration of BBB
• Small molecular size (<500 Da) • High lipid solubility
• Active transport mechanisms
(e.g. Pgp efflux pump)