WS08- Elderly PK changes prep Pharmacokinetics Absorption Least affected by age Reduced absorption of drugs which require active

ve transport e.g. Vit B12 Reduced first-pass metabolism due to reduced liver function/perfusion/enzymes o So drugs which are metabolised a lot (high extraction drugs) will get a boost in the bioavailability o But prodrugs which need to be activated first wont do as well Changes to gut physiology o Reduced perfusion (absorption gradients arent as good) o Decreased gut motility, leading to longer emptying times (so time to Tmax is increased) Changes to perfusion o Reduced absorption from IM or SC Distribution Protein binding altered, two main binding proteins: o Albumin- binds acid drugs Amount decreases with age, increased free fraction E.g. Warfarin, phenytoin o Alpha 1-glycoprotein- binds basic drugs Amount increases with age, reduced free fraction E.g. lidocaine Altered volume of distribution o Decrease in body water, increase in body fat o Hydrophilic drugs have a decrease in Vd, lipophilic drugs have an increase in Vd Special case: digoxin o Has a high Vd due to binding to sites in muscles o Vd is lowered with age due to less muscle being present o Compounded by the fact that renal insufficiencies can cause a buildup of substances which can outcompete digoxin for these sites Metabolism Liver is changed: o Reduced liver mass (less liver present) o Reduced blood flow The reduced blood flow is a worry, because high capacity drugs like propranolol will be metabolised less o Remember: high capacity drugs are limited in metabolism by flow rate Low capacity drugs arent affected as much, reducing flow rate doesnt affect it significantly BUT in saying that, we also need to consider the enzymes o Phase I enzymes (i.e. the CYP enzymes) MIGHT decrease with age, leading to longer half-lives of benzos o Phase II enzymes are untouched, too important. Excretion Reduced renal activity leads to water soluble drugs being excreted less, their clearance reduces, half-life increases

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Use creatinine clearance to make dose adjustments as required E.g. digoxin clearance is affected by a change creatinine clearance

Pharmacodynamics A bit less understood, but probably due to changes in the fact that the elderly may express less receptors (i.e. lower receptor density) at the target tissue (reduced effects) or reduced homeostatic mechanisms (cant correct properly for the small changes drugs make so the elderly are more at risk of ADRs) Examples: o Cardiovascular- beta blockers become less selective (because beta 1 receptor density reduces), no rebound tachycardia with short acting calcium channel blockers (baroreceptors are less sensitive in the elderly) Reminder: calcium channel blockers need to be given as extended release, because short use will cause rebound tachycardia. o CNS- more vulnerable to sedation and anticholinergic effects Very, very important as its a falls risk Start very low, go very slow Avoid if possible (e.g. avoid benzos) Nortryptiline is the best choice for the elderly, lowest anticholinergic effects