College Answer

As the general population ages, and many elderly are admitted to intensive care units and/or encountered during intensive care ward consultations, this topic is highly relevant. Unfortunately candidate performance generally lacked sufficient depth and breadth in this area. Good answers were expected to mention changes in body compartments (eg total body water, lean body mass decrease, etc), consequences of changes in organ function (eg deteriorating glomerular filtration rate, reduced liver blood flow, etc), alterations in protein levels and binding, increased likelihood of drug interactions and the influence of disease states.

Syllabus: Generic Pharmacology III2d
References: Millers’ Anaesthesia Chp 19

Discussion

The college answer, while highly critical of trainees, offers little in the way of explaining what precisely was expected from them. Nor are examples offered. One might imagine that a structured answer with examples might have attracted marks. The answer below is offered in the format of [mechanism] = [consequences](example) so as to satisfy the criteria of the answer. A detailed discussion of these issues can be found in the chapter on pharmacokinetics of old age. 

Absorption

• Decreased gastric emptying rate = decreased oral absorption (digoxin, levodopa)
• Increased gastric pH = decreased absorption of drugs which are dependent for pH for their dispersion (enteric-coated drugs); = increased absorption of weak based (methyldopa), decreased absorption of strong acids (amoxycillin)
• Decreased intestinal absorptive surface = age-dependent decrease in drug absorption (indomethacin, prazosin and digoxin)
• Decreased active transport = decreased transport of electrolytes and vitamins (zinc, calcium, folate and B12. )
• Structural changes to stratum corneum = decreased transcutaneous absorption of hydrophilic substances (caffeine, aspirin)
• Poor cutaneous circulation = decreased transcutaneous absorption (clonidine)
• Unpredictable muscle circulation = erratic IM absorption (penicillin)

Distribution

• 10-15% decrease in total body water = decreased Vd for hydrophilic drugs (ethanol, lithium)
• 10-15% increase in total body fat = increased Vd for lipophilic drugs (amiodarone, verapamil)
• Decreased serum albumin = increased free fraction of albumin-bound drugs (phenytoin)
• Increased serum α₁-glycoprotein levels = decreased free fraction of alkaline drugs (metaclopromide, erythromycin)
• P-glycoprotein efflux pump dysfunction = increased permeability of the BBB and this increased  effect-site concentration of CNS drugs (rifampicin, cyclosporin)

Metabolism

• Decreased hepatic tissue mass = decreased clearance by Phase I reactions (ibuprofen, propanolol, fentanyl) but not by Phase II reactions (aspirin, valproate, phenytoin)
• Decreased hepatic blood flow = decreased clearance of high extraction ratio drugs (morphine, verapamil, lignocaine)
• Decreased portal blood flow = increased oral bioavailability of high extraction ratio drugs (propanolol, labetalol)

Elimination

• Decreased glomerular filtration and decreased tubular function = decreased renal clearance of water-soluble drugs and metabolites (β-lactams, aminoglycosides)

Decreased dose response

• Decreased receptor sensitivity = increased dose requirements (β-blockers, adenosine)

Increased dose response

• Increased sensitivity to toxic effects = toxicity at normally safe doses (antimuscarinic drugs, sedatives/hyponotics)
• Decreased homeostatic compensation for drug effects = increased risk of adverse effects, narrowed therapeutic index (eg. antihypertensives and postural hypotension)