Question 20

Created on Mon, 07/10/2017 - 03:48
Last updated on Tue, 12/26/2017 - 04:39
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Outline the pharmacokinetic consequences of old age. Illustrate your answer with examples.

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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)

References

Jansen, Paul AF, and Jacobus RBJ Brouwers. "Clinical pharmacology in old persons." Scientifica 2012 (2012).

Turnheim, Klaus. "When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly." Experimental gerontology 38.8 (2003): 843-853.

Turnheim, Klaus. "Drug dosage in the elderly." Drugs & aging13.5 (1998): 357-379.

EVANS, MARK A., et al. "Gastric emptying rate in the elderly: implications for drug therapy." Journal of the American Geriatrics Society 29.5 (1

Russell, Tanya L., et al. "Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women." Pharmaceutical research 10.2 (1993): 187-196.

Merfeld, A. E., et al. "The effect of pH and concentration on α‐methyldopa absorption in man." Journal of pharmacy and pharmacology 38.11 (1986): 815-822.

Holt, Peter R. "Intestinal malabsorption in the elderly." Digestive Diseases 25.2 (2007): 144-150.

Bender, A. Douglas. "Effect of age on intestinal absorption: implications for drug absorption in the elderly." Journal of the American Geriatrics Society 16.12 (1968): 1331-1339.

Kaestli, Laure-Zoé, et al. "Use of transdermal drug formulations in the elderly." Drugs & aging 25.4 (2008): 269-280.

Holdsworth, Mark T., et al. "Transdermal fentanyl disposition in elderly subjects." Gerontology 40.1 (1994): 32-37.

Roskos, Kathleen V., Howard I. Maibach, and Richard H. Guy. "The effect of aging on percutaneous absorption in man." Journal of Pharmacokinetics and Pharmacodynamics 17.6 (1989): 617-630.

Klein, C., et al. "Transdermal clonidine therapy in elderly mild hypertensives: effects on blood pressure, plasma norepinephrine and fasting plasma glucose." Journal of hypertension. Supplement: official journal of the International Society of Hypertension 3.4 (1985): S81-4.

Kentala, Erkki, Timo Kaila, and Jussi Kanto. "Intramuscular atropine in elderly people: pharmacokinetic studies using the radioreceptor assay and some pharmacodynamic responses." Basic & Clinical Pharmacology & Toxicology 65.2 (1989): 110-112.

Divoll, Marcia, et al. "Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex." Anesthesia & Analgesia 62.1 (1983): 1-8.

Collart, P., et al. "Kinetic study of serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people." Sexually Transmitted Infections 56.6 (1980): 355-362.

Dube, A. H. "A comparison of serum concentrations produced by phenethicillin, penicillin V, and penicillin G after oral and intramuscular administration in geriatric patients." Antibiotics & Chemotherapy 11.10 (1961): 625-9.

GREENBLATT, DAVID J. "Reduced serum albumin concentration in the elderly: a report from the Boston Collaborative Drug Surveillance Program." Journal of the American Geriatrics Society 27.1 (1979): 20-22.

Routledge, PhA. "The plasma protein binding of basic drugs." British journal of clinical pharmacology 22.5 (1986): 499-506.

Le Couteur, David G., and Allan J. McLean. "The aging liver." Clinical pharmacokinetics 34.5 (1998): 359-373.

Mangoni, Arduino A., and Stephen HD Jackson. "Age‐related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications.British journal of clinical pharmacology 57.1 (2004): 6-14.

Toornvliet, Rolf, et al. "Effect of age on functional P‐glycoprotein in the blood‐brain barrier measured by use of (R)‐[11C] verapamil and positron emission tomography." Clinical Pharmacology & Therapeutics 79.6 (2006): 540-548.

Sun, Haiying, et al. "Drug efflux transporters in the CNS." Advanced drug delivery reviews 55.1 (2003): 83-105.