Pharmacokinetic and Pharmacodynamic Changes in Aging

1. Pharmacokinetic and Pharmacodynamic Changes in Aging Maggie Moy, PharmD UCSF Medical Center

2. Objectives • Overview of the main age-related physiologic changes relevant to pharmacology • Understand pharmacokinetic changes with aging and the influence on drug effects • Understand pharmacodynamics changes with aging and the influence on drug effects

3. Definitions • Pharmacokinetics • How the body affect the drugs • A.D.M.E • Pharmacodynamics • How the drugs affect the body

4. Pharmacokinetic changes in aging - Absorption • Reduced GI motility and blood flow • Decreased gastric acid secretion • Absorption of most drugs from GI tract is largely unchanged • Absorption from transdermal, SQ or IM route may decrease due to decreased blood perfusion in elderly

5. Pharmacokinetic changes in aging - Distribution • Lean body mass decreases, total body water decreases • For hydrophillic drugs, volume of distribution (Vd) decreases and results in higher plasma concentration • Use of diuretics may further increase plasma concentration

6. Pharmacokinetic changes – Distribution (con’t) • Total body fat increases • For lipophilic drugs, Vd increases • Half-life is directly proportional to Vd, half-life of lipophilic drugs increase • Longer time needed to reach steady state, and longer time needed to clear drugs • Age-related protein binding changes are not clinically significant

7. Pharmacokinetic changes - Metabolism • LFTs do not change significantly, but serum albumin slightly decreases • Hepatic blood flow, liver size and mass decrease • In vitro, oxidative enzyme (phase I pathway) activity and amount are unchanged • In vivo, phase I metabolic clearance of some drugs are reduced by aging, while some are not

8. Pharmacokinetic changes – Metabolism (con’t) • Apparently irrespective of which CYP enzyme is involved, but related to the extraction ratio • High extraction ratio drugs - decreased metabolism • Low extraction ratio drugs – unchanged • High interindividual variation in CYP enzymes activity • Conjugation (phase II pathway) is unchanged • Example: benzodiazepines

9. Pharmacokinetic changes – Excretion • Number of functional glomeruli starts to decrease after the age of 40 • Renal blood flow and tubular secretion decreases • GFR decrease by 25-50 % between the ages of 20 and 90 • Effects on clearance of hydrophilic drugs • Effects on nephrotoxicity

10. Pharmacokinetic changes – Excretion • Role of serum creatinine in predicting renal function • Muscle mass decreases with aging, and creatinine production decreases • GFR may have decreased while serum creatinine is unchanged

11. Pharmacodynamic changes • Elderly patients often have altered sensitivity to drugs due to changes in: • Receptor / neurotransmitter • Signal transduction • Homeostatic mechanism

12. Pharmacodynamic changes • Neurologic system • Common age-related changes: decrease brain mass, number of neurons and synapses • Reduction in dopamine contents and dopamine receptors in CNS –  risk of EPS from dopaminergic blockade • Reduction in cholinergic neurons and receptors –  risk of adverse effects from anticholinergics

13. Pharmacodynamic changes • Neurologic system (con’t) • Functional P-glycoprotein activity decreases at the blood-brain barrier -  exposure of drugs at the brain • Increased GABA receptor signaling efficacy -  sensitivity to sedative-hypnotics, anesthetics, propofol. • Increased risk of over-sedation, impaired cognition, confusion, delirium

14. Pharmacodynamic changes • Cardiovascular system • Common age-related changes: decreased elasticity of vessels, cardiac reserve, and sensitivity of baroreceptors • Greater BP effect from DHP CCB in treatment-naïve elderly, but effect is transient • Greater drop in BP and HR in response to non-DHP CCB, while prolongation of PR interval is less • Decreased response to agents acting on  receptors • No age-related changes in  response

15. Pharmacodynamic changes • Cardiovascular agents (con’t) • Decreased diuretic and natriuretic effects from diuretics, but higher systemic toxicity • Greater sensitivity to nitrates • ACE inhibition does not deteriorate with age • Overall increased sensitivity to medications that affect blood pressure • Higher risk of orthostasis • Higher risk of fall

16. Pharmacodynamic changes • Hematologic system • Warfarin: increased inhibition of vitamin-K dependent clotting factors • Heparin: no change in relationship between plasma level and anticoagulant effect • Cell density of the bone marrow decreases -  sensitivity to bone marrow suppressing medications

17. Pharmacodynamic changes • Endocrine system •  insulin secretion and insulin sensitivity with aging • decreased glucose tolerance • Glucose counter-regulation is also impaired • Higher risk of hypoglycemia from sulfonylurea • Respiratory system • Decreased lung elasticity, vital capacity, and respiratory muscle strength • Increases sensitivity to respiratory depression from opiates, BZD etc

18. Conclusion • Aging causes pharmacokinetic and pharmacodynamic changes in elderly patients • Increased sensitivity to medication effects • Nervous system and cardiovascular systems are most affected by pharmacodynamics changes • Increase risk of delirium and fall • Start low and go slow!

19. Reference • Kane RL, Ouslander JG, Resnick B, Malone ML. Essentials of Clinical Geriatrics, 8th Ed, McGraw Hill; 2018 • Bowie MW, Slattum PW. Pharmacodynamics in older adults: a review. The American Journal Geriatric Pharmacotherapy. 2007; 5:263-303. • Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications. Clinical Pharmacokinetics. 1998; 35:49-64. • Mangoni AA, Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical application. British Journal of Clinical Pharmacology. 2003; 57:6-14. • Turnheim, K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Experimental Gerontology. 2003; 38:843-853. • Welker KL, Mycyk MB. Pharmacology in the geriatric patient. Emergency Medicine Clinics of North America. 2016; 34:469–481