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2. How Pharmacokinetic and Pharmacodynamic Changes in the Elderly Affect Prescribing
Sandra A. Jacobson, M.D.
Research Associate Professor
University of Arizona College of Medicine Phoenix

3. Absorption
Receptor effects
Distribution
Metabolism
Elimination

4. Absorption
Receptor effects
Distribution
Metabolism
Elimination

5. Absorption
Receptor effects
Distribution
Metabolism
Elimination

6. Absorption
Receptor effects
Distribution
Metabolism
Elimination

7. Absorption from the gut is an active process
Slower with
Aging
Use of antacids or bowel medications
The extent of absorption is relatively unaffected by aging
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

8. Absorption from the gut is an active process
Slower with
Aging
Use of antacids or bowel medications
The extent of absorption is relatively unaffected by aging
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

9. Absorption from the gut is an active process
Slower with
Aging
Use of antacids or bowel medications
The extent of absorption is relatively unaffected by aging
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

10. Parenteral dosing
Avoided in the geriatric population

11. Parenteral dosing
Avoided in the geriatric population IV
Can cause peak effects

12. Parenteral dosing
Avoided in the geriatric population IV
Can cause peak effects IM
Painful in those with small muscle mass
Erratic absorption

13. Distribution
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

14. Significantly affected by aging
Distribution
Significantly affected by aging
Lean body mass decreases
Relative increase in fat stores (even in thin individuals)
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

15. Fat-soluble drugs Water-soluble drugs
Fat storage site
Fat-soluble drugs
With repeated dosing, drugs can accumulate in fat
Subsequent release can be erratic
Half-life: directly proportional to volume of distribution
Lipophilic drugs: longer half-life in geriatric patients
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

16. Fat-soluble drugs Water-soluble drugs Fat storage site
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

17. Fat-soluble drugs Water-soluble drugs Fat storage site
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

18. Fat-soluble drugs Water-soluble drugs Fat storage site
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

19. Fat-soluble drugs Water-soluble drugs
Fat storage site
Fat-soluble drugs
With repeated dosing, drugs can accumulate in fat
Subsequent release can be erratic
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

20. Fat-soluble drugs Water-soluble drugs
Fat storage site
Fat-soluble drugs
With repeated dosing, drugs can accumulate in fat
Subsequent release can be erratic
Half-life: directly proportional to volume of distribution
Lipophilic drugs: longer half-life in geriatric patients
Water storage site
Water-soluble drugs
Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993

21. Phase I Phase II Oxidation: CYP450 enzymes
Glucuronidation: UGT enzymes (liver and small intestine)
Liston HL, Markowitz JS, DeVane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21: , 2001

22. Phase I Phase II Oxidation: CYP450 enzymes
Significantly affected by normal aging
Glucuronidation: UGT enzymes (liver and small intestine)
Not affected by normal aging
Medications metabolized through glucuronidation are preferred in geriatrics
Liston HL, Markowitz JS, DeVane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21: , 2001

23. Phase I Phase II Oxidation: CYP450 enzymes
Significantly affected by normal aging
Glucuronidation: UGT enzymes (liver and small intestine)
Not affected by normal aging
Two important isoenzymes: CYP1A2 and CYP3A4
CYP3A4: most clinically relevant
Medications metabolized through glucuronidation are preferred in geriatrics
Liston HL, Markowitz JS, DeVane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21: , 2001

24. Aging affects the liver

25. Aging affects the liver
Slower metabolism and clearance (varies)

26. Aging affects the liver
Slower metabolism and clearance (varies)
Liver function tests:
Poorly correlated with metabolizing activity

27. Elimination or clearance

28. Major determinant of the steady-state plasma concentration
Elimination or clearance

29. Elimination or clearance
Major determinant of the steady-state plasma concentration
P-glycoprotein: action as efflux pump

30. Aging
Reduction of pump function , hepatic blood flow and renal clearance

31. Aging Reduced clearance
Reduction of pump function , hepatic blood flow and renal clearance
Reduced clearance
Increased steady-state drug concentration
Greater therapeutic and toxic effects
Can be offset by a reduction in dosing rate
The reason for the start low and go slow rule

32. Aging Reduced clearance
Reduction of pump function , hepatic blood flow and renal clearance
Reduced clearance
Increased steady-state drug concentration
Greater therapeutic and toxic effects
Can be offset by a reduction in dosing rate

33. Aging Reduced clearance
Reduction of pump function , hepatic blood flow and renal clearance
Reduced clearance
Increased steady-state drug concentration
Greater therapeutic and toxic effects
Can be offset by a reduction in dosing rate
The reason for the start low and go slow rule

34. Kidney excretion
Rate determined by GFR

35. Kidney excretion Rate determined by GFR
GFR is reported when creatinine is ordered

36. Kidney excretion Rate determined by GFR
GFR is reported when creatinine is ordered
If no GFR: MDRD equation online

37. Kidney excretion Rate determined by GFR
GFR is reported when creatinine is ordered
If no GFR: MDRD equation online
Patient’s age, gender, ethnicity and serum creatinine

38. Half-life, Volume of Distribution and Clearance
0.693.𝑉𝑑 𝐶𝐿
t1/2=

39. Half-life, Volume of Distribution and Clearance
0.693.𝑉𝑑 𝐶𝐿
t1/2=

41. After 4 to 5 times the half-life

42. Time to steady state

43. Pharmacodynamics
Elderly patients have greater psychotropic drug effects than younger patients given the same dose of medication
Greater sensitivity to drugs
Higher drug concentrations at CNS receptors
Baseline differences
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

44. Pharmacodynamics
Elderly patients have greater psychotropic drug effects than younger patients given the same dose of medication
Greater sensitivity to drugs
Higher drug concentrations at CNS receptors
Baseline differences
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

45. Pharmacodynamics
Elderly patients have greater psychotropic drug effects than younger patients given the same dose of medication
Greater sensitivity to drugs
Higher drug concentrations at CNS receptors
Baseline differences
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

46. Receptor changes with aging
Reduction in
M1 receptor signal transduction
Acetylcholinesterase activity
Increased sensitivity to anticholinergic effects
Even small doses can be problematic
Diphenhydramine and related drugs
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

47. Receptor changes with aging
Reduction in
M1 receptor signal transduction
Acetylcholinesterase activity
Increased sensitivity to anticholinergic effects
Even small doses can be problematic
Diphenhydramine and related drugs
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

48. Receptor changes with aging
Reduction in
M1 receptor signal transduction
Acetylcholinesterase activity
Increased sensitivity to anticholinergic effects
Even small doses can be problematic
Diphenhydramine and related drugs
Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011

49. Key Points
Normal aging does not affect glucuronidation (but affects oxidation)
Medications metabolized through glucuronidation are preferred in the elderly
“Start low and go slow” rule
By reducing the dosing rate, you can counteract reduced drug clearance
Greater psychotropic effects in the elderly
Greater drug sensitivity, higher CNS concentration and baseline differences

50. Key Points
Normal aging does not affect glucuronidation (but affects oxidation)
Medications metabolized through glucuronidation are preferred in the elderly
“Start low and go slow” rule
By reducing the dosing rate, you can counteract reduced drug clearance
Greater psychotropic effects in the elderly
Greater drug sensitivity, higher CNS concentration and baseline differences

51. Key Points
Normal aging does not affect glucuronidation (but affects oxidation)
Medications metabolized through glucuronidation are preferred in the elderly
“Start low and go slow” rule
By reducing the dosing rate, you can counteract reduced drug clearance
Greater psychotropic effects in the elderly
Greater drug sensitivity, higher CNS concentration and baseline differences

52. Key Points
Normal aging does not affect glucuronidation (but affects oxidation)
Medications metabolized through glucuronidation are preferred in the elderly
“Start low and go slow” rule
By reducing the dosing rate, you can counteract reduced drug clearance
Greater psychotropic effects in the elderly
Greater drug sensitivity, higher CNS concentration and baseline differences

53. Next Presentation - Antipsychotics in Geriatrics: Clinical Uses, Interactions, Drug Selection and Formulations