1. PHARMACOLOGY AND THE OLDER PATIENT David J. Mokler, Ph.D. Department of Pharmacology College of Osteopathic Medicine University of New England

2. Learning Outcomes  What are the physiologic changes that occur as we age that alter our response to drugs?  What is the effect of these changes on the pharmacokinetics of commonly used drugs?  What is anti-cholinergic syndrome?  What are other classes of drugs that can cause cognitive impairment?  What are the problems that are associated with the increased use of herbal medicines?  What steps can we take to decrease the problems associated with polypharmacy?

3. ALTERED PHYSIOLOGIC VARIABLES IN OLDER PATIENTS Physiologic VariableAdultsElderly Absorption Esophageal motility  Gastric emptying time (half time, min) 47123 Achlorhydria (incidence, %) 526 Muscle mass and blood flow 

4. ALTERED PHYSIOLOGIC VARIABLES IN OLDER PATIENTS Physiologic VariableAdultsElderly Distribution Serum albumin 4.73.8 Alpha-1 acid glycoprotein (mg/dL) 28102 Total body water (L/kg weight).50.47 Adipose tissue (% total body weight) Male 1836 Female 3345

5. ALTERED PHYSIOLOGIC VARIABLES IN OLDER PATIENTS Physiologic VariableAdultsOlder Adult Metabolism Liver weight (gm/kg body weight) 2520 Hepatic blood flow (mL/min) 1400800 Antipyrine clearance (mL/hr/kg) 4728 Elimination Glomerular filtration rate 12285 Renal blood flow (mL/min/1.73m2) 1100600

6.  From Timiras, 1994

7. Diazepam Pharmacokinetics  Klotz et al., J. Clin. Invest., 1975

8. ChlordiazepoxideN-desmethylchlordiazepoxide Demoxepam N-desmethyldiazepam Oxazepam glucuronide Clorazepate Prazepam Halazepam Hydroxyprazepam Lorazepam Diazepam N-methyloxazepam Alprazolam α –hydroxy-alprazolam Metabolism of Benzodiazepines

9. Plasma Half-Lives in Young and Old DrugYoung (20-30)Elderly (65-80) Penicillin G20.7 min39.1 min Tetracycline3.5 hr4.5 hr Digoxin51 hr73 hr Diazepam20 hr80 hr Lidocaine80.6 hr139.6 hr Chlordiazepoxide8.9 hr16.7 hr Phenobarbital71 hr107 hr Warfarin37 hr44 hr

10. Physiological Changes  No significant changes in absorption  Increased adipose tissue changes distribution of fat soluble drugs  Decreased cardiac output  Little effect on hepatic metabolism for most drugs  Decreased renal excretion most significant

11. Representative Drugs Showing Low Oral Availability Due to Extensive First-Pass Hepatic Elimination  Alprenolol  Amitriptyline  Desipramine  Dextropropxyphene  Dihydroergotamine  Diltiazem  5-flurouracil  Hydralazine  Labetolol  Methylphenidate  Metoprolol  Morphine  Nifedipine  Nitroglycerin  Pentazocine  Propranolol  Verapamil

12. DRUGS WITH ANTI-CHOLINERGIC PROPERTIES  Anti-psychotics: Chlorpromazine  Anti-depressants: Amitriptyline, doxepin  Anti-arrhythmics: Quinidine, disopyramide  Anti-parkinson drugs: Benztropine, trihexyphenidyl  Anti-spasmodics: Atropine  Anti-histamine: Diphenhydramine, chlorpheneramine  Proprietary sleep aids, cold medications

13. Anti-Cholinergic Syndrome  Systemic  Tachycardia  Warm, dry, flushed skin  Decreased secretions  Decreased bowel motility (constipation)  Urinary retention  Mydriasis, blurred vision  Hyper-pyrexia  Cardiac conduction problems

14. Anti-Cholinergic Syndrome  Neuropsychiatric  Anxiety  Agitation  Confusion  Delirium  Increased forgetfulness  Hallucinations  Seizures

15. Other Drugs That May Cause Dementia or Cognitive Impairment  Alcohol  Benzodiazepines  Beta-blockers  Cimetidine  Corticosteroids  Digoxin  Levodopa  Lithium  NSAIDs  Phenytoin  Quinidine

18. Herbal Drug Use Today Arch Intern Med. 2005

19. Copyright restrictions may apply. Kelly, J. P. et al. Arch Intern Med 2005;165:281-286. Use of herbal products according to year of interview and age of subject

20. Copyright restrictions may apply. Kelly, J. P. et al. Arch Intern Med 2005;165:281-286. Weekly Prevalence of Use of Most Commonly Reported Herbal and Other Natural Dietary Supplements in 1998-1999 and 2002 According to Age Among Men*

21. Copyright restrictions may apply. Kelly, J. P. et al. Arch Intern Med 2005;165:281-286. Weekly Prevalence of Use of Most Commonly Reported Herbal and Other Natural Supplements in 1998-1999 and 2002 According to Age Among Women*

22. Herbal Therapies

24. A stepwise approach to polypharmacy  Disclose all medications being used, including OTC, herbals and supplements  Identify medications by generic name and drug class  Identify the clinical indication for each drug  Know the side effect profile for each drug  Identify risk factors for adverse drug reactions  Eliminate medication with no therapeutic benefit  Eliminate medication with no clinical indication  Substitute safer medication  Avoid treating adverse drug reactions with a drug  Use a single drug with infrequent dosing