1. Geriatric Pharmacology
Lisa Rosenberg, MD
Touro University Nevada
April 6, 2011

2. Basic Principles of Geriatrics Emory University Division of Geriatric Medicine and Gerontology
Aging
Is not a disease
Does not cause symptoms
Occurs at different rates among individuals and among organs/organ systems
Increases susceptibility to disease and other bad events (homeostenosis)

3. Basic Principles of Geriatrics
Medical Conditions in Older Adults
Chronic
Multiple
Multifactorial
Acute conditions superimposed on chronic
Treatment of one condition can affect other conditions

4. Basic Principles of Geriatrics
Reversible or Treatable Conditions are
Under-detected
Conditions attributed to age
Atypical presentations
Geriatric syndromes
Systematic screening can identify a deficiency

5. Basic Principles of Geriatrics
Importance of Functional Ability and Quality of Life (QoL)
Unclear mortality benefit of medications
Small changes can greatly affect function and QoL
Function and QoL can both be measured and followed

6. Basic Principles of Geriatrics
Cognitive/Affective Disorders
Prevalent
Under-diagnosed
Affect treatment plans, compliance

7. Basic Principles of Geriatrics
Iatrogenesis - Common and Treatable
Adverse drug events
Polypharmacy and the prescribing cascade
Drug-disease interactions
Complications of hospitalization
Iatrogenesis:

8. Two Parts of Geriatric Pharmacology
Pharmacokinetics “what the body does to the drug” absorption, distribution, metabolism, clearance Pharmacodynamics “what the drug does to the body” transmitters, receptors, second messengers

9. Physiologic Changes With Aging - Pharmacokinetics
Absorption
Distribution
Metabolism
Clearance/Elimination

10. ABSORPTION
No significant change with age, per se Affected by Achlorhydria Prolonged transit time in gut Competing compounds, especially OTC’s

11. DISTRIBUTION Body Composition
Decreased water and lean muscle mass as % of body weight Decreases Vd of hydrophilic drugs Increased fat as % of body weight Increases Vd of lipophilic drugs

12. DISTRIBUTION Body Composition
Changes in transport proteins – clinically relevant mainly in chronic disease or severe undernutrition Mainly affects loading dose of drugs like digoxin, warfarin Albumin – binds many drugs, especially weakly acidic drugs Orosomucoid (α-acid glycoprotein) – binds mainly basic drugs

13. METABOLISM
Variable decline in liver’s ability to metabolize, among individuals, among enzymatic processes and among drugs, mainly related to change in liver size and blood flow
Acetylation, conjugation do not change appreciably with age
Oxidative metabolism (cytochrome P450 system) does decline with aging, resulting in variably decreased clearance of drugs
*Age-related decline in liver’s ability to recover from injury
Types of Processes
Usual products
Change with Age
Phase I
Oxidation
Hydroxylation
Reduction
Active metabolites
Greater
Phase II
Conjugation
Inactive metabolites
Lesser

14. METABOLISM
Genetics, nutrition, environmental exposure, disease (e.g. congestive heart failure) and other drugs all have a greater effect on drug metabolism than does age alone. Ideal drug for an older adult undergoes phase II metabolism and does not compete for, induce or suppress its own metabolism.

15. (Ideal weight in kg) (140 - age)
ELIMINATION
Kidney is main organ of elimination
One third of older adults have truly preserved creatinine clearance (means 2/3 of older adults do not)
Serum creatinine tends NOT to change with age…falsely reassuring
Cockcroft-Gault formula* (ages 40-80)
(Ideal weight in kg) (140 - age)
(72) (serum Cr in mg/dL)
*multiply by 0.85 if female

16. ELIMINATION
Lungs important in elimination of volatile drugs Volatile drugs tend not to be used in elderly due to age-associated changes in lung function as well as greater prevalence of active pulmonary disease

17. Pharmacodynamics

18. Pharmacodynamics
Homeostatic mechanisms that diminish with aging: Postural blood pressure control Posture control Extrapyramidal functions Cognitive function Thermoregulation

19. Pharmacodynamic Changes with Aging
Limitations in our understanding of this:
Difficulty in accounting for baseline differences
Dependence on cultural/educational differences (when assessing drug effects on cognition or other subjective symptoms)
Dependence on cultural differences when assessing subjective responses
Cross-sectional Studies – Limitations
Assume mean changes between age groups reflect changes in the individual over time
Birth cohort effects confound those of age
Selective mortality effects

20. Pharmacodynamics CNS-active drugs -reasons for altered dynamics
Altered neurotransmitters/receptors
Hormonal changes (sex and growth hormones)
Impaired cerebral glucose metabolism
Decreased oxygen with cerebrovascular changes
Better CNS penetration with age (reduced p- glycoprotein activity)
P-glycoprotein

21. Pharmacodynamics Benzodiazepines
Changes especially important because of association with falls, hip fractures Demonstrated by EC50 of midazolam decreased by 50% in older adults PD differences documented variably for benzodiazepines Likely mechanism is change in distribution of drug to the brain in older adults -N.B. EC50 reflects relationship between serum concentration and drug effect
EC50 = serum concentration at which 50% of patients or subjects demonstrate an effect, such as sedation

22. Pharmacodynamics Anesthetics, NMB, Opioids
Anesthetics – increased sensitivity Neuromuscular blockers – no change in sensitivity but decreased dosing requirements due to changes in pharmacokinetics Opioids – increased sensitivity and changed kinetics

23. Pharmacodynamics Cardiovascular Drugs
ACE-inhibitors
No change with age per se
Decrease in sensitivity after repeated dosing (seen in both age groups, enzyme induction)
Only age-related difference was that younger group more likely to have headaches, older group more likely to be orthostatic, lightheaded

24. Pharmacodynamics Cardiovascular Drugs
Dihydropyridines – greater response observed in treatment-naïve elderly, diminishes in as little as three months
Non-dihydropyridines
Decrease in sensitivity of PR response (which is prolonged in the young)
Enhanced HR and BP responses
Possibilities for the dihydropyridine response observed are:
age-related change in baroreceptor response, which can correct itself
Effect of baseline BP on response elicited by the medication

25. Pharmacodynamics Autonomic Agents
β-sensitivity decreases with age - prevalence of high-affinity receptors ↓ with age; does not explain diminished response to β antagonists - may be related to Gs proteins -adrenoceptors couple with G proteins -Gs proteins demonstrate ↓ with age exception: activity of β-blockers in elderly with very high blood pressure α-sensitivity has shown varied responses

26. Pharmacodynamics Diuretics
Traditional approach to looking at drug effect does not apply Action is at luminal surface in nephron No change in drug sensitivity with age GFR is greatest predictor of diuretic response *diuretics further ↓ GFR *HCTZ not an effective antihypertensive if CrCl < 30 mL/min Appear due to pharmacokinetic changes

27. Pharmacodynamics Anticoagulants
Increased risk of pathologic bleeding Warfarin – no PK effect but greater decrease in K-dependent clotting factor synthesis Sensitivity difficult to quantify Serum levels of warfarin don’t apply AGE IS ONE OF GREATEST PREDICTORS OF ANTICOAGULANT REPSONSE

28. Interacting Drugs Impact Mechanism Prevention Warfarin, NSAIDs
Increased risk of bleeding
NSAIDs irritate gastric lining & impair platelet function
Monitor weekly INR and for s/s of bleeding
Warfarin, sulfa
Increased warfarin activity
Change in gut flora responsible for K production
Dec. warfarin dose by 50% during and 1 wk after abx
Warfarin, macrolide
(highly probably, often delayed)
Increased effect of warfarin
E-mycin inhibits warfarin metab. and clearance; change in gut flora
If macrolide necessary, monitor INR qod. ID pathogen to confirm need.
Warfarin, quinolones
Change in gut flora; ? change in warfarin metab. and clearance
Monitor INR qod if quinolone is necessary
Warfarin, phenytoin
Increased effects of both drugs
Keep INR at lower end of thx range. Monitor INR and PTN lvl.
ACE-inhibitors, K+ supplements
Elevated serum K+
Decreased aldosterone/K+ secretion
Monitor K+; are both drugs necessary?
ACE-inhibitors, aldactone/
spironolactone
Probably additive effect
Digoxin, amiodarone
Digoxin toxicity
? amio ↓ clearance of digoxin; ? additive effect at sinus note
Dig lvl prior to amiodarone; decrease dig dose and monitor weekly
Digoxin, verapamil
Digoxin toxicity, bradycardia, heart block
Synergistic effect of slowed impulse conduction and reduced contractility
Monitor HR and EKG (PR interval)
Theophylline, quinolones
Theophylline toxicity
Quinolones inhibit hepatic metabolism of theophylline
Monitor theophylline lvl AND watch for s/s

29. Drug Errors/Adverse Drug Events
Drug error: inappropriate/incorrect omission, administration (timing or route), dose; included administration to the wrong patient Adverse Drug Event: any drug-related incident that results in harm to a patient; does not necessarily mean that an error was made What is the difference between an adverse drug event and an adverse drug reaction? An adverse drug reaction implies/requires a causal (and temporal) link between drug and event.

30. Adverse Events: Risk Factors
Advanced age Gender (female) Frailty (physiologically advanced age) Polypharmacy Multiple prescribers Prior adverse drug reactions Cognitive impairment

31. Serotonin Syndrome
Caused by elevated levels of serotonin -too high a dose of some medications -medication combinations -some illicit drugs and herbal supplements Signs/Symptoms: agitation, confusion, tachycardia, HA, diaphoresis, diarrhea

33. Serotonin Syndrome - Treatment
Stop medication
Hydrate patient
Cool to counteract hyperpyrexia
Benzodiazepines for agitation
Primary prevention: avoid multidrug regimens

34. Neuroleptic Malignant Syndrome
Usually develops within first two weeks of treatment
Most serious adverse effect of neuroleptics
Features:
Muscle rigidity – “lead pipe”
Autonomic dysregulation
Hyperthermia (hours to days after exposure)
Altered mental status (even coma)

35. Neuroleptic Malignant Syndrome
Treatment
Stopping culprit medication
Cool patient
Support vital functions (normalize VS)
Mild: benzodiazepine
Moderate: ?dopaminergic agonist (bromocriptine)
Severe: dantrolene to address muscle rigidity
Use atypical antipsychotics in future (eg. quetiaptine/Seroquel)

36. Tousi 2008

37. Disorders Related to Parkinson’s Disease
Parkinsonism-hyperpyrexia syndrome
Withdrawal/decrease of dopaminergic medications
Also: amantadine and anticholinergics
Fever, rigidity, autonomic instability, risk of aspiration pneumonia
Rx: dopaminergics, supportive care +/- methylprednisolone
Important that patients going into surgery still receive their Parkinson’s Disease medications

38. Disorders Related to Parkinson’s Disease
Parkinsonian dyskinesia
Levodopa-induced
Related to disease severity and dose
Use of dopamine agonist as initial therapy can delay
Exhausting if prolonged, risk of rhabdomyolysis
Treatment: lower dose of dopaminergics, mild benzodiazepine for dyskinesia; ? amantadine

39. Dystonic Reactions Acute dystonic reaction
Usually occurs ≤ 24 hrs after medication
Neuroleptics/antiemetics
DDx includes meningitis, CVA, electrolyte abnormalities, drug toxicity
Rx: Stop ppt’ing medication, anticholinergics
Benztropine, IV diphenhydramine
Laryngeal dystonia with multiple system atrophy
Myoclonus – from opiate toxicity or withdrawal
Baclofen withdrawal – life-threatening syndrome
Rigidity, fever, change in mental status, worsening dystonic symptoms

40. One Final Message
The only way to find the mistakes in a patient’s medication regimen is to look at the list as if the previous prescriber made a mistake …even if the previous prescriber was you.

41. Prescribing Cascade
The tendency to prescribe a medication to address a sign or symptom caused by another medication Usually not appreciated

42. Anticholinergic Side Effects

43. Medications with Anticholinergic Effects
Add to this:
Tolterodine
Furosemide
Digoxin

44. Rational Prescribing for Older Adults
Careful drug history
Look for drug reactions and interactions
Prescribe for a specific indication
Make goals and endpoints of therapy clear
Simplify regimen as much as possible
Start with conservative dose and dose intervals – explain to patient that achieving an effective dose may take time
“start low and go slow”

45. Acknowledgements
Emory University Geriatric Educational Resources Rosemary D. Laird, MD, University of Kansas Multidisciplinary Medication Management Project UCSF Primary Care Lecture Series