Geriatric pharmacotherapy and polypharmacy

Sushmitha

Associate consultant-Geriatrics, Kauvery Hospital, Alwarpet, Chennai

Introduction

Every day, elderly people consume many drugs that help them manage their diseases and improve the quality of their lives. However, the same medications can harm them through Adverse Drug Reactions (ADR) and drug interactions. Understanding the pharmacokinetic and pharmacodynamic changes in elderly people is essential to avoid errors in managing them.

Pharmacokinetic Challenges

Gastrointestinal absorption	Unchanged passive diffusion and no change in bioavailability for most drugs ↓ Active transport and↓ bioavailability for some drugs(calcium in hypochlorhydria) ↓ First-pass effect and ↑ bioavailability for some drugs (propranolol and labetalol).
Distribution	Body fat increases, lean muscle mass decreases, decrease in circulating volume, decrease in cardiac output, decrease in albumin levels which causes ↓ Vd and ↑ plasma concentrations of water-soluble drugs ↑ Vd and ↑ half-life for fat-soluble drugs ↑ or ↓ free fraction of highly plasma.
protein-bound drugs	Decreased p-glycoprotein activity in BBB causes their brains to be exposed to higher drug concentrations.
Hepatic metabolism	↓ Clearance and ↑ t 1/2 for some oxidatively metabolized drugs(steroids,paracetamol) ↓ Clearance and ↑ t 1/2 of drugs with high hepatic extraction ratio(Amitryptiline,lidocaine,morphine).
Renal excretion	↓ Clearance and ↑ t 1/2 Renally Eliminated drugs (digoxin, aminoglycosides).

*V_d – Volume of Distribution; BBB – Blood Brain Barrier; t 1/12 – Half Life.

Pharmacodynamic Challenges

Altered sensitivity because of decreased receptor number or affinity or changes in post-receptor response.

Decreased sensitivity: β-Agonists, β-Blockers, Furosemide, vaccines.

Increased sensitivity: H1 -antihistamines, Metoclopramide, Neuroleptics, Opioids, Warfarin, BZD, Dopaminergic Agonists.

Impairment of physiologic and homeostatic mechanisms: Increased risk of symptomatic orthostasis and falls (with antihypertensives, antipsychotics, and TCAs), urinary retention and constipation (with drugs with anticholinergic properties), falls and delirium (with every sedating drug).

Drug Interactions with Enzymes

CYP1A2	Inducers: Char-broiled beef, cruciferous vegetables, omeprazole, smoking Inhibitors: Cimetidine, Ciprofloxacin, Fluvoxamine
CYP2C	Inducers: Rifampin Inhibitors: Amiodarone, Fluconazole
CYP2D6	Inducers: None known Inhibitors: Fluoxetine, Paroxetine Quinidine, Ritonavir
CYP3A4	Inducers: Carbamazepine, Phenytoin Rifampin, St John’s wort. Inhibitors: Erythromycin, Ketoconazole

Drug-Disease interactions

Heart failure	NSAIDs and COX-2 inhibitors, non-dihydropyridine CCBs (avoid only for systolic heart failure); pioglitazone, cilostazol; dronedarone.
Syncope	AChEIs (Acetylcholinesterase inhibitors), peripheral α-blockers (e.g., doxazosin); TCAs (e.g., amitriptyline), chlorpromazine; olanzapine.
Delirium	Anticholinergics, benzodiazepines, chlorpromazine; corticosteroids, H2 receptor antagonists, sedative-hypnotics, antipsychotics.
Dementia and cognitive impairment	Anticholinergics, benzodiazepines, H2 receptor antagonists, non-benzodiazepine hypnotics (zolpidem, zaleplon), antipsychotics.
History of falls or fractures	Anticonvulsants, antipsychotics, benzodiazepines, no benzodiazepine hypnotics, TCAs, SSRIs, opioids.
Insomnia	Oral decongestants (e.g., pseudoephedrine and phenylephrine), stimulants (e.g., amphetamine, methylphenidate, armodafinil, modafinil), theobromines (e.g., theophylline and caffeine).

Medication-Related Problems

Medication errors was classified into two categories

Medication Errors

Prescribing
Dispensing
Administering
Monitoring

Adverse Drug Events

Adverse Drug Reactions
Therapeutic failure
Adverse Drug withdrawal events.

Adverse Drug Reactions (ADR)

A systematic review of 42 articles published from 1988–2015 suggests that 30% of hospital admissions in the elderly are related to adverse drug reactions. ADRs are very common and more than 50% are preventable according to many studies

Most common drugs associated are NSAIDs, Diuretics, Warfarin, ACEI, beta-blockers, Opioids.

Polypharmacy

Most common factor associated with ADR. It is the regular use of > or = 5 medications in an individual for various conditions. Monitoring patients’ active medication lists and De-prescribing any unnecessary medications are recommended to reduce pill burden.

De-prescribing: should be seen as a therapeutic intervention similar to initiating clinically appropriate therapy

Prescription of Potentially Inappropriate Medication

Selection of medications whose risk outweigh benefits or usage does not agree with accepted medical standards, this Incidence was 25–90%.

Various criteria have been developed, among those the more practical and reliable ones are

STOPP (Screening Tool of Older People’s Prescriptions ) START (Screening Tool to Alert to Right Treatment)
BEER’S criteria
Medication Appropriateness Index (MAI).

STOPP and START

Includes total of 114 criteria, 80 STOPP and 34 START, which were formed, by a panel of doctors, pharmacists, pharmacologists and primary care physicians with expertise in geriatric medicine and pharmacotherapy.

Examples of STOP criteria

Thiazide diuretics: In case of hypokalemia(k+ <3mEq/l), hyponatremia(Na+ <130),hypercalcemia and in gout.

Loop diuretics: As treatment for hypertension. For depenent edema,without evidence of heart failure/liver failure/kidney failure.

Verapamil/Diltiazem: In heart failure can worsen it.

Dual antiplatelet: As secondary stroke prevention unless the patient had a stent inserted in the previous 12 months or concurrent ACS

Warfarin or NOACs: For 1^st DVT without provoking risk factors,for longer than 6months.for 1^st PE without provoking risk factors, for longer than 12 months.

Aspirin: Long term at doses >160mg per day. with concomitant PUD.as monotherapy or as combination with warfarin or NOACs in chronic AF.

Benzodiazepines or hypnotics: With acute or chronic respiratory failure, if fallen in past 3months. For longer than 4 weeks (no indication for longer treatment; all benzodiazepines/ hypnotics should be withdrawn gradually if taken for more than 4 weeks as there is a risk of causing a withdrawal syndrome)

Selective serotonin re-uptake inhibitors (SSRIs): With a history of clinically significant hyponatraemia (below 130 mmol/l within the previous 2 months).

Citalopram and Escitalopram: With QT-interval prolongation or with concomitant drugs that cause prolonged QT-interval.

Antipsychotics

Long-term (i.e. beyond 1 month) as hypnotics (risk of confusion, hypotension, extra-pyramidal side effects, falls). Long-term (beyond 1 month) in those with Parkinsonism or Lewy Body Disease (likely to worsen extra-pyramidal symptoms).
If fallen in past 3 months.
With moderate –marked antimuscarinic/anticholinergic effects. (Chlorpromazine, clozapine) with a history of prostatism or previous urinary retention (high risk of urinary retention).
In patients with behavioural and psychological symptoms of dementia (BPSD), unless symptoms are severe and other non-pharmacological treatments have failed (increased risk of stroke).

Alpha1-receptor blocker: In those with symptomatic orthostatic hypotension or micturition syncope.

Anticholinergic drugs: With dementia, or chronic cognitive impairment (risk of increased confusion, agitation), Narrow-angle glaucoma (risk of acute exacerbation of glaucoma), Chronic prostatism (risk of urinary retention).

Examples of START criteria

Antiplatelet therapy: (one of aspirin, clopidogrel, prasugrel or ticagrelor) with documented history of coronary, cerebral or peripheral vascular disease.

Anticoagulation: For atrial fibrillation, using the CHA2DS2-VASc and HAS- BLED score and discuss the risk and benefit with the patient. Offer anticoagulation to people with a CHA2DS2-VASc score of 2 or above (1 or above for males), taking bleeding risk into account. Anticoagulation can be either Warfarin or a NOAC.

Levodopa or dopamine agonist: in idiopathic Parkinson’s disease with definite functional impairment and resultant disability.

Antidepressant (non TCA): In the presence of moderate-severe depressive symptoms lasting at least three months (higher risk of adverse drug reactions with TCAs than with SSRIs or SNRIs).

SSRI (or SNRI if SSRI is contra-indicated): For persistent severe anxiety that interferes with independent functioning

Dopamine agonist: (ropinirole or pramipexole or rotigotine) for moderate-severe Restless Legs Syndrome

Acetylcholinesterase inhibitor: (e.g. donepezil, rivastigmine, galantamine – or Memantine if others not tolerated) for mild-moderate Alzheimer’s dementia or Lewy Body dementia (rivastigmine) following review and recommendation by specialist team. Use donepezil first line.

Topical vaginal oestrogen or vaginal oestrogen pessary: For symptomatic atrophic vaginitis.

Alpha1-receptor blocker: With symptomatic prostatism, where prostatectomy is not considered necessary.

5-alpha reductase inhibitor: (e.g., finasteride) with symptomatic prostatism, where prostatectomy is not considered necessary.

Lifestyle advice for women with overactive bladder:

Recommend a trial of caffeine reduction.
Consider advising modification of high or low fluid intake.
Advise women who have a BMI greater than 30 to lose weight.

Therapeutic failure

Defined as ‘failure to accomplish the goals of treatment due to inadequate drug therapy and not due to natural progression of the disease. eg. omission of necessary medications, inadequate dosing or duration, on-adherence to medications’

The necessary medications more likely to be absent are cardiovascular medications and CNS drugs. Patients with multimorbidity and those with limited ADL are at higher risk of under treatment.

Frailty

Frailty is a state of heightened vulnerability and leads to increased risk of poor outcomes at times of health stressors. Ageing is not equal to frailty. Assessing frailty can identify persons at lower risk despite their advanced age and others at high risk despite their relative youth

Case Presentation

An 85-year-old bright relatively healthy male who was a retired engineer with a history of hypertension controlled with indapamide. He is fully independent in performing his basic and instrumental ADL. He stopped playing golf last year to look after his 75-year-old wife, who has moderately severe Alzheimer’s disease.

He experienced a 1-hour episode of retrosternal chest pain radiating to his left shoulder, but he ignored it. When he finally saw his family physician 1 week later, an ECG demonstrated new inferior Q waves, ECHO demonstrated an EF of 55% with hypokinesis of the IW in the left ventricle, consistent with a recent MI.

His family physician prescribed enteric-coated aspirin, an ACEI and a β-blocker, all of which are well tolerated. He declined further investigations because he felt well at that time and wants to resume looking after his wife.

A cholesterol profile demonstrates LDL cholesterol level of 145 mg/dL and an HDL cholesterol level of 35 mg/dL.

Should he be prescribed a statin for secondary prevention of cardiovascular events?

Arguments Favouring Statin Therapy

He is not very frail. He is old chronologically, but less old biologically.
There is no compelling evidence that atherosclerosis is substantially different in an 85-year-old adult than in an 80-year-old adult.
He is otherwise healthy, has no other competing comorbidities, and therefore has a remaining life expectancy of approximately 5 years.
In the PROSPER trial, the benefits of statin therapy became apparent after 1 year.
He is at high risk for a recurrent cardiac event, which might leave him unable to care for his wife.

Arguments against Statin Therapy

His age exceeds clinical trial inclusion criteria and he is therefore too old.
Potential risk for adverse events.

Principles of Optimal Geriatric Pharmacotherapy

Consider whether the drug is necessary
Understand the pharmacology of the drug
Know the adverse effect profile
Start at lower dose
Establish clear therapeutic end points
Monitor for adverse drug reactions
Slowly taper medications to prevent withdrawal events
Regularly review chronic medications to stop unnecessary drugs
Assess if there is omission of any essential drugs
Review adherence and simplify regimens if possible

Dr. K. Sushmitha
Associate Consultant – Geriatrics

Geriatric pharmacotherapy and polypharmacy

Geriatric pharmacotherapy and polypharmacy

Sushmitha

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