Prescribing for Older Patients


Enzyme inhibitors

Enzyme inducers

Erythromycin, clarithromycin

Carbamazepine

Sulphonamides

Phenytoin

Ciprofloxacin

Topiramate

Fluconazole, miconazole, ketoconazole

Clotrimazole

Amiodarone

Rifampicin

Diltiazem, verapamil

Dexamethasone

Cimetidine

Primidone

Fluoxetine, paroxetine

St. John’s wort



One of the most important age-related pharmacokinetic changes is the predictable decline in renal function. Normal ageing results in reduced renal size, perfusion and concentrating ability. Indeed, a gradual decline in glomerular filtration rates begins at the age of 30 years. This is potentiated by conditions such as hypertension and diabetes and by nephrotoxic medications such as NSAIDs, gentamicin and vancomycin. It is recommended that glomerular filtration rate (GFR) is estimated for all older patients at regular intervals using readily available formulae such as the Cockcroft and Gault [13] equation or the modified diet in renal diseases (MDRD) [14]. It must be remembered that serum creatinine concentration is not a reliable measure of renal function in older people because of age-related reductions in muscle mass. Approximately 50% of older patients have a normal serum creatinine level but a reduced creatinine clearance estimate.

Acute kidney injury (AKI) is common in older patients with acute illness and can occur for multiple reasons including hypotension, dehydration, sepsis, cardiorenal syndrome/cardiac failure or NSAID use. In this context, a regularly prescribed renally eliminated medication (e.g. digoxin, dabigatran or metformin) may need to be temporarily withheld or dose reduced in order to avoid high serum levels and toxicity. Once renal impairment has been identified (be it AKI or chronic kidney disease) and creatinine clearance (Cr Cl) estimated, the need for dose alteration of renally eliminated drugs must be determined. In general, dose adjustment is needed when the creatinine clearance is below 60 ml/min (see Table 21.2).


Table 21.2
Drugs that require dose adjustment with impaired renal function (precise dose adjustments for each drug are available in comprehensive formularies such as the British National Formulary [15])

















































Drug/class

Examples

Cardiac drugs

Digoxin, atenolol, sotalol

Lipid lowering drugs

Pravastatin, rosuvastatin, fibrates

Hypoglycaemic drugs

Metformin, glibenclamide, Glimepiride, gliptins, insulin

Diuretics

Thiazide diuretics have limited efficacy if CrCl is <30 ml/min

Avoid potassium-sparing diuretics if CrCl <30 ml/min

Anticoagulants

Apixaban, rivaroxaban, dabigatran, low molecular weight heparin (enoxaparin, tinzaparin)

Drugs for gout

Allopurinol, colchicine

Bone anti-resorptive drugs

Avoid bisphosphonates if CrCl <30 ml/min

Analgesic drugs

Opioids (morphine, codeine, pethidine), NSAIDs

Anticonvulsants

Topiramate, levetriacetam, vigabatrin

Psychotropic drugs

Lithium, gabapentin, amisulpride

Antibiotics

Aminoglycosides (e.g. gentamicin), vancomycin, carbapenems (e.g. meropenem), piperacillin/tazobactam, ciprofloxacin, ceftazidime

Antifungals

Fluconazole, sulfamethoxazole

Antivirals

Acyclovir, ganciclovir, famciclovir

Drugs exert their effects by binding as agonists, partial agonists or antagonists to target molecules and receptors within the body; pharmacodynamics is the study of these effects. Receptor expression, density, activity and affinity change with age, thus leading to altered (usually increased) pharmacodynamic effects of commonly prescribed drugs including anticoagulants, opioids and antipsychotics. In practice, this means that older patients frequently have exaggerated responses to medications at doses that are normally used in younger patients, e.g. the anticoagulant response to warfarin is often increased in older patients compared to a similar dose in a younger patient, thus increasing their bleeding risk. Older patients are particularly susceptible to the central nervous system (CNS) effects of anticholinergics, benzodiazepines, opioids and other centrally acting or psychoactive drugs because of increased blood-brain barrier permeability, reduced cholinergic neurotransmission and alterations in receptor density, affinity and intracellular responses. Clinical examples of the effect of altered pharmacodynamics sensitivity are presented in Table 21.3. It is usually recommended to start such drugs at the lowest possible dose and to slowly up-titrate according to response.


Table 21.3
Age-related changes in pharmacodynamic response to commonly prescribed drugs




































































Drug type

Specific drug

Pharmacodynamic response

Potential clinical consequence

Analgesia

Morphine


Excessive sedation, confusion, constipation, respiratory depression

Anticoagulant

Warfarin


↑ Bleeding risk

Dabigatran (age ≥75 years, weight <50 kg)


Apixaban


Cardiovascular system drugs

Angiotensin-receptor blocker


Hypotension (↑ acute antihypertensive effect)

Diltiazem


Enalapril


Verapamil


Hypotension (↑ acute antihypertensive effect), bradyarrhythmias (↑ cardiac conduction effects)

Propranolol


Less reduction in heart rate

Diuretics

Frusemide


↓ Diuretic effect and size of peak of diuretic response

Psychoactive drugs

Benzodiazepines


Excessive sedation, confusion, postural sway, falls

Antipsychotics


Excessive sedation, confusion

Others

Levodopa


Dyskinesia, confusion, hallucinations


↑, Increased pharmacodynamic response; ↓, reduced pharmacodynamic response

Prescribers should also be aware of age-related changes in homeostatic and thermoregulatory mechanisms. With increasing age, there is a reduction in aortic and large-vessel elasticity and compliance often resulting in systolic hypertension, lower diastolic blood pressure and a tendency towards left ventricular hypertrophy. In addition, baroreceptor sensitivity and resting heart rate are reduced, thus increasing the risk of postural hypotension and falls. Many drugs can exacerbate postural hypotension including antihypertensives, vasodilators (doxazosin and tamsulosin) and drugs with anticholinergic properties, e.g. tricyclic antidepressants and first-generation antihistamines. Falls are commonly caused by orthostatic hypotension. Drugs that contribute to reducing blood pressure in any way should be carefully reviewed and dose reduced or discontinued as appropriate.



21.4 Drug-Drug and Drug-Disease Interactions


Older patients often have multiple co-morbidities for which they are prescribed multiple medications. Drug-drug interactions (Table 21.4) are usually predictable through known pharmacokinetic and pharmacodynamic principles as previously described. Certain drugs may also worsen coexisting diseases in older patients. These should be minimised and safer alternatives be prescribed where possible. Table 21.5 presents some clinically important drug-disease interactions including the major geriatrics syndromes of dementia, delirium, incontinence and falls, which are often significantly exacerbated by commonly prescribed medications.


Table 21.4
Clinically important drug-drug interactions in older patients



























































Drug

Drug

Interaction

Effect

Antihypertensive agent

Vasodilator, antipsychotic, TCA

Combined hypotensive effect

Orthostatic hypotension, falls

Antihypertensive agent

NSAIDs

NSAID antagonises hypotensive effect

↓ Antihypertensive effect

Potassium sparing diuretics

ACE inhibitors, spironolactone

Combined potassium sparing effects

↓ Renal function, hyperkalaemia

Digoxin

Diuretics

Diuretic-induced hypokalaemia

↑ Effect of digoxin (arrhythmia, toxicity)

Digoxin

Amiodarone, diltiazem, verapamil

↓ Clearance of digoxin

↑ Effect of digoxin (arrhythmia, toxicity)

Phenytoin

Cytochrome p450 enzyme inhibitorsa

↓ Clearance of phenytoin

↑ Effect of phenytoin

Thyroxine

Cytochrome p450 enzyme inducersa

↑ clearance of thyroxine

↓ Effect of thyroxine

Lithium

NSAIDs, diuretics

↓ Clearance of lithium

↑ Effect of lithium (arrhythmia, toxicity)

Phenothiazines

Drugs with anticholinergic properties

Combined anticholinergic effects

Confusion, constipation, urinary retention, dry mouth


TCA, tricyclic antidepressant; NSAID, non-steroidal anti-inflammatory drug

aSee Table 21.1



Table 21.5
Clinically important drug-disease interactions in older patients




















































Disease or condition

Drug

Effect of drug on disease or condition

Hypertension

NSAIDs, high sodium content drugs

↑ Blood pressure

Orthostatic hypotension

Diuretics, anticholinergics, levodopa, vasodilators

Falls, syncope, hip fracture

Falls

Benzodiazepines, antipsychotics, opioids, anticholinergics

↑ Risk of falls, sedation, gait instability

Osteoporosis

Corticosteroids

Fracture

Poorly controlled gout

Thiazide diuretic

Hyperuricaemia, ↑ risk acute exacerbation of gout

Cognitive impairment, dementia

Anticholinergics, benzodiazepines, TCAs

↑ Confusion, delirium

Cardiac failure

Verapamil, disopyramide

Exacerbation of heart failure

Renal failure

Aminoglycoside antibiotics, NSAIDs, radiological contrast

Acute kidney injury, worsening of creatinine clearance

Peptic ulcer disease

NSAIDs, anticoagulants

Peptic ulcer, upper gastrointestinal haemorrhage

Benign prostatic hyperplasia

Anticholinergics, alpha-agonists

Urinary retention


21.5 Polypharmacy


Polypharmacy refers to the use of several drugs concurrently. Though multiple medications are often clinically justifiable, it is well established that polypharmacy in older patients is associated with inappropriate prescribing (i.e. where the risk of treatment outweighs the potential clinical benefit), adverse drug reactions (ADRs) and non-specific syndromes in older people including weight loss, falls and cognitive and functional decline. The World Health Organization defines an ADR as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, alteration of the dosage regimen or withdrawal of the product [16]. Patients taking two concurrent medications have a 13% risk of ADR, which rises to 38% for four medications and 82% for greater than seven medications prescribed simultaneously [17]. Adverse consequences of polypharmacy are summarised in Table 21.6.


Table 21.6
Polypharmacy in older patients: clinical associations

















1.

↑ Risk of ADR including drug-drug and drug-disease interactions

2.

↑ Likelihood of inappropriate prescribing including use of drugs without clear clinical indication

3.

↑ Likelihood of prescribing cascades, i.e. where a drug is prescribed to treat a symptom attributable to an adverse effect of another drug

4.

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May 1, 2018 | Posted by in Uncategorized | Comments Off on Prescribing for Older Patients
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