Appropriate prescribing in the elderly: Current perspectives

Table 1 Pharmacokinetics and ageing

Absorption	↓ amount of saliva
	↑ gastric pH
	↓ gastric acid secretion
	↑ gastric emptying time
	↓ gastric surface area
	↓ gastrointestinal motility
	↓ active transport mechanisms
Distribution	↓ cardiac output
	↑ peripheral vascular resistance
	↓ renal blood flow
	↓ hepatic blood flow
	↓ body water
	↑ body fat tissue
	↓ serum albumin levels
	↑ for lipid soluble and decrease for water soluble drugs
Metabolic	↓ microsomal hepatic oxidation
	↓ clearance
	↑ steady state levels
	↑ half lives
	↑ levels of active metabolites
	↓ first pass metabolism due to reduced ↓ blood flow
Excretion	↓ in renal perfusion
	↓ in renal size
	↓ in glomerular filtration rate
	↓ tubular secretion
	↓ in tubular reabsorption

↑: Increased; ↓: Reduced.

Table 2 Common cytochrome P450 isoenzyme inhibitors and inducers

Enzyme inhibitors	Enzyme inducers
Amiodarone	Carbamazepine
Allopurinol	Ethanol
Cimetidine	Isoniazid
Citalopram, sertraline	Phenytoin
Ciprofloxacin	Phenobarbital
Diltiazem, verapamil	Rifampcin
Fluxetine, paroxetine	St. Johns Wort
Erythromycin, clarithromycin
Fluconazole, ketoconazole
Omeprazole
Sulphonamides
Grapefruit Juice

Table 3 Common used drug classes which require dose adjustment with chronic kidney disease

Drug class	Adjust dose in CKD stage 1-3	Avoid in CKD stages 4 and 5
ACE-inhibitors and Angiotensin 2 receptor blockers	All ACE inhibitors	Olmesartan
Diuretics	Potassium-sparing and thiazide diuretics	Potassium-sparing and thiazide diuretics
Beta-blockers	Acebutolol, atenolol, bisoprolol, nadolol, sotalol	Sotalol
Lipid lowering agents	Pravastatin, rosuvastatin, fibrates	Glyburide, metformin, exanitide
Hypoglycaemic agents	Gliclazide, acarbose, insulin, gliptins
Analgesia (NSAIDs and opioids)	Codeine, tramadol, morphine, oxycodone,	All NSAIDs, pethidine
Psychotropic agents	Lithium, gabapentin, pregabalin, topiramate, vigabatrin, bupropion, duloxetine, paroxetine, venlafaxine
Miscellaneous	Allopurinol, colchicine, digoxin	Dabigatran Rivaroxaban (CI stage 5, dose adjust in stage 4 CKD) Apixaban (CI stage 5, dose adjust in stage 4)

CKD: Chronic kidney disease; ACE-inhibitors: Angiotensin-converting-enzyme inhibitor; NSAIDs: Non-Steroidal anti-inflammatory drugs; CI: Contraindicated.

Table 4 Age-associated changes in pharmacodynamic response to commonly prescribed drugs

Drug type	Specific drug	Pharmacodynamic response in older people	Potential clinical consequence
Analgesia	Morphine	↑	Excessive sedation, confusion, constipation, respiratory depression
Anticoagulant	Warfarin Dabigatran in those ≥ 75 yr with a body weight of < 50 kg)	↑	Increased bleeding risk
Cardiovascular system drugs	Angiotensin II receptor blockers	↑	Hypotension
	Diltiazem	↑
	Enalapril	↑
	Verapamil	↑
	Propranolol	↓
Diuretics	Frusemide	↓	Reduced diuretic effect at standard doses
	Bumetanide	↑
Psychoactive drugs	Diazepam	↑	Excessive sedation, confusion, postural sway, falls
	Midazolam	↑
	Temazepam	↑
	Haloperidol	↑
	Traizolam	↑
Others	Levodopamine	↑	Dyskinesia, confusion, hallucinations

↑: Increased pharmacodynamic response; ↓: Reduced pharmacodynamic response.

Table 5 Commonly used drugs - comparison of prescription between older and younger patients

Drug	Typical dose in younger patient (< 65 yr)	Typical dose in older patient (≥65 yr)	Reason for different dose in the elderly
Anti-arrhythmics
Digoxin	Loading dose is 1-1.5 mg in divided doses over 24 h Maintenance dose 125-250 mcg OD	Loading dose is 1 mg in divided doses over 24 h Maintenance dose 62.5-125 mcg OD	Water soluble contributing to increased plasma levels in the elderly
Anti-coagulants
Warfarin	Standard initiation dose, e.g., 10 mg daily for two days	Lower initiation dose, e.g., 5 mg daily for two days	Increased sensitivity to anticoagulant effect
Dabigatran	150 mg BD	Patient > 80 yr 110 mg BD Patient 75-80 yr 150 mg BD in setting or normal eGFR	Increased sensitivity to anticoagulant effect
Anti-hypertensive
Ramipril	Initiation dose 2.5 mg	Initiation dose 1.25 mg	Lower initial dose and gradual dose titration required (higher risk of ADE in the elderly)
Psychoactive drugs
Diazepam	2 mg TDS	1 mg BD	Lipid soluble with higher volume of distribution in older people thus contributing to a prolonged duration of effect

OD: Once daily; BD: Twice daily; TDS: Three time daily.

Table 6 Important drug interactions in older patients

Drug	Drug	Interaction	Effect
Anti- hypertensive agents	NSAID	NSAID antagonizes hypotensive effect	↓ antihypertensive effect
Aspirin	NSAID, oral corticosteroids	↑ risk of peptic ulceration	Peptic ulceration
Calcium channel blockers	Enzyme inducers	↑ clearance of calcium channel blocker	↓ anti-hypertensive effect
Digoxin	Diuretics	Diuretic-induced hypokalaemia	↑ effect of digoxin (arrhythmia, toxicity)
Digoxin	Amiodarone, Ditiazem, Verapamil	↓ clearance of digoxin	↑ effect of digoxin (arrhythmia, toxicity)
TCA	Enzyme inhibitors	↓ clearance of TCA	Arrhythmia, confusion, orthostatic hypotension, falls
Phenytoin	Enzyme inhibitors	↓ clearance of phenytoin	↑ effect of phenytoin, toxicity
Thyroxine	Enzyme inducers	↑ clearance of thyroxine	↓ effect of thyroxine

NSAID: Non-steroidal anti-inflammatory drug; TCA: Tricyclic anti-depressants.

Table 7 Key considerations when prescribing for older patients

Use non-pharmacological treatment whenever possible

Include the patient (and carer where appropriate) in prescribing decisions

Ensure each medication has an appropriate indication and a clear therapeutic goal (this involves careful clinical assessment and appreciation of time to obtain treatment effect and life expectancy)

Start at the smallest dose and titrate slowly according to response and efficacy

Use the simplest dosing regimen (e.g., once a day preferable to three times per day) and most appropriate formulation

Provide verbal and written instructions on indication, time and route of administration and potential adverse effects of each medication

Regularly review prescriptions in the context of co-exiting disease states, concurrent medications, functional and cognitive status and therapeutic expectation

Be aware that new presenting symptoms may be due to an existing medication, drug-drug interaction or drug-disease interaction (avoid prescribing cascade)

When stopping a medication check that it can be stopped abruptly or whether it needs to be tapered, e.g., long-term steroids, benzodiazepines

Table 8 Clinical example

An 80-year-old lady is referred with a four day history of general malaise, nausea, vomiting and recurrent falls. Her past medical history includes paroxysmal atrial fibrillation, non-obstructive coronary artery disease, hypertension, recurrent episodes of acute gout, dependent lower limb edema and “vertigo/dizziness”. Prior to this episode she was functionally independent and had normal cognition
Her medications were as follows: Simvastatin 40 mg daily; Verapamil 240 mg daily; Quinine Sulphate 300 mg daily, Perindopril 5 mg/Indapamide 1.5 mg daily; Digoxin 250 mcg daily; Diclofenac 75 mg twice daily; Frusemide 40 mg daily; Betahistine 16 g three times per day; Paracetamol 1 g as required; Warfarin as per INR (target INR 2-3); Flurazepam 30 mg nocte. She was not taking OTC medications
On assessment she was pale and tired. Supine blood pressure was 122/70 mmHg; erect blood pressure after one minute was 92/62 mmHg
Pulse was 52 beats per minute. She had no clinical signs of congestive cardiac failure. She scored 9/10 on a short mental test score
Investigations showed a eGFR of 38 mL/min, serum potassium 2.8 mmol/L (low) and serum sodium 126 mmol/L (low). Haemoglobin was 10.2 g/dL with MCV 72fl (hypochromic microcytic anemia)
When evaluating the appropriateness of an older person’s prescription medications it is important to consider the following two questions:
1 Is there a clinical indication for the drug?
2 Could the drug be contributing to the presenting symptoms?
Using this approach each medication should be evaluated in turn and corrective action implemented
Medication	Clinical indication?	Contributing to presenting symptoms?	Action taken?
Simvastatin 40 mg	Yes (hyperlipidaemia, high cardiovascular risk)	Could cause muscle cramps and myopathy which could lead to falls (note patient prescribed quinine)	Check fasting lipid profile and creatine phosphokinase. Revise dose according to target lipid levels
Verapamil 240 mg	Yes (hypertension, arrhythmia)	Could cause hypotension and bradycardia. Increased risk of myopathy when prescribed with simvastatin	Consider discontinuation. Beta-blocker may be more appropriate choice as rate controlling agent
Quinine 300 mg	No clear indication	No	Muscle cramps may be due to statin. Review choice of statin. Discontinue Quinine
Perindopril 5 mg	Yes (hypertension)	Could contribute to postural hypotension and acute renal injury	Consider temporary withdrawal while investigating cause of renal dysfunction
Indapamide 1.5 mg	Yes (hypertension)	Could contribute to postural hypotension, acute renal injury, hyponatraemia and hypokalaemia. Can precipitate digoxin toxicity, hyperuricaemia and recurrent episodes of gout	Discontinue
Digoxin 250 mcg	Yes (atrial fibrillation)	Symptoms of digoxin toxicity. Dose too high given level of renal dysfunction	Discontinue. Beta-blocker may be more appropriate choice of rate controlling agent
Diclofenac 75 mg	Yes (acute gout)	Yes. Diclofenac may be causing renal impairment. Gastritis/peptic ulcer disease should also be considered because of nausea, vomiting and microcytic anemia. NSAIDs should not be prescribed with warfarin because of significantly increased risk of bleeding	Discontinue. Consider addition of allopurinol for gout prophylaxis
Frusemide 40 mg	Yes (hypertension)	Yes (hypotension, hyponatraemia, hypokalaemia, renal impairment)	Frusemide is not required as an anti-hypertensive in this patient. It has been prescribed to treat dependent lower limb edema. Leg elevation and compression stockings would be more appropriate
Betahistine 16 mg	No (prescribed for dizziness which is actually related to orthostatic hypotension)	No	Discontinue. No indication
Paracetamol 1 g	Yes (pain)	No	Continue
Warfarin	Yes (atrial fibrillation embolic prophylaxis)	May be contributing to anemia. Should not be co-prescribed with diclofenac as there is an increased risk of bleeding	Investigate cause of anemia. Consider future suitability for anticoagulation if high falls risk persists
Flurazepam 30 mg	No	Yes (falls, malaise)	Contact GP and pharmacy for prescription history. Do not suddenly discontinue because of risk of benzodiazepine withdrawal

INR: International normalized ratio; OTC: Over-the-counter; eGFR: Estimated glomerular filtration rate; MCV: Mean corpuscular volume.

Table 9 Explicit criteria for potentially inappropriate prescribing in older patients

Explicit criteria	Advantages	Disadvantages
Beers criteria[70]	Assesses prescribing quality Useful for education	Several drugs unavailable outside United States Does not include underuse of drugs, drug-drug interactions or duplicate drugs No under-prescribing indicators
Beers criteria[71]	Concise explanation of inappropriateness Severity ratings of adverse outcomes Assesses prescribing quality Useful for education	Several drugs unavailable outside United States Does not include underuse of drugs, drug-drug interactions or duplicate drugs No under-prescribing indicators
Beers criteria[72]	Concise explanation of inappropriateness Severity ratings of adverse outcomes Can be used by computerized clinical information systems	Several drugs unavailable outside the United States Controversy over some drugs labeled as inappropriate No drug to drug interaction No drug disease interactions No under prescribing
Beers criteria[73]	Concise explanation of inappropriateness Structured according to therapeutic classes and organ systems Drug disease interactions	Several drugs unavailable outside United States No drug-drug interaction No under prescribing
STOPP/START[74]	Organised by physiological system Concise list on inappropriate medications Includes drug and disease interactions, therapeutic duplications and prescribing omissions	Does not suggest safer alternatives Does not address certain domains of prescribing, e.g., indication
McLeod criteria[113]	Concise list of inappropriate medications with safer alternatives suggested Useful for education	Obsolete indicators, e.g., beta blockers in heart failure No under-prescribing indicators Several drugs unavailable outside United States
IPET 2000 (Improved prescribing in the elderly tool)[114]	Concise Useful for education	Not comprehensive Predominantly cardiovascular and psychotropic drugs No under-prescribing indicators
Zhans criteria[115]	Less restrictive than previous criteria	Several drugs unavailable outside United States No drug to drug interaction No drug disease interactions No under-prescribing indicators
French Consensus Panel List[116]	Concise explanation of inappropriateness Includes drug duplications Safer alternatives suggested	No clinical studies to date No under prescribing
Rancourt[117]	26 Drug drug interactions 10 drug duplications	Large number of criteria to get through in clinical practice Data only on long term care setting
Australian Prescribing Indicators Tool[118]	Includes drug duplication Includes under-prescribing	Not validated and time consuming Derived from Australian data sources limiting international applicability
Norwegian General Practice (NORGEP) Criteria[119]	Can be applied to medication list with no clinical information	No drug prescribing No drug-disease interactions No studies to date outside Norway
Priscus List[120]	Provides therapeutic alternatives Recommendations on dose adjusting and monitoring	No studies to date published outside Germany
Thailand Criteria[121]	Drug interactions Drug disease interactions	No studies to date outside country of origin