We dislike poly-pharmacy as much as it is possible, and we would never exhibit a remedy of any kind unless we had a scientific reason for so doing and unless we were prepared to defend our method of treatment.
Elderly patients are responsible for the consumption of a large volume of drugs, and over the last 20 years this tendency has significantly increased. While effective medical treatment is a pivotal issue in the management of illnesses and an indispensable measure allowing many comorbid patients to survive, in the aged population the use of multiple drugs remains an important risk factor for hospital admission, adverse drug reactions (ADRs) and mortality. As the older population grows, pharmacovigilance is becoming an increasingly important issue worldwide. In Europe, the EMA (European Medicines Agency) plays an important role in the development, approval and monitoring of medicines for older people.
In the surgical setting, poly-medication has been revealed to be an important determinant for perioperative complications and to deserve careful understanding in both preoperative evaluation and the perioperative course.
Poly-medication: A (Hyatrogenic) Geriatric Condition?
Older patients are susceptible to multiple diseases, have more than one disease at a time, are often vulnerable and take up and eliminate medicines differently from younger patients. They consult different specialists, accumulate different prescriptions and tend to perpetuate them over time. Self-medication with over-the-counter and herbal drugs is common, and elderly patients tend to not report it. For their part, many doctors tend not to systematically check patients’ medication regimen before adding a new prescription, and therapeutic duplication or overprescription are not unusual. For instance, facing a drug-induced adverse reaction (metoclopramide-induced parkinsonism), less experienced doctors misdiagnose symptoms and treat them by prescribing one more drug (initiation of anti-Parkinson’s treatment), so increasing the risk of ADRs: this phenomenon is called “prescription cascade.” These events are more frequently observed among institutionalized patients.
The cost of poly-medication is impressive and has dramatically increased worldwide in the last 20 years: currently, some 16–20% of the global population accounts for more than 40% of the total drug expenditure in all the Western and many non-Western countries.
According to the WHO, the term poly-medication refers to a patient taking five or more medications. Poly-medication is not negative in principle; what makes the difference is appropriateness of the prescription. Inappropriate medication occurs when:
one or more drugs are prescribed that are not or no longer needed, either because there is no evidence-based indication, the indication has expired or the dose is unnecessarily high
one or more drugs fail to achieve the therapeutic goals they are intended for
one or the combination of several drugs cause unacceptable ADRs or put the patient at high risk of ADRs
the patient is not willing/able to take one or more medicines as intended.
Appropriate poly-medication is present when:
all drugs are prescribed for the purpose of achieving specific therapeutic goals
therapeutic goals are actually being achieved or there is reasonable chance they will be achieved in the future
drug therapy has been optimized to minimize the risk of ADRs
the patient is motivated and able to take all medicines as intended (NHS 2015).
Many of the drugs whose use would be justified by an underlying condition present an unfavorable risk/benefit ratio in the elderly, due to unacceptable side effects, the need for close monitoring or significant interaction with other prescribed drugs.
The AGS (American Geriatrics Society) guideline “Beers Criteria for Potentially Inappropriate Medication Use in Older Adults” aims to optimize medication prescription in the elderly. De-prescribing unnecessary medication is a basal criterion to reduce ADRs. Drugs to be avoided or used with caution include anticholinergics, sedatives, antipsychotics, NSAIDs and others.
The list and the guideline were originally published in 1997. The last update, which includes more than 40 potentially problematic medications or classes of medication organized across five lists (including a list of 13 medication combinations that may lead to harmful interactions and a synthesis of some medications that should be avoided in case of renal insufficiency), was made in 2015 (AGS 2015).
Information about the prevalence of poly-medication in Europe is not detailed and mostly based on small studies. An investigation by the EU (CORDIS; cordis.europa.eu/result/rcn/157256_en.html (last accessed February 2017)) showed that poly-medication among older European citizens varies between 25 and 50%; higher prevalence is reported among nursing home residents and the over-75s. A study on potentially inappropriate drugs use in institutionalized elderly patients (Fialová et al. 2005) showed that almost 20% used at least one inappropriate drug; the highest values (41.1%) were registered in Eastern Europe. A more recent Spanish study (Fajareldines et al. 2016) showed a percentage of potentially inappropriate medication of 55% in hospitalized patients, 26% in ambulatory patients and 80% in emergency patients.
A growing awareness exists that careful management of patients’ medication regimen is essential in reducing perioperative complications. The main aspects to consider are:
what are the effects of aging on pharmacokinetics and pharmacodynamics?
what are the assumed drugs (purpose, dosage, organ toxicity, side effects) and what is the patient’s metabolic condition (renal/hepatic insufficiency)?
what set of circumstances may occur regarding the medication prescription in that given patient (compliance with treatment, risk of errors, not taking a necessary drug)?
With aging, drug pharmacokinetics are altered to a varying degree, as a consequence of aging processes and associated conditions affecting metabolic processes (see Table 4.1).
|Pharmacokinetic parameter||Altered physiology with aging||Comments|
|Absorption||↓ Gastric secretion||Many drugs may diminish in their absorptive ability Time of onset of action may be delayed|
|↑ Gastric pH||Absorption is the pharmacokinetic parameter least affected by aging|
|↑ GI motility|
|↓ GI blood flow|
|Distribution||↓Total body water||Increased Vd of lipid-soluble drugs|
|↑ Lean body weight||Increased free fraction of drug|
|↑ Body fat|
|Metabolism||↓ Enzyme induction||Reduced hepatic clearance of drugs|
|↓ Hepatic mass||Increased potential for drug interactions|
|↓ Hepatic blood flow||For elderly patients, dosage should be reduced for hepatically cleared drugs|
|↓ Activity in mixed function oxydase system|
|Elimination||↓ GFR||For elderly patients, drug accumulation will occur for renally cleared drugs|
|↓ Renal blood flow|
GFR, glomerular rate; GI, gastrointestinal; Vd, volume of distribution.
Drug absorption can be modified by reduced acid gastric secretion (which is accentuated by antiacid and proton-pump inhibitor administration), decreased gastric emptying rate, reduced splanchnic blood flow and reduced mucosal absorptive surface. Changes can significantly alter drug absorption and consequently modify its onset time. The absorption of drugs undergoing first-pass metabolism (nitrates, propranolol) may also be increased.
Changes in body composition (increased body fat mass and reduced corporeal water) significantly modify drug distribution. Fat soluble drugs (diazepam) have a greater volume of distribution and may require careful dosage adjustments until the required result is obtained.
Reduced body water can affect the distribution volume of water-soluble drugs, and higher plasma concentration can be reached with a given dose. Reduced protein binding can result in increased plasma concentration, with higher quotes of free circulating drug and increased effects.
Slowing of any nature in metabolic processes prolongs the half-life of drugs and maximizes the risk of ADRs. Nutritional status and alcohol abuse may affect metabolic capacity. In the elderly, liver mass, hepatic blood flow and intrinsic metabolic activity (including the CYP450 enzyme system) are reduced and all the drugs metabolized by the liver have an increased half-life in variable measure; consequently, their dosage should be reduced.
Aging is accompanied by reduced renal function to varying degrees, which is related to reduction in renal blood flow, renal mass, and the number and size of functioning nephrons. Adjustments in drug dosage based on residual renal function (serum creatinine value) should be calculated, mostly for drugs prevalently eliminated by the renal route.
Aging can substantially modify drug action and various adverse effects may appear, mostly due to changes in receptor affinity and number of receptors, which may change over time (see Table 4.2). This is of particular relevance for drugs active on the cardiovascular system and the central nervous system (CNS). Patients receiving antihypertensive therapy for many years may experience unexpected orthostatic hypotension, due to deterioration of the baroreflex-mediated compensatory mechanisms.
|Drug class||Potential pharmacodynamic issues||Comments|
|Antihypertensives||Orthostatic hypotension||Additive effect at lowering blood pressure|
|Use with caution|
|Start with lower dose|
|Benzodiazepines||Increased sensitivity (e.g. drowsiness, confusion)||Use with caution|
|Avoid other central nervous system active drugs|
|Use lowest tolerable dose|
|β-Adrenergic blockers (e.g, propranolol)||β-receptors less responsive||May require greater β-blocker doses to have same effect|
|Anticoagulants (e.g, warfarin)||Greater sensitivity to drug action||Initiate with lower dose|
|Follow international normalized ratio closely|
|Diuretics||Greater sensitivity to drug action||Monitor blood pressure and electrolytes|
Sedation, confusion, dizziness and even seizures can be induced in the elderly by centrally acting drugs, due to similar mechanisms. The reduced cholinergic reserves in the elderly cause extreme sensitivity to anticholinergic drugs.
After the age of 65 years and mostly in cases of associated illnesses, mean drug consumption is reported to range between 3.9 (65–80 years) and 4.4 medications/day after the age of 80 years (Delpierre 2006). A need of 10–11 medications/day is not an exceptional condition in the oldest patients. The most frequently prescribed drugs are cardiovascular, followed by drugs acting on the CNS and analgesics. Over-the-counter and herbal drugs are also frequently consumed.
ACE inhibitors, sartans, antiarrhythmics, β-blockers and vasodilators are the cardioactive drugs most frequently taken by the elderly. Despite having reduced plasma renin activity, elderly hypertensive patients respond well to ACE inhibitors and tolerate them well. However, drug plasma concentrations may be increased by reduced renal clearance and excessive hypotension may occur, especially when associated with diuretics.
Digoxin is mostly prescribed to treat atrial fibrillation and heart failure. Age-related changes in drug metabolism increase the risk of toxicity, the signs of which are heart block, arrhythmia, anorexia, blurred vision or confusion. Vigilant monitoring is required, mostly in case of renal decline. Serum levels can be unreliable. When the therapeutic goal is reduction in cardiac rate, diltiazem or β-blockers should be preferred.
Benzodiazepines, sedatives and antipsychotics are disproportionately prescribed to elderly patients to treat psychiatric conditions such as dementia, delirium or psychosis, agitation, affective disorders or behavior alterations. In many cases, their use is inappropriate or can be reduced. First-generation drugs such as haloperidol and fluphenazine produce a block of the dopaminergic system than can induce parkinsonism in cases of plasma accumulation. Second-generation drugs (risperidone, olanzapine) are better tolerated, but induce multiple serotoninergic and dopaminergic transmitter system alteration. For all these drugs a dose-dependent toxicity has been reported. Major side effects of antipsychotics include dyskinesia, parkinsonism, dystonia, akatisia or different combinations of motor symptoms. Autonomic side effects are orthostatic hypotension, tachycardia, Q-T interval prolongation, constipation and urinary retention. Neuroleptic malignant syndrome is a severe, life-threatening condition presenting with autonomic hyperactivity, muscular rigidity and hyperthermia.
Anticholinergic drugs (AChs) inhibit vagal-controlled gastrointestinal, urinary and lung motor impulses. These drugs are used to treat a wide number of conditions that are common among the elderly. Drugs causing a strong ACh effect are numerous and include antiemetics, antispastics, bronchodilators, antiarrhythmics, antihypertensives, various analgesics, antihistamines, corticosteroids, smooth-muscle relaxants and psychotropic drugs.
AChs are associated with multiple adverse effects to which older patients, who have reduced cholinergic reserves, are prone. Those effects include memory impairment, confusion, impaired homeostatic regulation, dry mouth, blurred vision, constipation, nausea, urinary retention and tachycardia. AChs can precipitate the course of narrow angle glaucoma or induce acute urinary retention in patients with prostate hypertrophy and are an important predisposing risk factor for postoperative delirium (see Chapter 14).
Acute ACh toxicity syndrome has a clinical presentation whose symptoms vary from minor, such as constipation or dry mouth, to severe, such as acute delirium, hyperthermia, coma and death.
To evaluate drug exposure effects, a Drug Burden Index, incorporating drugs with anticholinergic or sedative effects, the total number of medications and dosage has been defined (Hilmer et al. 2009).
Antiplatelet, anticoagulant and fibrinolytic drugs are frequently taken by older patients to prevent, postpone or attenuate the severity of thrombotic events, such as stroke, transient ischemic attack, myocardial infarction, systemic or pulmonary embolism and deep vein thrombosis. Prevention of thromboembolic complications of atrial fibrillation and of coronary stent occlusion are the most frequent indications. The most common ADE induced by these drugs is bleeding. A critical point is to establish whether the benefits of the treatment outweigh the risk of bleeding, which is increased in elderly patients; on one hand bleeding is in fact associated with earlier mortality and on the other predictors of ischemic versus bleeding events may coexist in the same patient (ESC 2015).
New direct oral anticoagulants (DOACs) have been shown not to cause excessive bleeding and to be associated with equal or greater efficacy than conventional therapy (Sardar et al. 2014, Heffner 2016).
In accordance with the ACCP (2012) guidelines, issued in 2012 and recently (2016) updated (see Chapter 37), in case of minor procedures, such as cataract or dental, patients receiving ASA as secondary prevention or patients at low risk for bleeding receiving ASA therapy can safely maintain the treatment perioperatively. The same can be applied to patients at moderate or high risk for cardiovascular events undergoing non-cardiac surgery. However, for patients at low risk for cardiovascular events and receiving ASA, the ACCP suggestion is to stop the drug 7–10 days before surgery.
In patients undergoing cardiac surgery and being under only ASA treatment, the ACCP guidelines suggest continuing or discontinuing the drug perioperatively in accordance with the risk entity: patients at high to moderate risk should maintain their treatment, whereas those at low risk are suggested to interrupt ASA 7–10 days before surgery. In cases of cardiac surgery on patients under dual antiplatelet drug treatment, ACCP guidelines suggest to continue ASA and stop clopidogrel/prasugrel five days before surgery.
A strong recommendation concerns patients who received a coronary stent shortly before surgery: in these patients surgery should be postponed until the completion of dual antiplatelet treatment (six weeks after implantation of a bare stent and six months after a drug-eluting stent), as the risk of coronary re-occlusion is high. In case of urgent, non-deferrable surgery, dual treatment should be maintained perioperatively, because the risk of bleeding is less severe than that of myocardial re-infarction (ACC/AHA 2016).
Criteria for perioperative management of antiplatelet, anticoagulant and fibrinolytic drugs administered to prevent surgery-related thromboembolic complications are discussed in Chapter 37.