Polypharmacy Toxicities

Drugs with similar effects cause toxicity when used in combination, i.e. pharmacodynamic interactions. This is more likely to occur in patients with increased susceptibility to drug effects, such as the frail elderly.

The presence of multiple medicines also increases the risk of pharmacokinetic interactions whereby one medicine increases the concentrations of another medicine, leading to toxicity.

General advice

• Hypotension, sedation, bleeding, nephrotoxicity, anticholinergic toxicity, and serotonin toxicity are common preventable polypharmacy toxicities in susceptible patients.
• QT prolongation (leading to Torsades de Pointes), myelosuppression, severe cutaneous adverse reactions (SCAR), and hepatotoxicity leading to severe liver failure, are less common, but can be fatal.
• Consider using the NZ Formulary interaction checker.
• If you are unsure, discuss with the ward pharmacist, or contact Medicines Information (80900).

Serotonin Toxicity

• Characterised by cognitive, neuromuscular, and autonomic effects:
  • Cognitive – confusion, delirium, and agitation
  • Neuromuscular – restlessness and muscular spasms
  • Autonomic effects – fever, sweating, tachycardia, blood pressure fluctuations, mydriasis, nausea, and diarrhoea.
• Mild toxicity is common, and under-recognised.
• Severe toxicity can cause seizures and has been associated with fatalities.
• Usually due to the combined effect of two or more serotonergic drugs, but can occur due to overdose of a single drug, or in susceptible patients.
• Usually responds to drug withdrawal and supportive measures.
• Tramadol used in combination with an SSRI is a common cause of serotonin toxicity.

The following list is not exhaustive, but shows some common examples:

Anticholinergic Toxicity

• Often presents as falls, mild cognitive impairment, or delirium.
• Specific effects may include memory impairment, confusion, hallucinations, dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia.
• Harm is more likely in susceptible patients including those with pre-existing neurological dysfunction, a multiple anticholinergic drugs regimen, and the elderly.
• Anticholinergic burden comes from the anticholinergic potency and the dose of the drug prescribed.
• As a rule of thumb one ‘strongly’ anticholinergic drug, or at least two ‘moderately’ anticholinergic drugs, can lead to clinically apparent anticholinergic effects (see list below).
• If anticholinergic toxicity is suspected this should be treated by reducing doses. Avoid sudden complete cessation as this can induce a cholinergic rebound syndrome.

The following list is not exhaustive, but shows common examples:

Inhaled (e.g. tiotropium, ipratropium, glycopyrronium, and umeclidinium) or topical anticholinergic drugs have low systemic exposure, but may have systemic effects at high doses or in susceptible patients.

QT Interval Prolongation

• Drugs that prolong cardiac repolarisation prolong the QT interval and can lead to Torsades de Points (TdP), ventricular tachycardia, and ventricular fibrillation.
• QT prolongation is a QTc interval (i.e. QT interval corrected for heart rate) greater than 450 milliseconds (ms) in men or 460 ms in women.
• Arrhythmias occur more often at QTc intervals greater than 500 ms, usually in association with predisposing risk factors.
• QTc prolongation can be genetic or acquired from hypokalaemia, hypomagnesaemia, or drugs.
• A prolonged QT is often seen with Class I and III antiarrhythmic agents (e.g. sotalol, amiodarone, flecainide).
• Drug-induced QT prolongation usually occurs within days of starting the offending drug(s).
• Classifying QTc prolonging drugs is difficult. A respected source is www.crediblemeds.org.

The following table is not exhaustive, but shows common examples:

Predisposing factors

• The risk of arrhythmias at any given QTc interval varies between patients.
• The risk for developing TdP when starting a QT prolonging drug is increased by the specific drug and by the following predisposing factors:
  • Electrolyte disturbances (esp. hypokalaemia and hypomagnesaemia)
  • Bradycardia (< 50 beats/min)
  • Myocardial ischaemia / infarction
  • Renal or hepatic disease
  • Hypoglycaemia
  • Congenital long QT syndrome
  • Heart failure
  • Hypothyroidism
• Drug interactions can increase the risk of QTc prolongation and TdP by the following mechanisms:
  • Two drugs may cause QTc prolongation independently with an additive effect.
  • One drug may decrease the clearance of another drug that prolongs the QTc interval.
  • One or more drugs may cause electrolyte disturbance, bradycardia, or other effects that predispose the individual to the QT prolonging effects of another drug.
  • The macrolide antimicrobials erythromycin and clarithromycin prolong QTc. They also inhibit the clearance of drugs metabolised by CYP3A. This has implications when co-prescribed with drugs metabolised by CYP3A that also prolong the QTc interval.

Monitoring

ECG measurement of the QTc interval prior to and early on in treatment (when at, or approaching, steady-state) is recommended for all patients:

• when prescribed a QTc prolonging antiarrhythmic (above).
• when prescribed a second, or more, QTc prolonging drugs.
• with predisposing risk factors who have been prescribed one QTc prolonging drug.

Nephrotoxicity

• Prerenal due to decreased glomerular pressure, with the combination of decreased plasma volume, and dilation of the efferent arteriole.
• Nephritis due to auto-immune effects (e.g. amoxicillin, and proton pump inhibitors).
• Zoledronic acid may results in acute kidney injury (AKI) due to “tubule-toxicity”. Ensuring adequate hydration status prior to administration reduces the risk of associated AKI.
• The use of nephrotoxic medications in combination can lead to renal impairment, and can exacerbate AKI.
• These medications include ACE-inhibitors/ARBs, diuretics and NSAIDs – avoid co-prescribing the "triple whammy" of all three.
• Consider withholding nephrotoxic medications in the setting of acute kidney impairment or dehydration.

Topic Code: 93252

must be prescribed or recommended by a consultant.