RSS
Drug-drug interactions are critical to monitor in older adults due to the high prevalence of polypharmacy in this population. Age-related changes in pharmacokinetics and pharmacodynamics also increase the risk of adverse effects. This fact sheet addresses key interactions and provides some management strategies.
Drug-Drug Interactions (DDIs)
Mechanisms
Pharmacokinetic interactions
- Absorption: Older adults have increased gastric pH, which causes less drug to be released from tablets and capsules. They also have decreased gastrointestinal (GI) motility, allowing more time for drugs to be absorbed. These two changes have an overall net zero effect on drug absorption.
- Distribution: Most psychotropics are highly protein-bound. Older adults often have reduced serum albumin levels and less muscle mass, leading to decreased drug protein binding. As a result, a higher proportion of the drug remains unbound (free) and active in circulation, potentially increasing drug effects and toxicity.
- Metabolism: The activity of CYP1A2 and CYP3A4 enzymes declines with age (mnemonic: A for age), leading to increased drug levels of their substrates. In contrast, CYP2D6 activity remains largely unchanged in older adults.
- Inhibitors reduce enzyme activity, leading to increased drug levels of substrates processed by the enzyme. When prescribing a medication with a known inhibitor, consider:
- Using lower doses and titrating more gradually.
- Choosing an alternative medication that is not metabolized by the inhibited enzyme.
- Inducers enhance enzyme activity, resulting in decreased drug levels of the enzyme's substrates. When prescribing a medication with a known inducer, consider:
- Using higher doses to achieve therapeutic effects.
- Selecting a different medication not metabolized by the induced enzyme.
- Even with dose adjustments, inhibitors and inducers increase the likelihood of adverse drug reactions due to the altered pharmacokinetics. Careful monitoring is essential when combining these agents.
- Inhibitors reduce enzyme activity, leading to increased drug levels of substrates processed by the enzyme. When prescribing a medication with a known inhibitor, consider:
| CYP Enzyme | Substrates | Inducers | Inhibitors |
|---|---|---|---|
| CYP1A2 | Clozapine, caffeine, olanzapine, melatonin | Omeprazole, smoking | Cimetidine, ciprofloxacin, fluvoxamine, grapefruit juice |
| CYP2C19 | Citalopram, clomipramine, diazepam | Carbamazepine, rifampin, St. John's wort | Fluoxetine, fluvoxamine, omeprazole |
| CYP2D6 | Aripiprazole, codeine, duloxetine, fluoxetine, haloperidol, metoprolol, paroxetine, perphenazine, risperidone, tricyclic antidepressants (TCAs), tramadol, venlafaxine | Rifampin | Bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, sertraline |
| CYP3A4 | Benzodiazepines, carbamazepine, HIV drugs, lurasidone, methadone, quetiapine | Carbamazepine, phenytoin, rifampin, St. John's wort | Clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, ritonavir |
- Excretion: Older adults have reduced renal and hepatic clearance. This means that more of the drug stays around.
Clinical Pearl
All these pharmacokinetic changes reinforce the adage in older adults to "start low and go slow" in order to lessen the risk of adverse effects and drug-drug interactions.
Pharmacodynamic interactions: Additive or antagonistic effects on drug action.
| Medication Class | Example Drugs | Common Interactions | Clinical Implications |
|---|---|---|---|
| Antipsychotics | Aripiprazole, olanzapine, quetiapine, risperidone | CNS depressants, QTc-prolonging agents (eg, antiarrhythmics, macrolides) | Enhanced sedation, metabolic syndrome, risk of arrhythmias |
| Benzodiazepines | Clonazepam, diazepam, lorazepam | CNS depressants (eg, opioids, alcohol), CYP3A4 inhibitors (eg, ketoconazole) | Enhanced sedation, fall risk, respiratory depression |
| MAOIs | Phenelzine, selegiline, tranylcypromine | SSRIs, SNRIs, TCAs, tyramine-rich foods | Serotonin syndrome, hypertensive crisis |
| Mood Stabilizers | Lamotrigine, lithium, valproate | Angiotensin-converting enzyme inhibitors, antipsychotics, diuretics, NSAIDs, SSRIs | Increased toxicity (lithium), hepatotoxicity (valproate), serious skin reactions (lamotrigine with valproate) |
| SNRIs | Duloxetine, venlafaxine | Anticoagulants, antihypertensives, NSAIDs, other SNRIs/SSRIs | Bleeding risk, hyponatremia, increased blood pressure, serotonin syndrome, urinary retention (duloxetine) |
| SSRIs | Citalopram, escitalopram, sertraline | Anticoagulants, antiplatelet agents, antipsychotics, NSAIDs, other SSRIs and SNRIs | Hyponatremia, increased bleeding risk, serotonin syndrome, QTc prolongation (citalopram) |
| TCAs | Amitriptyline, nortriptyline | Anticholinergics, antihistamines, CNS depressants, MAOIs | Cardiac conduction disturbances, CNS depression, enhanced anticholinergic effects, falls, hypertensive crisis |
Specific Drug-Drug Interactions
Antidepressants
SSRIs/SNRIs and NSAIDs/Anticoagulants (Warfarin)
Interaction
Increased risk of bleeding.
Management
- Monitor INR closely with warfarin.
- Consider alternative antidepressants such as bupropion or mirtazapine, which have a lower bleeding risk.
- Educate patients on signs of bleeding.
- Use gastroprotective agents (eg, proton pump inhibitors).
SSRIs/SNRIs and Linezolid/Triptans
Interaction
Risk of serotonin syndrome.
Management
- Monitor for symptoms of serotonin syndrome if a triptan is ordered for headache, though this interaction is uncommon.
- Avoid co-prescribing with linezolid, an antibiotic used for vancomycin-resistant Enterococcus faecium (VRE), as it has monoamine oxidase inhibitor (MAOI) properties.
SSRIs/SNRIs and Pain Medications (Tramadol, Meperidine, Fentanyl)
Interaction
The FDA has warned that all opioids can increase the risk of serotonin syndrome when combined with serotonergic antidepressants.
Management
Avoid co-prescribing.
Antipsychotics and QTc-Prolonging Drugs
Antipsychotics and QTc-Prolonging Drugs
Interaction
Increased risk of QTc prolongation leading to torsades de pointes, which can cause sudden cardiac death.
Monitor
ECG regularly; avoid combining QTc-prolonging drugs if possible.
Medications
- The antipsychotics with the lowest risk of QTc prolongation are aripiprazole, brexpiprazole, cariprazine, and lurasidone.
- While antipsychotics are often blamed for QTc prolongation, several medications prescribed on medical units can also prolong QTc. Be especially wary of combinations with the following (Fazio G et al, World J Cardiol 2013;5(4):87–93):
- Antibiotics
- Macrolides: Azithromycin, clarithromycin, erythromycin
- Fluoroquinolones: Ciprofloxacin, levofloxacin, moxifloxacin
- Antibiotics
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