Prescribing basics

Drug Interactions

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Introduction

Polypharmacy is becoming a significant issue due to the increasing prevalence of multi-morbidity and the growing population.1Β Polypharmacy can be harmful as the risk of drug interactions and adverse effects significantly increases.Β 

Prescribers must consider whether interactions between drugs, foods, supplements or the patient’s condition can undermine the intended benefit and cause harm.

A drug-drug interaction is an effect that the administration of one drug has on another drug(s), often causing a harmful effect.

Generally, two broad categories of drug-drug interactions exist: pharmacokinetic and pharmacodynamic. This article will cover both categories and include examples of common drug interactions.Β 

You might also be interested in our Prescribing Safety Assessment Question Bank which contains over 500 prescribing questions.

Pharmacokinetic interactions

Pharmacokinetic interactions occur when one drug alters the absorption, distribution, metabolism or excretion of another, resulting in either an increase or decrease of the available drug to produce a pharmacological effect.2

Absorption

Drug absorption is heavily dependent on the route of administration due to the extent of first-pass metabolism through the liver.

The amount of drug that is absorbed to exhibit an effect is dependent on the bioavailability of the drug.

Oral drugs will have varied bioavailability due to the extent of first-pass metabolism, whereas intravenous drugs will have 100% bioavailability as they bypass the gastrointestinal tract.

Drug interactions can alter the absorption rate, reducing or enhancing the pharmacological effect. Delayed absorption is clinically significant when a rapid effect isΒ required (e.g. analgesia).2 Reduction in the total amount absorbed can result in ineffective therapy (e.g. antibiotics).2

Example: doxycycline with iron (e.g. ferrous sulfate)

Oral iron can decrease the absorption of tetracycline antibiotics (e.g. doxycycline). Tetracyclines have a strong affinity for iron, creating a poorly soluble chelate that is less readily absorbed by the gastrointestinal tract, resulting in much lower serum concentrations of the antibiotic.3,4

The reduction in absorption of tetracycline could be as profound as 90%, significantly reducing the antibacterial effects.4

Action: administer the iron preparations at least three hours before or three hours after the tetracycline.

Distribution

Drugs bind to plasma proteins with varying specificity. When heavily protein-bound drugs are displaced by another drug, this can cause a sizeable increase in unbound free drug, resulting in a greater pharmacological effect.2

Example: warfarin with naproxen

Naproxen, and other non-steroidal anti-inflammatory drugs (NSAIDs), can prolong bleeding times and cause gastrointestinal toxicity. These effects are aggravated when given with anticoagulants (e.g. warfarin).

Naproxen can displace warfarin from the plasma protein binding sites, leading to more unbound warfarin available, increasing its pharmacological effect (as well as toxic effects):5,6

  • Warfarin is 99% protein bound, and 1% is unbound (free)
  • If naproxen displaces warfarin by just 1%, it will result in warfarin being 98% protein bound and 2% unbound
  • This effect causes a 100% increase in the free-form drug (from 1% to 2%)
  • This can have a substantial impact on warfarin’s pharmacological and toxic profile

Action: monitor the patient’s INR and for signs of bleeding. Alter the warfarin dosing to ensure in normal reference range for relative indication.

Metabolism

Drug metabolism commonly occurs in the liver through phase I reactions (oxidation, reduction, or hydrolysis) or phase II reactions (e.g. glucuronidation).2

Most drug metabolism is carried out by phase I reactions involving the isoenzyme cytochrome P450 (CYP450). Hepatic CYP enzymes interact with various drugs, often inducing or inhibiting their metabolism.

Drugs that induce the metabolism of CYP enzymes increase the metabolism of the second drug resulting in a reduced drug concentration and pharmacological effect, potentially rendering it subtherapeutic.

In contrast, drugs that inhibit the metabolism of CYP enzymes decrease the metabolism of the second drug resulting in increased drug concentration, pharmacologicalΒ effect, and potential toxicity.Β Β 

The full effects do not occur immediately:7

  • Enzyme induction: takes approximately two-three weeks to develop and wear off
  • Enzyme inhibition: takes only days to develop

Enzyme inducers

Common enzyme inducers can be remembered using the mnemonic GP RAPS:

  • Griseofulvin
  • Phenytoin
  • Rifampicin
  • Alcohol (chronic)
  • Phenobarbital
  • Sulfonylureas (e.g. gliclazide)
Example: phenytoin with desogestrel

Phenytoin is a potent CYP3A4 inducer which induces the metabolism of oral progesterone-only contraceptives (e.g. desogestrel), subsequently reducing their effect and potentially allowing ovulation to occur.8 Contraceptive exposure can be reduced by up to 50%Β and may cause intermenstrual breakthrough bleeding and spotting.8

Action: use alternative methods of contraception (intrauterine devices, depots or barrier methods); for less than two months use of phenytoin, consider additional consistent use of condoms during and for at least 28 days after stopping phenytoin.8

This interaction may occur with other enzyme-inducing drugs and oral contraceptives, so always check for individual interactions.Β 

Enzyme inhibitors

Common enzyme inhibitors can be remembered using the mnemonic SIC FAM:

  • Sodium valproate
  • Isoniazid
  • Cimetidine/Carbamazepine
  • Azole-Antifungals
  • Alcohol (acute/binge)
  • Macrolides/Metronidazole
Example: clarithromycin with simvastatin

Clarithromycin induces the CYP3A4 enzyme responsible for metabolising simvastatin, subsequently increasing the plasma concentrations of simvastatin. Simvastatin exposure is increased eight to tenfold by multiple doses of clarithromycin and about fourfold following a single dose.8 This interaction can potentially cause toxicity, leading to myopathies and rhabdomyolysis.8

Action: concurrent use is contraindicated; withhold simvastatin while administering clarithromycin.

Excretion

Some drugs are eliminated through the kidneys by glomerular filtration and active tubular secretion.2 If drugs are excreted through the same active transporter system in the kidneys, the excretion of each drug is reduced due to competition in the proximal tubule.7

Example: methotrexate with NSAIDs

This is a multifactorial interaction. However, methotrexate is a substrate for OAT1 and/or OAT3, which are involved in the active renal secretion of drugs. There is evidence that competition with NSAIDs for these transporters exists.8

Furthermore, methotrexate is cleared unchanged from the body by renal excretion. NSAIDs can increase methotrexate concentrations due to their nephrotoxic effects. There is evidence that methotrexate clearance reduces by approximately 40% following ibuprofen use, potentially causing accumulation of methotrexate and toxic adverse effects.9

Action: ideally, avoid NSAIDs with methotrexate and use alternative analgesia. Alternatively, monitor methotrexate levels or observe for toxic effects if NSAID use is unavoidable.


Pharmacodynamic interactions

Pharmacodynamic interactions are much more predictable than pharmacokinetic interactions due to the knowledge of the pharmacology of the drugs. Pharmacodynamic interactions involve drugs that have either similar or antagonistic pharmacological properties.

Similar effects are usually due to drugs acting on the same physiological systems, often termed additive/synergistic interactions.7 This interaction can either potentiate the pharmacological effect (providing greater pharmacological effects) or potentiate adverse effects (causing greater toxic effects).Β 

Antagonistic effects are usually down to the competition of drugs at receptor sites, often termed antagonism interactions.7 This usually occurs when one drug binds to the receptor site, blocking the second drug from binding to the same receptor site, resulting in reduced pharmacological effects of the second drug.

Example of a beneficial additive/synergistic interaction: ramipril with amlodipine

Ramipril and amlodipine work synergistically to reduce blood pressure at an enhanced level due to the different mechanisms of action:

  • Ramipril inhibits the ACE enzyme from converting angiotensin I to angiotensin II (causing increased vasodilation due to inhibition of bradykinin breakdown)
  • Amlodipine exhibits its antihypertensive effects due to the direct relaxation of the vascular smooth muscles

Action: no action is required unless hypotension occurs.

Example of a harmful additive/synergistic interaction: enoxaparin with apixaban

The additive effects of concurrent administration of enoxaparin with apixaban cause additive anti-Xa activity. This increases the risk of bleeding.8 Concurrent administration can cause up to a 42% increase in anti-Xa activity compared to apixaban alone. Therefore concurrent administration is contraindicated according to the MHRA.10, 11Β 

Action: concurrent administration is contraindicated. If given together, monitor signs for excessive bleeding; if appropriate, consider giving an antidote.

Example of an antagonism interaction: propranolol with salbutamol

Non-cardioselective beta-blockers (such as propranolol) block beta-2 receptors in the bronchi, reducing normal bronchodilation, which can exacerbate bronchoconstriction in patients with asthma.8 Similarly, non-cardioselective beta-blockers may antagonise the bronchodilator effects of beta-agonists (such as salbutamol), potentially causing bronchospasms in patients with respiratory conditions.

Although cardioselective beta-blockers (such as bisoprolol) do not generally inhibit bronchodilation, there is a potential risk, especially at higher doses.8

Action: non-cardioselective beta-blockers should be avoided in patients with asthma or COPD; if use is unavoidable, they should be initiated at smaller doses with close monitoring.

There are two broad types of beta blockers:

  • Cardioselective (cardio specific) acting on the beta-1 receptors in the heart (therefore reducing bronchoconstriction in the lungs)
  • Non-cardioselective acting on the beta-2 receptors on heart and lung receptors.

The mnemonic below is an easy way to remember the cardio-selective (cardio-specific) beta-blockers. All other beta blockers are non-cardioselective.

Mnemonic: Cardioselective Beta Blockers Are MEAN
  • Celiprolol
  • Bisoprolol
  • Betaxolol
  • Acebutolol
  • Metoprolol
  • Esmolol
  • Atenolol
  • Nebivolol

Other common drug interactions

Table 1. Other clinically important drug interactions.

Interaction Explanation Action

Omeprazole with clopidogrel

Omeprazole can decrease the antiplatelet effects of clopidogrel

Use only if the risk of gastrointestinal bleeding outweighs the risk of clopidogrel treatment failure

Consider switching to a different PPI (except esomeprazole) or an H2-receptor antagonist (except for cimetidine)

SSRIs with NSAIDs

SSRIs can increase the risk of upper gastrointestinal bleeding when given with NSAIDs

Advise patients on the risk of bleeding, and consider using alternative analgesia

Methotrexate with trimethoprim

Risk of severe bone marrow suppression & subsequent pancytopenia (may be fatal) when given concurrently

Monitor full blood count when administered concurrently. This interaction can still occur even after methotrexate has been stopped for three months

Consider using folinic acid as an antidote if needed

Verapamil with beta-blockers

Additive cardiac depression effects (leading to bradycardia, asystole, sinus arrest)

This interaction can also occur with ocular beta blockers

Intravenous verapamil should not be given. Oral verapamil can have some benefits but must be closely monitored

ACE inhibitors with potassium-sparing diuretics (e.g. spironolactone/eplerenone)

Concurrent use increases the risk of hyperkalaemia and acute kidney injury

Use the lowest possible doses; the maximum dose of spironolactone should not exceed 25mg

Monitor potassium closely and consider stopping if severe adverse effects occur


Managing drug interactions

If you encounter a potentialΒ drug interaction on a patient’s prescription or drug chart, check if the drug therapy isΒ established orΒ newly prescribed. If drug therapy is established, check if the patient has tolerated the therapy, additional monitoring may be required.7

If the interaction is potentially dangerous, seek an alternative drug. If the interaction is low or moderate risk, monitor for adverse effects.7

Some drugs in the same class can interact differently (e.g. ranitidine versus cimetidine). Adverse effects can occur when the drug is stopped (e.g. rebound tachycardia when beta-blockers are stopped).7

Be aware that elderly patients are at higher risk of drug interactions due to polypharmacy and altered metabolism.7

Before prescribing, always check for interactions with high-risk drugs such as CYP inducers/inhibitors and drugs with a narrow therapeutic index (e.g. lithium).7

Check interactions with non-prescription drugs such as over-the-counter, herbal supplements, and recreational drugs. It is important to ask about non-prescription drugs as part of the medication history.7


Editor

Dr Chris Jefferies


References

  1. Duerden, M, Avery, T, Payne, R. 2013. Polypharmacy and medicines optimisation: Making it safe and sound. TheKing’sFund. Available from: [LINK]
  2. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press
  3. Albert A, Rees CW. Avidity of the tetracyclines for the cations of metals. Nature (1956) 177, 433–4.PubMed
  4. Albert A, Rees CW. Avidity of the tetracyclines for the cations of metals. Nature (1956) 177, 433–4.PubMed
  5. Pullar T. Interaction of ibuprofen and warfarin on primary haemostasis. Br J Rheumatol (1989) 28, 265–6.PubMed
  6. Medicines.org.uk. 2021. Warfarin 0.5mg Tablets – Summary of Product Characteristics (SPC) – (eMC). [online] Available from: [LINK] [Accessed 14 March 2023]
  7. Wiffen, P., Mitchell, M., Snelling, M., Stoner, N. (2017) Oxford handbook of clinical pharmacy. Oxford: Oxford University Press
  8. Baxter K, Preston CL (eds), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press
  9. Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC. The effects of salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis. Eur J Clin Pharmacol (1992) 42, 121–5.PubMed
  10. Barrett YC, Wang J, Song Y, Pursley J, Wastall P, Wright R, Lacreta F, Frost C. A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost (2012) 107, 916–24.PubMed
  11. Medicines and Healthcare Products Regulatory Agency. New oral anticoagulants apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto). Drug Safety Update (2013) 3, A1. Available from: [LINK]

 

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