11/13/24, 7\:43 PM Guide | Drug interactions

Drug interactions

Table of contents

Introduction

Polypharmacy is becoming a signi
population. 1
Polypharmacy can be harmful as the risk of drug interactions and adverse e
Prescribers must consider whether interactions between drugs, foods, supplements or the patient’s condition can
undermine the intended bene
A drug-drug interaction is an e
e
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.

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 e
2

Absorption

liver.
Drug absorption is heavily dependent on the route of administration due to the extent of
The amount of drug that is absorbed to exhibit an e
Oral drugs will have varied bioavailability due to the extent of
100% bioavailability as they bypass the gastrointestinal tract.
Drug interactions can alter the absorption rate, reducing or enhancing the pharmacological e
clinically signi2
Reduction in the total amount absorbed can result in
ine
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 a
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%, signi
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 speci
can cause a sizeable increase in unbound free drug, resulting in a greater pharmacological e
2
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Example\: warfarin with naproxen
Naproxen, and other non-steroidal anti-in
gastrointestinal toxicity. These ewarfarin).
Naproxen can displace warfarin from the plasma protein binding sites, leading to more unbound warfarin available,
increasing its pharmacological e
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 e
This can have a substantial impact on warfarin’s pharmacological and toxic pro
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 e
In contrast, drugs that inhibit the metabolism of CYP enzymes decrease the metabolism of the second drug resulting in
increased drug concentration, pharmacological e
The full e
7
Enzyme induction\: takes approximately two-three weeks to develop and wear o
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 e8
Contraceptive exposure
can be reduced by up to 50% 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.
Enzyme inhibitors
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Common enzyme inhibitors can be remembered using the mnemonic SIC FAM\:
Sodium valproate
Isoniazid
Cimetidine
Azole-Antifungals
Alcohol (acute/binge)
Macrolides/Metronidazole
Example\: clarithromycin with simvastatin
Clarithromycin inhibits 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 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 e
approximately 40% following ibuprofen use, potentially causing accumulation of methotrexate and toxic adverse e
9
Action\: ideally, avoid NSAIDs with methotrexate and use alternative analgesia. Alternatively, monitor methotrexate levels
or observe for toxic e

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 e
interactions. 7
This interaction can either potentiate the pharmacological e
potentiate adverse e
Antagonistic e
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 e
Example of a bene
Ramipril and amlodipine work synergistically to reduce blood pressure at an enhanced level due to the di
mechanisms of action\:
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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 e
Action\: no action is required unless hypotension occurs.
Example of a harmful additive/synergistic interaction\: enoxaparin with apixaban
The additive e
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, 11
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 e
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 speci
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-speci
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.
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Interaction Explanation Action
Omeprazole with
clopidogrel
SSRIs with NSAIDs
Methotrexate with
trimethoprim
Verapamil with beta-
blockers
Omeprazole can
decrease the antiplatelet
e
SSRIs can increase the
risk of upper
gastrointestinal bleeding
when given with NSAIDs
Risk of severe bone
marrow suppression &
subsequent
pancytopenia (may be
fatal) when given
concurrently
Additive cardiac
depression e
(leading to bradycardia,
asystole, sinus arrest)
This interaction can also
occur with ocular beta
blockers
Use only if the risk of
gastrointestinal bleeding
outweighs the risk of
clopidogrel treatment
failure
Consider switching to a
di
esomeprazole) or an H2-
receptor antagonist
(except for cimetidine)
Advise patients on the
risk of bleeding, and
consider using alternative
analgesia
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
Intravenous verapamil
should not be given. Oral
verapamil can have some
bene
closely monitored
ACE inhibitors with
potassium-sparing
diuretics (e.g.
spironolactone/eplereno
ne)
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 e

Managing drug interactions

If you encounter a potential drug interaction on a patient's prescription or drug chart, check if the drug therapy is established
or 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 e
7
Some drugs in the same class can interact di
drug is stopped (e.g. rebound tachycardia when beta-blockers are stopped).
7
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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

References

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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. W a r f a r i n 0 .5 m g T a b l e t s – S u m m a r y o f P r o d u c t C h a r a c t e r i s t i c s ( S P C ) – ( e M C ) . [online] [LINK] [Accessed 14 March 2023]
Available from\:
7. Wi
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 e
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]
Source\: geekymedics.com
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