This article discusses different mechanisms of drug interactions. We link to other SPS articles to help support decision making.

Mechanisms of drug interactions

Drug interactions occur when the effect of a drug is altered by co-administration of another drug, food or herbal product.

Most drug interactions can be split into two categories, pharmacodynamic interactions and pharmacokinetic interactions.

Significance of drug interactions

It may be possible to use interacting drugs together. You may need to take additional precautions, such as monitoring your patient or adjusting a dose.

Drug interactions may be:

  • potentially harmful and contraindicated
  • clinically significant and require action
  • clinically insignificant
  • beneficial and produce a desired therapeutic effect

Resources

There is no single comprehensive source of information for drug interactions. SPS has suggested resources to help healthcare professionals find information to answer questions about drug interactions.

Decision to prescribe

When prescribing interacting drugs, clinicians will need to consider, where relevant:

  • their confidence in the completeness of patient relevant medical and drug history, including herbal and over the counter (OTC) medications
  • what alternative treatment is available if there is a contraindication
  • their familiarity with prescribing and managing drug interactions
  • the mechanism and the clinical significance of the interaction
  • their confidence that the patient understands the risks and benefits and that the patient will be followed up appropriately
  • practical issues such as additional monitoring, ease of dose adjustments and whether an interacting drug might be safely withheld

Pharmacodynamic interactions

This occurs when two or more drugs have additive or opposing pharmacological effects.

Additive

The desired or adverse effects of two drugs given in combination may be the same. This can be beneficial or potentially harmful.

Harmful

The additive adverse effects of two or more interacting drugs used together can cause harm.

For example, low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) prescribed in combination could increase risk of bleeding. Do not use LMWHs and DOACs in combination.

Understanding direct oral anticoagulant (DOAC) interactions provides further information on risks and mechanisms of DOAC interactions.

As another example, opioids may enhance the sedative and respiratory depressant effects of promethazine. A reduction in the dose of opioid may be necessary.

Beneficial

The desired effect of two or more interacting drugs may be enhanced when used together.

For example, a combination of antihypertensives may be prescribed synergistically to enhance a reduction in blood pressure.

As another example, angiotensin-converting enzyme (ACE) inhibitors reduce the incidence of ankle oedema caused by calcium channel blockers.

Opposing

Opposing interactions occur when a combination of drugs with effects that are opposed to one another, cancel out the therapeutic benefit.

For example, corticosteroids oppose the blood glucose lowering effects of antidiabetics. Increasing the dose of the antidiabetic drug during corticosteroid therapy may be necessary.

Pharmacokinetic interactions

A drug may alter the absorption, distribution, metabolism or excretion of another drug. Increasing or decreasing the amount of drug available to produce a pharmacological effect.

Absorption

When one drug increases or decreases the absorption of another drug, the rate of absorption and the total amount absorbed can be affected. There are several ways this can occur.

Changes in gastrointestinal pH

A drug can change gastrointestinal pH which can affect the absorption of another drug.

For example, the bioavailability of ketoconazole is decreased by proton pump inhibitors. Ketoconazole should be administered with an acidic drink such as cola or orange juice to increase gastric acidity.

Adsorption and chelation

A drug can adsorb, chelate or complex into the other drug. This forms a product that is poorly absorbed and can result in ineffective treatment.

For example, antacids decrease the absorption of doxycycline. Separate administration by 2 to 3 hours to prevent mixing in the gut.

Changes in gastrointestinal motility

The rate at which the gut empties can be altered by a drug. This can reduce or increase the rate of absorption of other drugs.

For example, metoclopramide increases the rate of gastric emptying and consequently increases the rate of paracetamol absorption. Faster attainment of peak paracetamol levels may be beneficial if using the combination to treat acute migraine.

Drug transporter proteins

Drug transporter proteins such as P-glycoprotein located in the intestine can control oral bioavailability of drugs. Drugs can induce or inhibit the expression of drug transporter proteins.

For example, rifampicin induces P-glycoprotein, resulting in reduced digoxin absorption and consequently reduced digoxin blood levels.

Further information on P-glycoprotein interactions are coming soon.

Distribution

A drug may displace another from protein binding sites; resulting in increased levels of the displaced, unbound, pharmacologically active drug.

There are few clinically significant interactions due to this mechanism alone. It would generally only be significant for highly protein bound drugs with a narrow therapeutic index.

Metabolism

Many drugs are chemically altered within the body to make them easier to excrete. This chemical change, known as metabolism, is carried out predominately in the liver.

A drug can increase or decrease the metabolism of another drug. Induction or inhibition of the cytochrome P450 enzymes can lead to changes in blood levels of drugs metabolised by these enzymes.

Genetic variations exist in patients ability to metabolise drugs, explaining why some interactions vary in significance for different patients.

Further information on metabolism interactions are coming soon.

Excretion

Drugs are excreted by the body usually by the kidneys or the liver. One drug can interfere with the excretion of another drug. This can increase or decrease the rate at which the other drug is excreted by the body.

Frail and older patients may have reduced renal and hepatic function, and are more susceptible to interactions via this mechanism.

Renal excretion

A change in urinary pH, active renal tubular excretion or renal blood flow by one drug can alter the excretion of another drug.

For example, methotrexate is renally excreted. Since non-steroidal anti inflammatory drugs (NSAIDs) reduce renal blood flow, combined use may result in reduced methotrexate clearance.

Managing interactions with methotrexate provides specific guidance on managing common interactions with low dose methotrexate. 

Hepatic excretion

Enterohepatic recirculation is a recycling process which prolongs the time a drug is within the body. When a drug is metabolised, changes to its structure may enable its excretion in bile. If gut bacteria then metabolise it back to its original structure, the drug can be reabsorbed. Some drugs interfere with enterohepatic recirculation and may reduce the exposure of another drug.

For example, colestyramine can bind to other drugs and reduce enterohepatic recirculation, potentially reducing their blood levels. If colestyramine is used in combination with mycophenolate, it is essential to monitor the immunosuppressant effects of mycophenolate to ensure it remains effective.

Herbal interactions

Complementary and alternative medicines, including herbal medicines, can interact with prescribed drugs via the mechanisms mentioned above.

SPS has guidance on handling questions about herbal medicines, including potential drug – herb interactions and what resources to use.

Food interactions

Food can interact with prescribed drugs via the mechanisms mentioned above. Pharmacokinetic interactions affecting absorption and metabolism are known to be clinically significant.

Absorption

Nutritional feeds administered via an enteral feeding tube can bind to drugs co-administered via the same tube; reducing drug absorption and potentially bioavailability. The timing of the feed may need to be changed to prevent a reduction in drug bioavailability.

Metabolism

Grapefruit and grapefruit juice should be avoided with some oral drugs. Grapefruit inhibits the intestinal enzyme CYP3A4 and can increase the bioavailability and cause potential toxicity of drugs that are primarily metabolised by CYP3A4.

Tobacco interactions

Drug metabolism can be altered by tobacco smoke. SPS has information on what to consider and how to manage interactions with tobacco smoke.