Medicine Interactions

Associate Professor Louis Roller
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University

Article Objectives:

• Describe the concepts of medicine interactions, pharmacodynamics (pharmacological) and pharmacokinetics
• Demonstrate the importance of checking with the pharmacist to find information about potential medicine interactions and the clinical relevance of such interactions
• Identify the possibility of serious medicine interactions in individual patients who have consumed grapefruit and/or ceased smoking
• Discuss with the prescriber options provided by the pharmacist for changes in medications where a serious medicine interaction has occurred

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A Medicine Interaction May Be Defined As:

A measurable modification (in magnitude and/or duration) of the action of one medicine, by prior or concomitant administration of another substance, including: prescription, non-prescription medicines (including complementary medicines), food, alcohol, cigarette smoking or diagnostic tests.

Potential Outcomes May Be:

• Harmful, with increased toxicity of one or more medicines, or decreased efficacy
• Of no clinical significance; or
• Beneficial, with increased activity.

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Medicine interactions may be pharmacodynamic (leading to potentiation or antagonism) or pharmacokinetic (affecting each other at sites of absorption, distribution, metabolism and excretion). These will again lead to either potentiation or reduction of the effects of the targeted medicine.

Pharmacodynamic Interactions

Pharmacodynamic interactions are common, and can generally be anticipated and monitored based on sound pharmacological knowledge.

1. Medicines with similar pharmacological effects:

• Additive central nervous system (CNS) depressors (e.g. alcohol and CNS depressor medicines increase CNS depression)
• Anticholinergic agents with tricyclic antidepressants (TCAs) and selected antipsychotic agents increase anticholinergic effects
• Additive cardiac depressors (e.g. verapamil and beta blockers)
• Non-steroidal anti-inflammatory drugs (NSAIDs) and angiotensin converting enzyme inhibitors (ACE inhibitors) cause an increased risk of renal impairment and hyperkalaemia
• NSAIDs and warfarin
• Methotrexate and co-trimoxazole (both have increased anti-folate activity and toxicity)
• Statins and fibrates/gemfibrozil cause an increased risk of myopathy
• Selective serotonin re-uptake inhibitors (SSRIs) and TCAs increase serotonin levels
• NSAIDS and ACE inhibitors cause an increased incidence of renal failure
• Digoxin and amiodarone both have cardio-depressant properties; and
• St John’s Wort and other medicines that enhance serotonin function, which can lead to potential serotonergic syndrome (e.g. TCAs, monoamine oxidase inhibitors, SSRIs, selective noradrenaline re-uptake inhibitors (SNRIs), venlafaxine and others such as vortioxetine).

2. Medicines with opposing pharmacological effects:

• Opioids and naloxone (i.e. non-selective beta blockers and beta agonists)
• Hypnotics and pseudoephedrine (or caffeine)
• Oral hypoglycaemics and corticosteroids
• Metoclopramide antagonises the effects of dopaminergic agents in people with Parkinson’s disease; and
• Warfarin and Vitamin K have different effects on coagulation.

3. Medicines that alter effects of electrolytes:

• NSAIDs and antihypertensives (varied)
• Digoxin and ACE inhibitors (potassium); and
• Corticosteroids and thiazides (blood sugar concentrations).

Pharmacokinetic Interactions

1. Absorption

• Formation of complexes (e.g. antacids, iron, calcium, tetracyclines, quinolones, etc.)
• Changes in gastric pH (e.g. proton pump inhibitors (PPIs) being taken concurrently with a medication such as itraconazole impairs absorption)
• Changes in gastrointestinal mobility (e.g. metoclopramide or domperidone increases emptying)
• Pathological changes to the gastrointestinal tract (e.g. antibiotics and antineoplastic agents); and
• Inhibition or enhancement of absorption (e.g. P-glycoprotein (Pgp) can play a part in the inhibition or enhancement of absorption of a number of medications, which include colchicine, cyclosporine and dabigatran). It should be noted that a reduction in the rate of absorption will not always lead to a reduction in the extent of absorption.

2. Distribution

Distribution interactions mainly involve protein-binding changes. For example, acidic medicines such as digoxin, phenytoin and warfarin affect albumin, and medicines such as propranolol and TCAs affect the binding of alpha-1-acid glycoproteins. Protein-binding interactions are only occasionally significant and involve highly protein-bound medicines with a narrow therapeutic index.

3. Metabolism

A wide range of enzymes mediate the metabolism of medicines. Medicine metabolism via cytochrome P450 (CYP450) enzymes is the main determinant of clearance for many medicines. There are over thirty human CYP450 isoenzymes found in the liver, small intestine, kidney, lungs and brain. These are divided into:

Families	CYP1, CYP2, CYP3, etc.
Subfamilies	CYP1A, CYP2C, CYP2D, etc.
Individual enzymes	CYP3A4, CYP2D6, CYP1A2, etc.

They are influenced by genetics, diet, gender, and age.

A knowledge of the relevant cytochrome enzymes responsible for the metabolism of the medicine can help us predict relevant medicine interactions and variability.

Interacting medicines that inhibit metabolism will increase the medicine concentration. This can lead to rapid development of toxicity in 2-3 days since onset is determined by the dose, timing and half-life of the medicine.

In contrast, interacting medicines that induce metabolism will decrease the concentration (this may take some days).

These interactions are of course dependent on the half-life of the medication and the time the medicine takes to reach steady state. At steady state, the amount of the medication accumulated per unit of time equals the amount eliminated per unit of time.

Examples of cytochrome P450 (CYP450) substrate*, inhibitors and inducers (NB: these lists are not exhaustive):

CYP450	Substrates	Inhibitors	Inducers
CYP1A2	Diazepam, imipramine, propranolol, verapamil	Amiodarone, diltiazem, grapefruit juice, paroxetine	Carbamazepine, omeprazole, phenytoin, tobacco smoking#
CYP2B6	Bupropion, clopidogrel, cyclophosphamide, vortioxetine	Clopidogrel, prasugrel, thiotepa, ticlopidine	Efavirenz, nevirapine, phenytoin, rifampicin
CYP2C8	Loperamide, pioglitazone, rosiglitazone, vortioxetine	Gemfibrozil, nilotinib, terifluomide, trimethoprim	Rifampicin
CYP2C9	Carvedilol, celecoxib, fluoxetine, rosuvastatin	Amiodarone, diclofenac, fluvoxamine, trimethoprim	Bosentan, phenytoin, rifampicin, St John’s Wort
CYP2C19	Amitriptyline, citalopram, propranolol, terbinafine	Clarithromycin, efavirenz, fluconazole, modafinil	Carbamazepine, phenytoin, rifampicin, St John’s Wort
CYP2D6	Aripiprazole, dextromethorphan, hydrocodone, mirtazapine	Amiodarone, bupropion, duloxetine, methadone	Carbamazepine, dexamethasone, phenytoin, rifampicin
CYP3A4	Clindamycin, clomipramine, domperidone, ticagrelor	Amiodarone, aprepitant, ciprofloxacin, grapefruit juice (largest group)	Carbamazepine, etravirine, modafinil, phenytoin

*Substrate is the term used to indicate the medicine that is metabolised by the particular pathway(s).

#It should be noted that the sudden cessation of smoking on a person who has been taking ever-increasing doses of propranolol (to compensate for the enzyme induction of the propranolol by cigarette smoke), may lead to an increase in plasma levels of propranolol, to perhaps toxic levels.

The effect of the addition of an enzyme inhibitor or enzyme inducer is shown diagrammatically below:

4. Excretion

Interactions involving renal excretion mechanisms are usually only important in medicines with narrow therapeutic indices that are primarily excreted unchanged in the urine (e.g. methotrexate and lithium). The reabsorption of relatively non-polar weak acids and bases can be altered by changes in urinary pH (e.g. an increase in urinary pH will delay the excretion of amphetamines (including related substances such as pseudoephedrine), nicotine and morphine derivatives). The kidneys determine the rate of excretion. In cases where creatinine clearance is significantly reduced, the dose of medications excreted renally will need reduction.

Pharmacists are expected to use cautionary and advisory labels (C & A) on the containers of dispensed medicines. There are twenty four labels, and two that particularly refer to medicine interactions. These are Label 5 and Label 18.

Label 5 states:

“Ask your doctor or pharmacist before using any other medicine including over-the-counter medicines and herbal products.”

This label is used for those medicines that are known to either have a low therapeutic index and/or cause multiple interactions, usually via the inhibition of the metabolic clearance of a range of medicines. It is designed to assist consumers and pharmacists to be aware of potential interactions.

There is a long list of medications requiring this label. Some examples include agomelatine, allopurinol, amiodarone, digoxin, fluoxetine, phenytoin, venlafaxine, verapamil, and warfarin.

Label 18 states:

“Avoid eating grapefruit or drinking grapefruit juice while being treated with this medicine.”

Certain constituents of grapefruit have been shown to alter medicine bioavailability by selectively inhibiting CYP3A4 isoenzymes. This can greatly increase the concentration and risk of adverse events of some medicines.

There is a large number of medicines that will have their plasma levels elevated in the presence of grapefruit or grapefruit juice. A few examples include alprazolam, amiodarone, clopidogrel, colchicine, oxycodone, paroxetine, quetiapine, simvastatin, verapamil, and ziprasidone.

Conclusion

It is the role of the pharmacist to check each and every prescription that is to be dispensed for indications, contraindications, adverse effects, dosages and medicine interactions. A full medical and medication history is essential for the pharmacist to be able to provide appropriate decisions.

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Test your knowledge

Indicate whether the following statements are true or false:

1. The addition of a P450 enzyme inhibitor to a stable regimen of a medication, metabolised through that particular pathway, will lead to an increased plasma level of that medication
2. The addition of a P450 enzyme inducer to a stable regimen of a medication, metabolised through that particular pathway, will lead to a decreased plasma level of that medication
3. Pharmacodynamic interactions may result in potentiation of one or more medicines
4. Pharmacodynamic interactions may result in antagonism of one or more medicines
5. Pharmacodynamic interactions are unlikely to result in adverse medicine events
6. The significance of pharmacokinetic interactions are dependent on dose and concentration
7. All medicine interactions lead to adverse outcomes
8. Cigarette smoking may decrease the effects of some medicines
9. Grapefruit juice is likely to increase plasma levels of a number of medicines
10. Inhibition reactions tend to occur slowly, whilst inducer reactions occur rapidly

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Answers

1. (T)
2. (T)
3. (T)
4. (T)
5. (F)
6. (T)
7. (F)
8. (T)
9. (T)
10. (F)

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References

• Australian Medicines Handbook Pty Ltd 2015, Australian Medicines Handbook, AMH, Adelaide.
• MIMS Australia Pty Ltd 2016, FullEmimsMay16.exe, computer program, MIMS Australia Pty Ltd, St Leonards.
• Tatro, DS 2016, Drug Interaction Facts, Wolters Kluwer Health, St Louis, USA.

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