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.
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 are common, and can generally be anticipated and monitored based on sound pharmacological knowledge.
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.
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.
|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|
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.
“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.
“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.
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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