Drug interactions
Drug interactions :
An interaction is said to occur
when the effects of one drug are altered by the coadministration of
• another drug,
• herbal medicine,
• food,
• drink or
• other environmental chemical agents
Withdrawal
• Mibefradil
• terfenadine
• grepafloxacin
• Cisapride
Drug interactions are an important cause of prolongation of the
QT interval on the electrocardiogram which increases the risk
of developing a life-threatening ventricular arrhythmia .
MAOIs // Grapefruit juice
The recognition of clinically significant
interactions requires knowledge of –
• pharmacological mechanisms of drug
interactions
• a thorough understanding of high-risk
drugs
• vulnerable patient groups.
Susceptible patients
The risk of drug interactions increases with the number of
drugs used.
The rate of ADR in patients taking 6–10 drugs was 7%, rising to 40% in those
taking 16–20 drugs, with the exponential rise being largely attributable to
drug interactions.
In a high-risk group of emergency department patients, the risk of potential
adverse drug interaction was 13% in patients taking 2 drugs and 82%
in those taking 7 or more drugs
(Goldberg et al., 1996).
Although polypharmacy is common and often unavoidable, it places certain
patient groups at increased risk of drug interactions
Susceptible patients
Patients at particular risk
• hepatic or renal disease
• on long-term therapy for chronic disease (HIV
infection, epilepsy, diabetes,
• patients in intensive care,
• transplant recipients, patients
• undergoing complicated surgical procedures
• Critically ill and elderly patients are
Critically ill and elderly patients are at increased risk
• take more medicines but also because of
• impaired homeostatic
Examples of drugs with high risk of interaction
Concentration-dependent toxicity
• Digoxin
• Lithium
• Aminoglycosides
• Warfarin
• Cytotoxic agents
Steep dose–response curve
• Verapamil
• Sulphonylureas
• Levodopa
Examples of drugs with high risk of interaction
Patient dependent on therapeutic effect
• Immunosuppressives, e.g., ciclosporin, tacrolimus
• Glucocorticoids
• Oral contraceptives
• Antiepileptics
• Antiarrhythmics
• Antipsychotics
• Antiretrovirals
Saturable hepatic metabolism
• Phenytoin
• Theophylline
Mechanisms of drug interactions
Pharmacokinetic interactions
Pharmacokinetic interactions are those that affect
the processes by which drugs are • absorbed
• distributed
• metabolized or
• excreted.
Changes in gastro-intestinal pH.
Antacids, histamine H2 antagonists and omeprazole
can significantly decrease the bioavailability of
ketoconazole and itraconazole
(fluconazole and voriconazole is not significantly altered)
the potential for interaction may be minimised by leaving an interval of 2–3 h
between the antacid and the potentially interacting drug.
Adsorption, chelation and other complexing mechanisms.
•tetracyclines and the quinolone antibiotics
Most chelation and adsorption interactions can be avoided if an interval of 2–3 h
is allowed between doses of the interacting drugs.
Effects on gastro-intestinal motility.
Effects on gastro-intestinal motility
Anticholinergic agents used in the management of movement
disorders have been shown to reduce the bioavailability of
levodopa by as much as 50%, possibly as a result of increased
metabolism in the intestinal mucosa.
Opioids such as diamorphine and pethidine strongly inhibit
gastric emptying and greatly reduce the absorption rate of
paracetamol, without affecting the extent of absorption.
Codeine has no significant effect on paracetamol absorption.
Metoclopramide increases gastric emptying and increases the
absorption rate of paracetamol,
an effect which is used to therapeutic advantage in the treatment of
migraine to ensure rapid analgesic effect.
Induction or inhibition of drug transport
proteins.
The oral bioavailability of some drugs is limited by the
action of drug transporter proteins, which eject drugs that
have diffused across the gut lining back into the gut.
Digoxin is a substrate of P-glycoprotein and drugs that
inhibit P-glycoprotein, such as verapamil, may increase
digoxin bioavailability with the potential for digoxin toxicity
Malabsorption.
Drugs such as neomycin may cause a malabsorption
syndrome leading to reduced absorption of drugs such as
digoxin.
Orlistat is a specific long-acting inhibitor of gastric and
pancreatic lipases, thereby preventing the hydrolysis of
dietary fat to free fatty acids and triglycerides. This can lead to
reduced absorption of fat-soluble drugs co-administered with
orlistat.
Drug metabolism
cytochrome P450 (CYP450) mixed function oxidase system.
• phase I reactions
• phase II reactions
The CYP450 system comprises 57 isoenzymes
CYP1, CYP2, CYP3 and CYP4.
responsible for most (about 90%) of the metabolism of
commonly used drugs in humans
debrisoquine hydroxylase (CYP 2D6)
a family number, a subfamily letter and a number for an individual
enzyme within the subfamily
Polymorphisms
Polymorphisms affect metabolism
of substrate drugs.
The genes that encode specific cytochrome 450 isoenzymes can
vary between individuals and, sometimes, ethnic groups.
For inter-individual variability in CYP2D6 activity, people may be
described according to their ability to metabolize debrisoquine.
Poor metabolizers tend to have reduced first-pass metabolism,
increased plasma levels and exaggerated pharmacological
response to this drug, resulting in postural hypotension.
By contrast, ultra-rapid metabolizers may require considerably
higher doses for a standard effect.
About 5–10% of white Caucasians and up to 2% of Asians and
black people are poor metabolizers.
CYP3A
CYP3A4 (so similar that they cannot
CYP3A5
be easily distinguished)
most important of all drug-metabolising enzymes
- because it is abundant in both the intestinal epithelium
and the liver and it has the ability to metabolize a multitude
of chemically unrelated drugs from almost every drug class.
CYP3A is involved in the metabolism of more than half the
therapeutic agents that undergo alteration by oxidation.
The effect of a cytochrome 450 isoenzyme on a particular
substrate can be altered by interaction with other drugs.
Drugs may be themselves substrates for a cytochrome 450
isoenzyme and/or may inhibit or induce the isoenzyme.
If a drug is metabolised primarily by a single cytochrome 450
isoenzyme, inhibition or induction of this enzyme would have a
major effect on the plasma concentrations of the drug.
Example:- if erythromycin (an inhibitor of CYP3A4) is taken by a
patient being given carbamazepine (which is extensively
metabolised by CYP3A4), this may lead to toxicity due to higher
concentrations of carbamazepine.
Examples of drug substrates, inducers and inhibitors of the major
cytochrome P450 enzymes
Examples of drug substrates, inducers and inhibitors of the major
cytochrome P450 enzymes
Enzyme induction.
The most powerful enzyme inducers in clinical use are
the antibiotic rifampicin and antiepileptic agents such
as barbiturates, phenytoin and carbamazepine.
Some enzyme inducers can induce their own
metabolism (autoinduction) e.g. barbiturates and
carbamazepine.
Cigarette smoking, chronic alcohol use and the herbal
preparation St John's wort can also induce drugmetabolising enzymes.
Since the process of enzyme induction requires new
protein synthesis, the effect usually develops over
several days or weeks after starting an enzymeinducing agent and the effect generally persists for a
similar period following drug withdrawal.
Enzyme-inducing drugs with short half-lives such as
rifampicin will induce metabolism more rapidly than
inducers with longer half-lives, for example, phenytoin,
because they reach steady-state concentrations more
rapidly.
Enzyme induction usually results in a decreased pharmacological
effect of the affected drug.
St John's wort is now known to be a
potent inducer of CYP3A
When a patient receiving ciclosporin, tacrolimus, HIV-protease
inhibitors, irinotecan or imatinib takes St John's wort, there is a risk
of therapeutic failure with the affected drug.
If the affected drug has active metabolites, this may lead to
an increased pharmacological effect.
Examples of interactions due to enzyme induction
Enzyme inhibition.
Enzyme inhibition is responsible for many clinically significant
interactions.
A strong inhibitor is one that can cause ≥5-fold increase in
the plasma area-under-the-curve (AUC) value or more than
80% decrease in clearance of CYP3A substrates.
A moderate inhibitor is one that can cause ≥2- but <5-fold
increase in the AUC value or 50–80% decrease in clearance
of sensitive CYP3A substrates
A weak inhibitor is one that can cause ≥1.25- but <2-fold
increase in the AUC values or 20–50% decrease in clearance
of sensitive CYP3A substrates
Examples of interactions due to enzyme inhibition
Elimination interactions
Most drugs are excreted in either the bile or urine.
Changes in urinary pH.
Urine alkalinisation or acidification has been used as a
means of increasing drug elimination in poisoning with
salicylates and amphetamines, respectively.
Changes in active renal tubule excretion.
Drugs that use the same active transport system in the kidney tubules can
compete with one another for excretion
Probenecid may be given to increase the plasma concentration
of penicillins by delaying renal excretion.
Increased methotrexate toxicity, sometimes life-threatening, has been seen in
some patients concurrently treated with salicylates and some other non-steroidal
anti-inflammatory drugs (NSAIDs).
Elimination interactions
Changes in renal blood flow.
Blood flow through the kidney is partially controlled by the production of
renal vasodilatory prostaglandins.
If the synthesis of prostaglandins is inhibited by drugs such as indometacin, the
renal excretion of lithium is reduced with a subsequent rise in plasma levels.
Biliary excretion and the enterohepatic shunt.
Interaction between broad-spectrum antibiotics and oral
contraceptives.
Drug transporter proteins.
Elimination interactions
P-glycoprotein (P-gp)
Drug transporter proteins.
P-glycoprotein acts as an efflux pump, exporting s
urine, bile and the intestinal lumen.
Examples of inhibitors and inducers of
P-glycoprotein
ubstances into
Pharmacodynamic interactions
It is to be expected that a drug with an agonist action at a
particular receptor type will interact with antagonists at that
receptor.
naloxone
flumazenil.
α-Adrenergic agonists such as metaraminol may be used in the management of
priapism induced by α-adrenergic antagonists such as phentolamine.
Additive or synergistic interactions
Examples of additive or synergistic interactions
Drug or neurotransmitter uptake interactions
MAOIs
Drug–food interactions
Grapefruit juice inhibits intestinal CYP3A4
Drug–herb interactions
A number of herbal products have anti-platelet and anticoagulant properties
and may increase the risk of bleeding when used with aspirin or warfarin.
Mrs C is a 62-year-old woman with a history of
hypertension, atrial fibrillation and type 2 diabetes.
She is a non-smoker and obese. Her current medication
comprises flecainide 100 mg twice a day, aspirin 75 mg
daily, simvastatin 40 mg and diltiazem 180 mg daily.
Mrs C is suffering from a respiratory tract infection and
her primary care doctor has prescribed a 5-day course
of clarithromycin.
Questions
1. Are there likely to be any clinically significant drug interactions?
2. What advice do you give?
1. There is potential for interaction between simvastatin and
diltiazem and between simvastatin and clarithromycin.
Some statins, particularly simvastatin and atorvastatin, are
metabolised by cytochrome P450 (CYP3A4) and coadministration of potent inhibitors of this enzyme may
particularly increase plasma levels of these statins and so
increase the risk of dose-related side effects, including
rhabdomyolysis.
2. Clarithromycin is a potent inhibitor of CYP3A4 and diltiazem
is a less potent inhibitor.
2. Current advice is that diltiazem and simvastatin may
be given together provided the simvastatin dose does
not exceed 40 mg daily, so it is reasonable for this
therapy to be continued.
However, clarithromycin should not be given together
with simvastatin.
Myopathy and rhabdomyolysis have been reported in
patients taking the combination. Mrs C should be
advised not to take her simvastatin while she is taking
clarithromycin and to start taking it again after she has
completed the course of antibiotic.