Drug Interactions (DIs)

LECTURER
SANA HAIDER
Definition
“when the effects of one drug are altered by the co-administration of
another drug, herbal medicine, food, drink or other environmental
chemical agents.”
The net effect of the combination may manifest as an additive or
enhanced effect of one or more drugs, antagonism of the effect of one
or more drugs, or any other alteration in the effect of one or more
drugs.
For example, a combination of different antihypertensive drugs may be
used to improve blood pressure control, or an opioid antagonist may be
used to reverse the effect of an overdose of morphine.
Susceptible patients to DIs
• Patients on polypharmacy
• Patients with hepatic or renal disease, those on long-term therapy for
chronic disease (e.g. HIV infection, epilepsy, diabetes)
• Patients in intensive care
• Transplant recipients
• Patients undergoing complicated surgical procedures
• Critically ill and elderly patients
Mechanisms of drug interactions
These mechanisms can be conveniently divided into those with a
pharmacokinetic basis and those with a pharmacodynamic basis:

A) Pharmacokinetic interactions:
Pharmacokinetic interactions are those that affect the processes by
which drugs are absorbed, distributed, metabolised or excreted.
1. Absorption
Following oral administration, drugs are absorbed through the mucous
membranes of the gastro-intestinal tract.
A number of factors can affect the rate of absorption or the extent of
absorption (i.e. the total amount of drug absorbed) are:
a. Changes in gastro-intestinal pH.
b. Adsorption, chelation and other complexing mechanisms.
c. Effects on gastro-intestinal motility.
d. Induction or inhibition of drug transport proteins.
e. Malabsorption.
2. Drug distribution
Following absorption>drug distribution to various tissues>DIs due to
displacement from protein-binding sites (reduction in the extent of
plasma protein binding of one drug caused by the presence of another
drug, resulting in an increased free or unbound fraction of the
displaced drug).
Drugs>Highly bound to plasma proteins like albumin (acidic drugs like
warfarin) and α1-acid glycoprotein (basic drugs like tricyclic
antidepressants, lidocaine, disopyramide and propranolol).
Lidocaine has been given as an example of a drug fitting these criteria.
3. Drug metabolism
Metabolism refers to the process by which drugs and other compounds
are biochemically modified to facilitate their degradation and
subsequent removal from the body.
Liver is the principal site of drug metabolism.
Drug metabolism consists of:
Phase I reactions such as oxidation, hydrolysis and reduction
Phase II reactions which primarily involve conjugation of the drug with
substances such as glucuronic acid and sulphuric acid.
Phase I metabolism generally involves the CYP450 mixed function
oxidase system. The liver is the major site of cytochrome 450- mediated
metabolism.
CYP450 isoenzymes
The CYP450 system comprises 57 isoenzymes, each derived from the
expression of an individual gene.
Four main subfamilies of P450 isoenzymes are thought to be responsible
for most (about 90%) of the metabolism of commonly used drugs in
humans: CYP1, CYP2, CYP3 and CYP4.
The genes that encode specific cytochrome 450 isoenzymes can vary
between individuals and, sometimes, ethnic groups. These variations
(polymorphisms) may affect metabolism of substrate drugs.
Poor metabolizers tend to have reduced first-pass metabolism, increased
plasma levels and exaggerated pharmacological response to drugs. By
contrast, ultra-rapid metabolizers may require considerably higher doses
for a standard effect. About 5–10% of Caucasians and up to 2% of Asian
and black people are poor metabolizers.
CYP3A is probably the most important of all drug-metabolizing
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. It is likely that 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.
a) 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, notably barbiturates and
carbamazepine, can induce their own metabolism (auto-induction).
Cigarette smoking, chronic alcohol use and the herbal preparation St
John’s wort can also induce drug-metabolising enzymes.
Enzyme-inducing drugs with short half-lives such as rifampicin will induce
metabolism more rapidly than inducers with longer half-lives (e.g.
phenytoin) because they reach steady-state concentrations more rapidly.
Enzyme induction usually results in a decreased pharmacological effect of
the affected drug. For exp: St John’s wort is now known to be a potent
inducer of CYP3A. Thus, when a patient receiving cyclosporin, tacrolimus,
HIV-protease inhibitors, irinotecan or imatinib takes St John’s wort, there is
a risk of therapeutic failure with the affected drug.
b) Enzyme inhibition:
Enzyme inhibition is responsible for many clinically significant
interactions. Many drugs act as inhibitors of cytochrome 450 enzymes.
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
when the inhibitor is given at the highest approved dose and the shortest
dosing interval.
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 when the inhibitor is given at the highest approved dose and
the shortest dosing interval.
Concurrent administration of an enzyme inhibitor leads to reduced
metabolism of the drug and hence an increase in the steady-state drug
concentration.
Interactions of this type are again most likely to affect drugs with a
narrow therapeutic range such as theophylline, cyclosporin, oral
anticoagulants and phenytoin. For example, starting treatment with an
enzyme inhibitor such as amiodarone in a patient who is taking warfarin
could result in a marked increase in warfarin plasma concentrations and
increased bleeding risk.
A single glass of grapefruit juice can cause CYP3A inhibition for 24–48
hours, and regular consumption may continuously inhibit enzyme activity.
Consumption of grapefruit juice is therefore not recommended in
patients who are receiving drugs that are extensively metabolized by
CYP3A, such as simvastatin, tacrolimus and vardenail.
Enzyme inhibition usually results in an increased pharmacological effect
of the affected drug, but in cases where the affected drug is a pro-drug
which requires enzymatic metabolism to active metabolites, a reduced
pharmacological effect may result.
For example, clopidogrel is metabolized via CYP2C19 to an active
metabolite which is responsible for its antiplatelet effect. Proton pump
inhibitors such as omeprazole are inhibitors of CYP2C19 and may lead
to reduced effectiveness of clopidogrel when used in combination.
4. Elimination interactions
• Changes in urinary pH.
• Changes in active renal tubule excretion.
• Changes in renal blood low.
• Biliary excretion and the enterohepatic shunt.
• Drug transporter proteins.
B) Pharmacodynamic interactions
Pharmacodynamic interactions are those where the effects of one drug
are changed by the presence of another drug at its site of action.
Sometimes these interactions involve competition for specific receptor
sites, but often they are indirect and involve interference with
physiological systems.

Two types of interactions are:

1. Antagonistic interactions
2. Additive or synergistic interactions
1. Antagonistic interactions
A drug with an agonist action at a particular receptor type will interact
with antagonists at that receptor.
For example, the bronchodilator action of a selective β2-
adrenoreceptor agonist such as salbutamol will be antagonized by β-
adrenoreceptor antagonists.
Therapeutic effect can be achieved as specific antagonists may be used
to reverse the effect of another drug at receptor sites; examples include
the opioid antagonist naloxone and the benzodiazepine antagonist
flumazenil.
2. Additive or synergistic interactions
If two drugs with similar pharmacological effects are given together, the
effects can be additive.
For example, the concurrent use of drugs with CNS depressant effects
such as antidepressants, hypnotics, antiepileptics and antihistamines
may lead to excessive drowsiness, yet such combinations are frequently
encountered.
Another example is the risk of ventricular tachycardia and torsade de
pointes associated with the concurrent use of more than one drug with
the potential to prolong the QT interval on the electrocardiogram.
Drug–food interactions
Food can cause clinically important changes in drug absorption through
effects on gastro-intestinal absorption or motility.
For example, iron tablets and antibiotics, the advice that certain drugs
should not be taken with food.
The interaction between tyramine in some foods and MAOIs, and the
interaction between grapefruit juice and CCBs.
Drug–herb interactions
Up to 24% of hospital patients report using herbal remedies (Constable
et al., 2007). Such products often contain pharmacologically active
ingredients which can give rise to clinically significant interactions when
used inadvertently with other conventional drugs.
For example, extracts of Glycyrrhizin glabra (liquorice) used for treating
digestive disorders may cause significant interactions in patients who
are taking digoxin or diuretics.
Herbal products such as Chinese ginseng (Panax ginseng), Chan Su
(containing bufalin) and Danshen may also contain digoxin like
compounds which can interfere with digoxin assays, leading to falsely
elevated levels being detected.
The most widely discussed drug–herb interactions are those involving
St John’s wort (Hypericum extract), an unlicensed herbal medicine used
for depression which has been implicated in interactions, for example,
with hormonal contraceptives, ciclosporin and antiepileptic drugs.