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Drug Interactions
Drug Interactions
Introduction:
Drug interactions have been
recognized for over 100 years.
Increasing availability of
complex therapeutic agents and
widespread polypharmacy has led to a
higher potential for drug interactions.
Drug interactions have become
an important cause of adverse drug
reactions (ADR).
Examples of Adverse Drug
Interactions:
1. Mibefradil:
The worldwide withdrawal of the calcium channel blocker mibefradil shortly
after its launch.
Serious drug interactions were reported, highlighting the importance of
identifying potential interactions before marketing.
2. Medicines Withdrawn or Restricted:
Terfenadine, grepafloxacin, and cisapride were withdrawn from the market
due to adverse effects.
Thioridazine had its use restricted because of prolongation of the QT interval
on the electrocardiogram.
QT prolongation increases the risk of developing a life-threatening ventricular
arrhythmia called torsade de pointes.
3. Herbal and Complementary Medicines:
The increasing availability and non-
prescription use of herbal and
complementary medicines have raised
awareness of their potential for adverse
interactions.
St. John's wort, a herbal extract for
depression, can cause serious
interactions due to its enzyme-inducing
effects.
4. Food and Drink Interactions:
Monoamine oxidase inhibitor
antidepressants (MAOIs) have a well-
known interaction with tyramine-
containing foodstuffs.
Grapefruit juice inhibits cytochrome P450 3A4 and can interact with drugs
like simvastatin and atorvastatin, increasing the risk of adverse reactions.
Determining Clinically Significant Interactions:
The medical literature contains numerous drug interaction studies and case
reports.
However, only a relatively small number of interactions are likely to cause
clinically significant consequences.
Recognizing clinically significant interactions requires understanding
pharmacological mechanisms, high-risk drugs, and vulnerable patient groups.
Definition of Drug Interaction:
An interaction occurs 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 combination can result in additive or enhanced effects, antagonism of
drug effects, or any other alteration in the effects of one or more drugs.
Clinically Significant Interactions:
Clinically significant interactions refer to combinations of therapeutic agents
that directly impact the patient's condition.
Certain drug interactions can provide therapeutic benefits. For example,
combining different antihypertensive drugs to improve blood pressure control
or using an opioid antagonist to reverse the effects of a morphine overdose.
However, this chapter focuses on clinically significant interactions that have
the potential for undesirable effects on patient care.
Importance of Clinically Significant Interactions:
Clinically significant interactions can lead to adverse drug reactions and
impact patient safety.
Understanding these interactions is crucial for healthcare professionals to
make informed decisions regarding medication management.
Identifying and managing clinically significant interactions helps prevent
potential harm, optimize treatment outcomes, and enhance patient care.
Examples of Clinically Significant Interactions:
Drug interactions that result in increased toxicity or reduced efficacy of a
medication.
Interactions that potentiate side effects or adverse reactions.
Interactions leading to altered drug metabolism or pharmacokinetics.
Interactions involving drugs with narrow therapeutic indices.
Interactions that affect drug levels or efficacy in specific patient populations
(e.g., elderly, pediatric, pregnant, or individuals with comorbidities).
Considerations for Managing Clinically Significant Interactions:
Regular review of medication regimens to identify potential interactions.
Consultation with pharmacists or other healthcare professionals
knowledgeable in drug interactions.
Adjusting drug doses, changing therapy, or selecting alternative medications
when necessary.
Providing patient education regarding potential interactions and advising
them to inform healthcare providers about all medications, including over-
the-counter drugs, herbal supplements, and dietary changes
Mechanisms of Drug Interactions:
1. Pharmacokinetic Interactions:
Pharmacokinetic interactions affect the processes of drug absorption,
distribution, metabolism, and excretion.
Interactions in these processes can result in changes in drug concentration at
the site of action, leading to toxicity or reduced efficacy.
Variability among individuals in these processes makes it difficult to predict
the extent of these interactions.
Absorption:
- Drug absorption occurs when drugs are taken orally and are absorbed through the
mucous membranes of the gastrointestinal tract.
- Several factors can affect the rate and extent of drug absorption.
- Antacids and other medications that modify gastric pH can influence the rate of
absorption but have minimal impact on the extent of absorption, except for certain
drugs like ketoconazole and itraconazole, which require gastric acidity for optimal
absorption.
2. Adsorption, Chelation, and Complexing Mechanisms:
- Some drugs react within the gastrointestinal tract to form chelates or complexes,
rendering them unabsorbable.
- Tetracyclines and quinolone antibiotics can form insoluble complexes with
divalent or trivalent metal cations (e.g., iron) or with antacids containing calcium,
magnesium, or aluminum, leading to reduced plasma drug concentrations.
- Co-administration of bisphosphonates with calcium supplements can significantly
reduce the bioavailability of both drugs.
- Adsorbents like charcoal or anionic exchange resins (e.g., colestyramine) can
reduce the absorption of certain drugs, including propranolol, digoxin, warfarin,
tricyclic antidepressants, ciclosporin, and levothyroxine.
- It is important to note that most interactions in the gut result in reduced absorption,
primarily affecting the absorption rate rather than the extent of drug absorption.
- In cases where absorption rate is crucial, such as with short half-life drugs or those
requiring rapid achievement of high plasma concentrations, delayed absorption can
have clinical significance.
- Administering interacting drugs with an interval of 2-3 hours between doses can
often help avoid absorption interactions.
Drug Distribution:
After absorption, drugs undergo distribution to various tissues, including their
site of action.
Many drugs and their metabolites bind strongly to plasma proteins.
Acidic drugs, such as warfarin, are primarily bound to albumin, while basic
drugs like tricyclic antidepressants, lidocaine, disopyramide, and propranolol
are bound to α1-acid glycoprotein.
Drug interactions can occur during the distribution phase, mainly through
displacement from protein-binding sites.
A drug displacement interaction happens when the presence of another drug
reduces the extent of plasma protein binding of one drug, resulting in an
increased free or unbound fraction of the displaced drug.
In vitro studies have demonstrated that drugs can be displaced from plasma
proteins, but clinical pharmacokinetic studies suggest that once displacement
occurs, the concentration of the free drug rises temporarily and then rapidly
falls back to its previous steady-state concentration due to metabolism and
distribution.
The time it takes for the free drug concentration to return to its previous steady
state depends on the half-life of the displaced drug.
The short-term rise in free drug concentration is generally of little clinical
significance but may need to be considered in therapeutic drug monitoring.
For example, if a drug displaces phenytoin from its protein-binding sites in a
patient taking phenytoin, the total plasma phenytoin concentration (free plus
bound) will decrease, while the free (active) concentration remains the same.
Clinically significant interactions solely due to protein-binding displacement
are rare.
In some cases, sustained changes in steady-state free plasma concentration
may occur with parenteral administration of drugs that are extensively bound
to plasma proteins and have non-restrictive clearance (efficient elimination by
organs).
Lidocaine is an example of a drug that fits these criteria
Drug Metabolism:
Clinically important drug interactions often involve the effect of one drug on
the metabolism of another.
Metabolism refers to the biochemical modification of drugs and other
compounds to facilitate their degradation and elimination from the body.
The liver is the primary site of drug metabolism, although other organs such
as the gut, kidneys, lung, skin, and placenta also contribute.
Drug metabolism involves phase I reactions
(oxidation, hydrolysis, reduction) and phase II
reactions (conjugation with substances like
glucuronic acid and sulphuric acid).
Phase I metabolism is mainly mediated by the
cytochrome P450 (CYP450) mixed function
oxidase system, with the liver being the major site.
However, the enterocytes in the small intestinal
epithelium can also play a role.
The CYP450 system consists of 57 isoenzymes,
each derived from an individual gene. They are
classified using a nomenclature system based on
family number, subfamily letter, and individual
enzyme number.
Four main subfamilies (CYP1, CYP2, CYP3,
CYP4) of P450 isoenzymes are responsible for the
metabolism of about 90% of commonly used drugs
in humans.
CYP2D6 (debrisoquine hydroxylase) is one of the
most extensively studied isoenzymes and exhibits
significant interindividual variability.
Polymorphisms in CYP2D6 can affect the
metabolism of substrate drugs.
Certain CYP450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4) are responsible for the metabolism of most
commonly used drugs.
Genetic variations (polymorphisms) in the genes encoding specific CYP450
isoenzymes can impact drug metabolism and vary between individuals and
ethnic groups.
CYP3A4 and CYP3A5 are the two isoenzymes of the CYP3A family, which
plays a crucial role in drug metabolism. CYP3A4 is abundant in both the
intestinal epithelium and the liver, and it metabolizes a wide range of
chemically unrelated drugs from various drug classes.
Drug interactions can occur through the inhibition or induction of CYP450
isoenzymes. Some drugs can be substrates for a particular isoenzyme and also
inhibit or induce that isoenzyme.
The oxidation of a drug typically involves multiple CYP isoenzymes,
resulting in the production of several metabolites. Inhibition or induction of a
single isoenzyme may have little effect on drug plasma levels unless the drug
is primarily metabolized by that specific isoenzyme.
If a drug is primarily metabolized by a single CYP450 isoenzyme and that
enzyme is inhibited or induced, it can significantly affect the plasma
concentrations of the drug.
For example, taking erythromycin (CYP3A4 inhibitor) along with
carbamazepine (metabolized by CYP3A4) can lead to increased
carbamazepine concentrations and potential toxicity.
Enzyme Induction:
Enzyme induction refers to the
process by which certain drugs or
substances increase the synthesis and
activity of drug-metabolizing
enzymes in the body, leading to
enhanced metabolism and clearance
of drugs.
Rifampicin, an antibiotic, and
antiepileptic agents such as
barbiturates, phenytoin, and
carbamazepine are powerful enzyme
inducers commonly used in clinical
practice.
Some enzyme inducers, like barbiturates and carbamazepine, can induce their
own metabolism, a phenomenon known as autoinduction.
Other substances, including cigarette smoking, chronic alcohol use, and the
herbal preparation St. John's wort, can also induce drug-metabolizing
enzymes.
The process of enzyme induction requires new protein synthesis, so the effect
typically develops gradually over several days or weeks after initiating an
enzyme-inducing agent. Similarly, the effect persists for a similar duration
after discontinuing the drug.
Enzyme-inducing drugs with short half-lives, like rifampicin, induce
metabolism more rapidly than those with longer half-lives, such as phenytoin,
due to reaching steady-state concentrations faster.
The dose of an enzyme-inducing drug may influence the extent of enzyme
induction, although some drugs can induce enzymes at any dose.
The pharmacological effect of the affected drug is generally decreased due to
enhanced metabolism and clearance resulting from enzyme induction.
St. John's wort is a potent inducer of CYP3A, an important drug-metabolizing
enzyme. Taking St. John's wort along with drugs like ciclosporin, tacrolimus,
HIV-protease inhibitors, irinotecan, or imatinib can increase the risk of
therapeutic failure with these drugs.
However, if the affected drug has active metabolites, enzyme induction may
lead to an increased pharmacological effect.
The effects of enzyme induction can vary significantly among individuals and
are influenced by factors such as age, genetic variations, concurrent drug
treatments, and the presence of underlying diseases.
Enzyme Inhibition:
Pharmacodynamics
1. Antagonistic
Interactions:
- Drugs with agonist actions at a
particular receptor can be
antagonized by drugs acting as
antagonists at the same receptor.
For example, the bronchodilator
effect of a selective β2-
adrenoreceptor agonist like
salbutamol can be antagonized by
β-adrenoreceptor antagonists.
- Therapeutically, specific antagonists may be used to reverse the effects of
another drug at receptor sites. Examples include naloxone (opioid antagonist) and
flumazenil (benzodiazepine antagonist).
- Certain drug classes have opposing pharmacological actions, such as
anticoagulants and vitamin K or levodopa and dopamine antagonist
antipsychotics.
3. Serotonin Syndrome:
- Serotonin syndrome is characterized by an excess of serotonin resulting from
therapeutic drug use, overdose, or interactions between drugs.
- It occurs when two or more drugs affecting serotonin are given concurrently
or when one serotonergic drug is stopped, and another is started.
- Symptoms include confusion, disorientation, abnormal movements,
exaggerated reflexes, fever, sweating, diarrhea, and changes in blood pressure.
- It is best prevented by avoiding combinations of serotonergic drugs, and
special care is needed when switching between selective serotonin reuptake
inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs).
Healthcare workers need to be alert to the possibility of drug interactions and take
appropriate steps to minimize their occurrence.
Drug formularies and the Summary of Product Characteristics provide useful
information about interactions.
Resources such as drug safety updates from regulatory agencies like the Medicines
and Healthcare products Regulatory Agency (MHRA), interaction alerts in
prescribing software, and specific websites for drug classes (e.g., HIV drugs) can be
helpful.
Interventions to Minimize Risk: