Drug Interactions
By: Kainat Gul
Introduction
• A drug interaction is a situation in which a substance affects the activity of a drug
when both are administered together. This action can be synergistic (when the drug's
effect is increased) or antagonistic (when the drug's effect is decreased) or a new
effect can be produced that neither produces on its own.
• Drug interactions may be the result of various processes. These processes may
include alterations in the pharmacokinetics of the drug. Such as alterations in the
absorption, distribution, metabolism, and excretion of a drug. Alternatively, drug
interactions may be the result of the pharmacodynamic properties of the drug, e.g.
the co-administration of a receptor antagonist and an agonist for the same receptor.
• Every time a drug is administered with any other prescription medicine, Over-the-
counter (OTC) products, herbs or even food we expose ourselves to the risk of a
potentially dangerous interaction.
• Understanding these potential reactions and their mechanisms help us to navigate the
hazardous effects of combining drugs with other medicines, food, herbs and vitamins
with confidence.
• Definition: It is defined as “an alternation in the duration or magnitude of
pharmacological effects of one drug produced by another drug, food, or
any other substance”.
Diagnosis
Evidence of Interaction
1
Preclinical
Trials
Clinical Trials
Case studies from pharmacovigilance
Drug interactions are thus:
• Mostly undesirable
• Rarely desirable(beneficial): for eg.,enhancement of activity of penicillins when administered
with probenecid.
The Net effect of a Drug Interaction is:
• Generally quantitative i.e. increased or decreased effect.
• Seldom qualitative i.e. rapid or slower effect.
• Precipitation of newer or increased adverse effect.
Factors contributing to drug interactions:
• Multiple drug therapy.
• Multiple prescribers.
• Multiple pharmacological effects of drug.
• Multiple diseases/predisposing illness.
• Poor patient compliance.
• Advancing age of patient.
• Drug-related factors.
Types
Typically, interactions between drugs come to mind (drug-
drug
interaction). However, interactions may also exist between d
rugs and foods (drug-
food interactions), as well as drugs and medicinal plants or
herbs (drug-plant interactions),
as well as drugs and Environmental/Chemical(drug-
chemical interactions) and also (drug-
disease interactions). But
there are essentially two types of drug interactions:
• Pharmacodynamic
• Pharmacokinetic
Pharmacodynamic
• Pharmacodynamic interactions are those in which the effect of one drug is
changed by the presence of another drug acting at the same biochemical or
molecular site (e.g., drug receptor or second messenger system), on the same
target organ, or on a different target but one that is associated with a common
physiological process essentially when one drug modulates the
pharmacologic effect of another by producing additive, synergistic or
antagonistic effects.
• Additive effect: An effect in which two substances or actions used in
Combination produce total affect the same as the sum of the individual
effects.
• synergistic effect: Interaction between two or more drug agents, entities,
factors, or substances that produces an effect greater than the sum of their
individual effects.
• Antagonistic effect: Interaction of two or more drug substances such that the
action of any one of them on living cells or tissues is lessened or diminished.
• One drug may alter the normal physiological environment whereby it can increase or decrease the effects of another drug as is exemplified
by the interaction produced by diuretic induced hypokalemia with the concurrent use of digoxin that results in digoxin toxicity.
• In a similar situation of diuretic usage concurrently with anti- arrhythmics like quinidine or sotalol a much more serious toxicity in the form
of Torsade de pointes can occur resulting in fatal ventricular arrhythmias. Pharmacodynamic interactions between drugs with additive
effects may be intentional, for example when combining antihypertensives, or unintentional, for example serotonin syndrome caused by
adding tramadol to a selective serotonin reuptake inhibitor (SSRI).
• Conversely, combining drugs with opposing effects can result in loss of drug effect, for example reduced bronchodilation by a beta2 agonist
prescribed with a non-selective betablocker. Considering drug effects by organ is a useful way to recognise pharmacodynamic interactions.
• This approach allows you to consider interactions between drugs with different modes of action, for example an anticholinergic and a
benzodiazepine.
These are of two types
1. Direct pharmacodynamic interactions.
2. Indirect pharmacodynamic interactions.
1. DIRECT PHARMACODYNAMIC INTERACTIONS: In which drugs having similar or opposing pharmacological effects are used
concurrently. The three consequences of direct interactions are:
a. Antagonism: The interacting drugs have opposing actions Example: Acetylcholine and noradrenaline have opposing effects on heart
rate.
b. Addition or summation: The interacting drugs have similar actions and the resultant effect is the some of individual drug responses
Example: CNS depressants like sedatives and hypnotics etc.
c. Synergism or potentiation: It is an enhancement of action of one drug by another Example: Alcohol enhances the analgesics activity of
aspirin.
2. INDIRECT PHARMACODYNAMIC INTERACTION: In which both the object and the precipitant drugs have unrelated effects, but
latter in some way alerts the effects of the former. Example: salicylates decrease the ability of the platelets to aggregate thus impairing the
Homeostasis if warfarin indused bleeding occurs.
Pharmacokinetics
• Pharmacokinetic interactions are those in which one drug results in an alteration (increase or
decrease) of the concentration of another drug in the system. Different parameters can be affected
by pharmacokinetic interactions, including a drug’s bioavailability, volume of distribution, peak
level, clearance and half-life. Such changes can lead to changes in drug plasma concentrations and
ultimately increase the risk of side effects or diminish the efficacy of one or more drugs.
Pharmacokinetic interactions are more complicated and difficult to predict because the interacting
drugs often have unrelated actions.
• Bioavailability is a measurement of the rate and extent to which a drug reaches the systemic
circulation.
• Peak level The highest level of drug that can be obtained in the blood usually following multiple
doses.
• Half-life This is the period of time required for the concentration or amount of drug in the body to
be reduced by one half.
Examples
• Drug-Drug interaction
• Drug- Herb interaction
• Drug-Environmental/Chemical
interaction
• Drug-Food interaction
• Drug-Disease interaction
Drug-Drug interaction
• Drug-drug interactions occur when two or more drugs react with
each other.
• This drug-drug interaction may cause you to experience an
unexpected side effect.
• For example, mixing a drug you take to help you sleep (a sedative)
and a drug you take for allergies (an antihistamine) can slow your
reactions and make driving a car or operating machinery
dangerous.
• Interactions between drugs (drug–drug interactions) may be
beneficial or harmful.
• Harmful drug–drug interactions are important as they cause 10–
20% of the adverse drug reactions requiring hospitalisation and
they can be avoided.
• Elderly patients are especially vulnerable with a strong relationship
between increasing age, the number of drugs prescribed and the
frequency of potential drug–drug interactions.
Drug-Drug interactions
• Drug-drug interactions occur when a drug interacts, or interferes, with another
drug. This can alter the way one or both of the drug's act in the body, or cause
unexpected side effects.
• Aspirin+ Warfarin Synergism (excessive bleeding)
• Antibiotic+ Blood thinner Antagonism (less effect)
• Decongestants+ Antihypertensive Potentation (high blood pressure)
• Codeine+ Paracetamol Addition ( increased analgesic effect)
• Clavulanic acid+ Amoxicillin Synergism (increased antibiotic effect)
• NSAID+ Cox 2 inhibitors Synergism (increased bleeding)
• SSRI’S+ Vitamin K Synergism (increased bleeding)
• Ant emetics+ Tranquilizers Unknown effect (breathing problems)
• H2 blockers+ PPI’S Alteration (increase ph of stomach)
• Phenobarbital + Warfarin Antagonism (less effect)
• Erythromycin + Warfarin Synergism ( increased bleeding)
Drug- Herb interaction
Herb drugs + Allopathic drug = Some Reactions HERB + DRUG Interaction
• When herbal medicinal products and western drugs administered together may
interact each other in body leading to kinetic and dynamic alterations.
• Herbs are often administered in combination with therapeutic drugs, raising the
potential of herb-drug interactions.
• Herbs or Herbal drugs often taken with the Allopathic drugs with belief that it will
have some Beneficial effect.
• Most of the herbal drugs are taken because of- Availability, Economic
consideration and its safety
HERB + DRUG Interaction
Pharmacokinetics Pharmacodynamic
Change the Herb may causes
Absorption Additive
Distribution Synergistic
Metabolism Antagonistic
Protein binding Unidentified Response
Excretion activity in relation to conventional
drug
of the drug thus changing
blood level of drug
Facts about
Herbal Drug Interactions
• Drug interaction is the 4th to 6th cause of death in
the world.
• About 70-80 herbs may increase the risk of
bleeding.
• Aristolochic acid from Kidamari (Aristolochia
Bracteolata) is toxic.
• Ephedra (Somlata) caused more than 54 deaths
and 1600 cases of adverse reaction.
Reason for Herb-Drug Interaction
1.Clinician lack of adequate knowledge about Drug-herb Interaction
2.No quality control and assurance for the purity and safety.
3.No advance research in this field.
4.Blind believe or over believe in Ayurverdic medicine
5.Avoidance of patient history about drug sensitivity
6.Adulteration in herbal drug
Less
Knowledge Herbal-Drug
No Documentation Interaction
No Quality Control
Mythological Believe
PHARMACOKINETIC
INTERACTION
Herbal drugs which shows Interaction related to
Absorption
Interferes with drug absorption through Laxative action (Aloe latex)
ALOE VERA
Decrease transit time
Decrease Intestinal Fluids
Decrease effectiveness of Alprazolam by decreasing its absorption.
GINGKO BILOBA
Ginkgo decreases absorption of Alprazolam rather than
inducing hepatic metabolism of alprazolam.
Enhance the absorption of sulfaguanidine and decreases blood
GINGER sugar
PHARMACOKINETIC
INTERACTION
Herbal drugs which shows Interaction related to
Metabolism
Up regulates the action of P450 liver enzyme
MILK THISTLE
Break drug down more efficiently
May lower blood levels of the drug, which can interfere with the
desired action.
Decrease effectiveness of Alprazolam by decreasing its absorption.
GINGKO BILOBA
Ginkgo decreases absorption of Alprazolam rather than inducing
hepatic metabolism of alprazolam.
PHARMACODYNAMIC
INTERACTION
Additive Effects Synergistic Effects Antagonistic Effects
Anticoagulant with Antidiabetic medication Fluphenzine – Antipsychotic
with Gymnema sylvestris. Flupentixol- Antipsychotic
Ginkgo Biloba Procyclidine- Anti cholinergic
drug used in parkinsonism
HERBS
Bioavailability and Effects
Condition Effect on Bioavailability & other risk factor
Phenytoin + Shankhpushpi Decrease Bioavailability
Increase Bioavailability by increases absorption of Phenytoin and propranolol also
Piperine from Piper nigrum slow down elimination of these drug.
Bromelain High blood and tissue levels when they are administered concurrently with
Amoxicillin and oxytetra cycline
Taken with corticosteroids or diuretics Risk of hypokalemia
Aloe Vera/ Barbadensis
Taken with cardiac glycosides and antiaaythmetic agent. Potentiate by reducing K + via
laxative effect (digitalis Toxicity)
Arjuna Bark Beneficial effect with other antihypertensive drugs
Ashwagandha Anti-diabetic action with conventional drugs.
Other Important Interactions
HERBS INTERACTION
Cinnamon Blood-glucose lowering effects of conventional anti-diabetics
Coffee Phenylpropanolamine and coffee may cause the mania or mood swing
Capsicum Moderately Reduces the absorption of dietary iron
Slightly increases the absorption of theophylline and increase its side effect.
Garlic Hypotension with ACE inhibitors (Prils)
With antiplatelet drugs, increases risk of bleeding. Decreases plasma
concentration of Saquinavir, decreases the drug effect.
Other Important Interactions
HERBS INTERACTION
Liquorice may cause fluid retention and therefore reduces the effect of antihypertensive.
Liquorices Root
Additive hypokalemia may also occur with loop and thiazide diuretics. It may cause Digoxin
toxicity.
Senna The risk of hypokalaemia Might be increased in patient taking
Corticosteroids
Patient taking Potassium depleting diuretics could experience excessive potassium loss if they
also regularly use senna
Increase risk of hypoglycemia with antidiabetics. Avoid use with Digoxin, warfarin and other
Ginseng anticoagulants, antidepressants (Phenelzine) due to additive effect.
Drug-Environmental/Chemical interaction
• These interactions are chiefly due to smoking that entails both
pharmacokinetic and pharmacodynamic reactions.
• The carcinogenic polycyclic aromatic hydrocarbons in
tobacco smoke are potent inducers of the
CYP4501A1/1A2/and possibly 2E1 enzymes.
• Smoking increases the activity of drug metabolizing enzymes
in the liver.
• PK interactions with smoking occur with drugs like caffeine,
clozapine, olanzapine, theophylline, haloperidol and
imipramine that are substrates of CYP1A2.
• Example: Diazepam, theophylline, olanzapine are metabolized
more rapidly, and their effect is decreased.
Drug-Food interaction
• Drug-food/beverage interactions result from drugs reacting
with foods or beverages.
• For example, mixing alcohol with some drugs may cause you
to feel tired or slow your reactions.
• A lack of standardization and contamination further
contribute to these interactions.
• The mechanisms of food-induced interactions are essentially
the same as that of drug interactions, however these occur
chiefly due to alterations in absorption that may impair their
nutritional benefit and to some extent due to altered
metabolism
Drug-Food interaction
• Food effects the rate and extent of absorption of drugs from the GI tract.
Example: Many antibiotics should be given at least 1hr before or 2hr after
meals to achieve optimal absorption.
• The type of food may be important with regard to the absorption of concurrently
administered Drugs.
Example: milk and other dairy products that contain calcium may decrease the
absorption of tetracycline and flouroquinolone derivatives.
• Diet also may influence urinary pH values.
• Certain vegetables, including Brussels sprouts, cabbage, turnips, broccoli,
cauliflower, & spinach, contain chemicals that include aryl hydrocarbon
hydroxylase enzyme activity.
• LEVODOPA: The mean % of the time patients were responding satisfactorily
to levodopa was
• 51% for high-protein diet
• 67% for low-protein diet over 3 meals,
• 77% for low-protein diet restricted to evening meal.
Drug-Food interactions
A drug-food interaction happens when the food you eat affects the ingredients in a medicine you are taking so the medicine cannot work
the way it should.
• Bisphosphonates+ Any drug Reduced effectiveness of drug`
• Benzodiazepines + grapefruit Inhabit enzymes involved in drug metabolism
• Digoxin + Oatmeal Decreased adsorption of drug
• Aspirin + Milk Upset stomach
• Acetaminophen + Alcohol Liver damage
• MAO Inhibitors + food(tyramine) Severe headache
• Tetracycline’s + calcium food Reduced absorption of drug
• Warfarin + Vitamin K Reduced effect of drug
• Celecoxib + Milk Upset stomach
• Naproxen + fatty food Upset stomach
• Oxycodon + Alcohol Coma , asthma
• Caffeine + food Rapid heartbeat
Drug-Disease interaction
• Drug- Disease condition interactions may occur when an existing
medical condition makes certain drugs potentially harmful.
• For example, if you have high blood pressure you could experience
an unwanted reaction if you take a nasal decongestant.
• Disease interactions tend to occur when a medication has the
potential to worsen a disease.
• The effect a drug has in certain patients may be unexpected not
related to the drug, but because of the patient’s disease pattern.
• It is important for the physician to know the patients entire disease
profile to plan a suitable therapeutic regimen to avoid drug
interactions carefully balancing the need to ensure that the patient is
given appropriate medicines to cover his ailments.
• This has to be viewed in the context that the patient sub-population
prone to interactions are either frail elderly hospitalized patients or
critically ill patients or those having chronic diseases
Drug-Disease interaction
Drug-condition interactions occur when a drug worsens or
exacerbates an existing medical condition.
• Nasal decongestants+ Hypertension Increased blood pressure
• NSAID’S+ Asthmatic patients Air way obstruction
• Minoxidil+ Heart failure Fluid rentation
• Calcium channel blocker + Heart failure Negative inotropic
activity
• Nicotine + high blood pressure Increased heart rate
• Beta blockers+ Heart failure Worsen asthma
• Metformin + Heart failure Increased lactate level
Role Of Pharmacist In
Avoiding Drug Interactions
Pharmacists in every practice setting need to be vigilant in
monitoring for potential drug interactions and advising
patients regarding drugs proper use, foods or beverages to
avoid when taking certain medications and about disease
conditions. It is imperative for pharmacists to keep up-to-
date on potential drug-food interactions of medications,
especially today’s new drugs, so that they may counsel
properly to the patient.
REDUSING THE RISK OF
DRUG INTERACTIONS
1. Knowledge of the pharmacological effects of drugs and of patient physiology together
allows recognition of potential pharmacodynamic drug– drug interactions.
2. Identify the patient’s risk factors.
3. Take thorough drug history. Any interactions between existing drugs in a given patient
have already occurred.
4. Be knowledge about the actions of the drugs being used. Drugs with a narrow
therapeutic index are particularly susceptible to pharmacokinetic drug–drug
interactions.
5. Consider therapeutic alternatives.
6. Avoid complex therapeutic regiments when possible.
7. Starting or stopping a drug is a prescribing decision that may cause a drug interaction.
8. Monitoring patients for drug toxicity or loss of efficacy is part of routine care.
9. Checking for changes in symptoms, biomarkers of effect, or drug concentrations soon
after prescription changes helps identify drug interactions early and can reduce harm.
10. Educate the patient
CONCLUSION
It has been projected that the possibility of drug
interactions increase almost exponentially with
the number of drugs used. Drug interactions
may cause either adverse effects or sometimes
therapeutic failure. It is desirable to understand
the basic pharmacology of drugs so as to avoid
giving drugs that are additive in nature or those
acting on the same or multiple sites as well as
to remember the important inducers of
metabolism. The prescriber and also the patient
should take care while taking any OTC, natural
products and food during the medication
