DRUG INTERACTIONS

DEFINITION

Drug interaction is defined as the pharmacological activity

of one drug is altered by the concominant use of another
drug or by the presence of some other substance.

The pharmacological result, either desirable or undesirable,

of drugs interacting with themselves or with other
endogenous chemical agents, components of the diet, or
with chemicals used in or resulting from diagnostic tests.
 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 drugs affect is
increased) or antagonistic (when the drugs effect is
decreased) or a new effect can be produced.
 Introduction

Drug interactions may be the result of various

processes. 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 pharmacodynamics properties of a drug e.g.
the co administration of a receptor antagonists and
agonist for the same receptor.
• The Drug whose Activity is effected by such an Interaction
is called as a “Object drug.”

• The agent which precipitates such an interaction is refered

to as the “Precipitant”.
 Types of drug Interactions

1.Drug-drug interactions.
2.Drug-food interactions.
3.Chemical-drug interactions.
4.Drug-laboratory test interactions.
5.Drug-disease interactions.
 1.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 drugs act in the body, or cause
unexpected side effects. The drugs involved can be
prescription medications, over-the-counter medicines
and even vitamins and herbal products.
 Not all drug-drug interactions are equal. Sometimes
when two drugs interact, the overall effect of one or
both of the drugs may be greater than desired. For
example, both aspirin and blood-thinners like warfarin
Coumadin - used to protect against heart attack - help
to prevent blood clots from forming. Using these
medications together, however, may cause excessive
bleeding.
 1.Drug-drug interactions

1. Aspirin+ Warfarin Synergism (excessive bleeding)

2. Antibiotic+ Blood thinner Antagonism (less effect)
3. Decongestants+ Antihypertensive

4. Potentation (high blood pressure)

5. Codeine+ Paracetamol Addition ( increased analgesic
effect)
6. Clavulanic acid+ Amoxicillin Synergism (increased antibiotic
effect)
7. NSAID+ Cox 2 inhibitors Synergism (increased bleeding)
8. SSRI’S+ Vitamin K Synergism (increased bleeding)
9. Ant emetics+ Tranquilizers Unknown effect (breathing problems)
10. H2 blockers+ PPI’S Alteration (increase ph of stomach)
11. Phenobarbital + Warfarin Antagonism (less effect)
12. Erythromycin + Warfarin Synergism ( increased bleeding)
 2.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. Drug-food
interactions can happen with both prescription and over-
the-counter medicines, including antacids, vitamins and
iron pills.
 Not all medicines are affected by food, but many
medicines can be affected by what you eat and when you
eat it. For example, taking some medicines at the same
time that you eat may interfere with the way your stomach
and intestines absorb the medicine. The food may delay
or decrease the absorption of the drug. This is why some
medicines should be taken on an empty stomach (1 hour
before eating or 2 hours after eating).
 2.Drug-food interactions
1. Bisphosphonates+ Any drug Reduced effectiveness
of drug`
2. Benzodiazepines + grapefruit Inhibit enzymes
involved in drug metabolism
3. Digoxin + Oatmeal Decreased adsorption
of drug
4. Aspirin + Milk Upset stomach
5. Acetaminophen + Alcohol Liver damage
6. MAO Inhibitors + food(tyramine) Severe headache
7. Tetracycline’s + calcium food Reduced absorption of
drug
8. Warfarin + Vitamin K Reduced effect of drug
9. Celecoxib + Milk Upset stomach
10. Naproxen + fatty food Upset stomach
11. Oxycodon + Alcohol Coma , asthma
12. Caffeine + food Rapid heart beat
 3.Chemical-drug interactions.

 Some drugs produce effects without altering cellular

function and without binding to a receptor. For
example, most antacids decrease gastric acidity
through simple chemical reactions; antacids are
bases that chemically interact with acids to produce
neutral salts.
 4.Drug-laboratory test interactions

 It is important that health care professionals be aware of

the potential for medications to interfere with clinical
laboratory tests. Medications can cause in vivo effects
when the concentration or activity of the analyte is
altered before the analysis and therefore the assay result
is true and accurate. An in vitro effect occurs when the
medication interferes with the assay, and the result is
erroneous and cannot be interpreted.
 5.Drug-disease interactions

 A drug-disease interaction occurs when a medication

has the potential to make a pre-existing disease
worse. 
 Frail elderly patients may be particularly susceptible
to these interactions, because they often have
multiple chronic diseases and take multiple
medications.
 Certain drugs have the capability to exacerbate
acute and/or chronic disorders. These drugs can
also blunt the typical signs and symptoms of an
existing disease.
 5.Drug-disease interactions

1. Nasal decongestants+ Hypertension Increased blood

pressure
2. NSAID’S+ Asthmatic patients Air way obstruction
3. Minoxidil+ Heart failure Fluid retention
4. Calcium channel blocker + Heart failure Negative inotropic
activity
5. Nicotine + high blood pressure Increased heart rate
6. Beta blockers+ Heart failure Worsen asthma
7. Metformin + Heart failure Increased lactate
level
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.

 Drug interactions are thus-

• Mostly undesirable
• Rarely desirable(beneficial): for eg.,enhancement of
activity of penicillin when administered with
probenecid.
 Factors contributing to drug
interactions:

1.Multiple drug therapy.

2.Multiple prescribers.
3.Multiple pharmacological effects of drug.
4.Multiple diseases/predisposing illness.
5.Poor patient compliance.
6.Advancing age of patient.
7.Drug-related factors.
 Mechanisms of drug interactions:

The three mechanisms by which an interaction can develop

are-

1.Pharmaceutical interactions.

2.pharmacokinetic interactions.

3.Pharmacodynamic interactions.
 Pharmaceutical interactions:

Also called as incompatibility. it is a physicochemical

interaction that occur when drugs are mixed in i.v. Infusions
causing precipitation or inactivation of active principles.

Example:-
Ampicillin, chlorpromazine & barbiturates interact with
dextran in solutions and are broken down or form chemical
compounds.
 Pharmacokinetic Interactions:

“These interactions are those in which ADME

properties of the object drug is altered by the precipitant
and hence such interactions are also called as ADME
interactions”.

• The resultant effect is altered plasma concentration of the

object drug.

• These are classified as:

1.Absorption interactions
2.Distribution interactions
3.Metabolism interactions
4.Excretion interactions
 Absorption interactions

Are those where the absorption of the object drug is

.
altered. The net effect of such an interaction is:

• Faster or slower drug absorption.

• More, or, less complete drug absorption.

 Major mechanisms of absorption
interactions are:

1. Complexation.

2. Alteration in gastrointestinal motility.

3. Alteration in GI pH.

4. Malabsorption syndrome.
 1.Complexation

 Drugs may form insoluble complexes by chelation in

the gastrointestinal tract. Chelation involves the
formation of a ring structure between a metal ion (e.g.,
aluminum, magnesium, iron, and to a lesser degree
calcium) and an organic molecule (e.g., antiinfective
medication), which results in an insoluble compound
that is unable to permeate the intestinal mucosa
because of the lack of drug dissolution.
 A second well-documented, clinically significant
example of this type of interaction involves the
complexation of tetracycline and iron. By this
mechanism, tetracycline antibiotic AUCs are decreased
by up to 80%.
 2. Gestrointestinal motility.

The presence or absence of food can affect the absorption

of drugs by a variety of mechanisms. High-fat meals can
significantly increase the extent of absorption of fat-soluble
compounds such as griseofulvin, cefpodoxime, and
cefuroxime. Prolonged stomach retention can cause
excessive degradation of acid-labile compounds such as
penicillin and erythromycin. Because the primary location
of drug absorption is the small intestine, changes in gastric
emptying and gastrointestinal motility may have significant
effects on drug exposure.
 3. Alteration in GI pH

 The passage of drugs through mucous membranes by

simple passive diffusion depends upon the extent to
which they exist in the non-ionised lipid-soluble form.
Absorption is therefore governd by the pKa of the drug,
its lipid-solubility, the pH of the contents of gut and
various other Parameters relating to the pharmaceutical
formulation of the drug. Thus the absorption of salicylic
acid by the stomach is much greater at low pH than at
high.
 4.Malabsorption syndrome.

 Neomycin causes malabsorption syndrome.

 The effect is to impair the absorption of a number of

drugs including digoxin and Penicillin V.
 Distribution interactions

 Depending on relative plasma concentrations and

protein-binding affinities, one drug may displace another
with clinically significant results. This interaction is much
more likely to occur with drugs that are at least 80 to
90% bound to plasma proteins, with small changes in
protein binding leading to large relative changes in free
drug concentration.

 Tolbutamide when given with Sulphonamides,

Tolbutamide shows Increased hypoglycemic effect.
 Metabolism Interaction

 The principal site of drug metabolism is the liver. Metabolism

generally converts lipophilic compounds into ionized
metabolites for renal elimination. Cytochrome P450 is a very
large family of haemoproteins (hemoproteins) that are
characterized by their enzymatic activity and their role in the
metabolism of a large number of drugs.
 Enzymatic inhibition
If drug A is metabolized by a cytochrome P450 enzyme and
drug B inhibits or decreases the enzyme's activity, then drug
A will remain with high levels in the plasma for longer as its
inactivation is slower. As a result, enzymatic inhibition will
cause an increase in the drug's effect. This can cause a
wide range of adverse reactions.
It is possible that this can occasionally lead to a paradoxical
situation, where the enzymatic inhibition causes a decrease
in the drug's effect: if the metabolism of drug A gives rise to
product A2, which actually produces the effect of the drug. If
the metabolism of drug A is inhibited by drug B the
concentration of A2 that is present in the blood will decrease,
as will the final effect of the drug.
 Enzymatic induction

If drug A is metabolized by a cytochrome P450 enzyme and

drug B induces or increases the enzyme's activity, then blood
plasma concentrations of drug A will quickly fall as its
inactivation will take place more rapidly. As a result,
enzymatic induction will cause a decrease in the drug's
effect.
As in the previous case it is possible to find paradoxical
situations where an active metabolite causes the drug's
effect. In this case the increase in active metabolite A2
produces an increase in the drug's effect.
Example:
Barbiturates were widely used as hypnotics. It was found
necessary to keep on increasing the dosage as time
went by to achieve the same hypnotic effect, the reason
being that the barbiturates increase the activity of the
micromosal enzymes so that pace of the metabolism
and excretion.

If another drug is present as well, which is metabolized

by the same range of enzymes, its enzymatic
metabolism and excretion increases and larger doses
are needed to maintain same therapeutic effect.
 EXCRETION INTERACTIONS

Are these where the excretion pattern of the object drug

is altered. Major mechanisms of excretion interactions are

1. Alteration in the Urinary pH

2. Alteration in renal blood flow

3. Changes in active kidney tubule excretion

4. Biliary excretion and the entero-hepatic shunt

 1. Alteration in the Urinary pH

 As with drug absorption in the gut, passive

reabsorption of drugs depends upon the extent to
which the drug exists in the non-ionised lipid-soluble
form which in its turn depends on its pKa and the pH of
the urine. Only the non-ionised form is lipid-soluble and
able to diffuse back through the lipid membranes of the
tubule cells. Thus at high pH values (alkaline), weakly
acid drugs eliminated fastly. Thus pH changes that
increase the amount in the ionized form increases the
loss of the drug and moving the pH in opposite
direction will increase their retention.
 2. Alteration in renal blood flow

 The flow of blood through the kidney is partially

controlled by the production of renal vasodilatory
prostaglandins. If the synthesis of these
prostaglandins is inhibited (e.g. by indometacin), the
renal excretion of lithium is reduced and its serum
levels rise as a result.
3. Changes in active kidney tubule
excretion
 Drugs that use the same active transport systems in the
kidney tubules can compare with one another for
excretion. For example, probenecid reduces the
excretion of penicillin and other drugs by successfully
competing for an excretory mechanism, thus the 'loser'
(penicillin) is retained.
4. Biliary excretion and the entero-
hepatic shunt
 A number of drugs are excreted in the bile, either
unchanged or conjugated to make them more water
soluble. Some of the conjugates are metabolised to
the parent compound by the gut flora which are then
reabsorbed. This recycling process prolongs the stay
of the drug within the body, but if activity of the gut
flora is decimated by the presence of an antibacterial,
the drug is not recycled and is lost more quickly. This
may possibly explain the rare failure of the oral
contraceptives that can be brought about by the
concurrent use of penicillins or tetracyclines.
 Pharmacodynamic interactions:

Are those in which the activity of the object drug at its site
of action is altered by the precipitant. Such interactions may be
direct or indirect.

These are of two types

1.Direct pharmacodynamic interactions
2.Indirect pharmacodynamic interactions
 DIRECT PHARMACODYNAMIC
INTERACTIONS:

In which drugs having similar or opposing pharmacological

effects are used concurrently.

The three consequences of direct interactions are

1.Antagonism.
2.Addition or summation.
3.Synergism or potentiation.
Antagonism:
The interacting drugs have opposing actions
Example: Acetylcholine and noradrenaline have opposing
effects on heart rate.

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 hypnotic etc

Synergism or potentiation:
It is an enhancement of action of one drug by another.
Example: Alcohol enhances the analgesics activity of
aspirin.
Indirect pharmacodynamic interaction:

In which both the object and the precipitant drugs have

unrelated effects.but the latter in Some way alerts the effects
but latter in some way alerts the effectsof the former.

Example: salicylates decrease the ability of the platelets to

aggregate thus impairing the Homeostasis if warfarin indused
bleeding occurs.
 CONSEQUENCES OF DRUG
INTERACTIONS:

The consequences of drug interactions may be:

• Major: Life threatening.

• Moderate: Deteriotion of patients status.

• Minor: Little effect.

 REDUCING THE RISK OF DRUG
INTERACTIONS:

1.Identify the patients risk factors.

2.Take through drug history.
3.Be knowledge about the actions of the drugs being used.
4.Consider therapeutic alternatives.
5Avoid complex therapeutic regiments when possible.
6.Educate the patient.
7.Monitor therapy.
INFLUENCE OF SMOKING ON DRUG
INTERACTIONS:

Smoking increases the activity of drug metabolizing

enzymes in the liver, Which result in the decreased
therapeutic effect.

Example: Diazepam, propoxyphene, theophylline,

olanzapine.
Are metabolized more rapidly,and their effect is decreased.
 INFLUENCE OF ALCOHOL ON DRUG
INTERACTION:
Chronic use of alcohol beverages may increases the rate of
metabolism of drugs such as warfarin and phenytoin, probably
by increasing the activity of hepatic enzymes.

• Acute use of alcohol by non alcoholic individuals may cause

an inhibition of hepatic enzymes.

• Use of alcoholic beverages with sedatives and other

depressants drugs could result in an excessive depressant
response.
 INFLUENCE OF FOOD ON DRUG
INTERACTION:
Food effects the rate and extent of absorption of drugs from the
GI tract.
Example: Many anti biotics should be given atleast 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: Dietary items such as milk and other dairy products that
contain calcium may decrease .
The absorption of tetracycline and flouroquinolone
derivatives.
• Diet also may influence urinary pH values.
 Role of pharmacist in avoiding
drug interactions

PATIENT COUNSELING:
1. Only take medication that has been specifically
prescribed for you by your physician; 

2. Medication must be taken properly to ensure its

safety and effectiveness; 

3. Unless otherwise instructed, take medicine on an

empty stomach to achieve a faster onset of action; 
 Role of pharmacist in avoiding
drug interactions
4. When taking medicine with food or around a meal
time is not recommended, take medicine one hour before
meal/food or two hours after meals or eating food;

5. Take your medicine with a full glass (1 cupful or 8 oz.)

of water; 

6. Avoid concurrent use of alcohol with medicine; 

7. Avoid consuming excessive quantities of chocolate

and beverages containing caffeine (coffee, tea, colas);
 Role of pharmacist in avoiding
drug interactions
8. If you have any questions / concerns about your
medicine or you believe you are having an adverse drug
reaction or drug interaction, consult your pharmacist or
physician immediately. If there is a problem, your
pharmacist can contact your physician, who can
prescribe other medication to avoid the risk
 Role of pharmacist in avoiding
drug interactions

 Avoiding the combination entirely

 Adjusting the dose of the object drug

 Spacing dosing times to avoid the interaction

 Monitoring for early detection

 Role of pharmacist in avoiding
drug interactions

 Provide information on patient risk factors that

increases the chance of an adverse outcome

 Improve computerized screening systems

 Excessive number of drug interactions on the systems

 Drug class differences not handled correctly

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.
Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on
therapy, presents to the clinic to get more medication to treat his thrush
He has been taking his brother’s medication, which seemed to help at first
and then stopped working. He would like to get some more to clear the white
plaques on his tongue.
His current regimen is:
Nevirapine 200 mg bid
Zidovudine 300 mg bid
Lamivudine 150 mg bid
He has one pill of his brother’s medication left. The physician brings it to the
pharmacy to determine what medication it is. The tablet is identified as
ketoconazole 200 mg

Is this an appropriate medication to use

with his current regimen?
What are some counseling points for this
patient?