DRUG INTERACTIONS

Drug Interactions with

Classical Examples
WHAT IS A DRUG
INTERACTION?
 An interaction is said to occur when the effects of one
drug are changed by the presence of another drug, herbal
medicine, food, drink or by some environmental chemical
agent.

 “...when medicines fight each other...”, or

 “...when medicines fizz together in the stomach...”, or

 “...what happens when one medicine falls out with

another...”
WHAT IS A DRUG
INTERACTION?
 The outcome can be harmful if the interaction causes an
increase in the toxicity of the drug.

 A reduction in efficacy due to an interaction can sometimes be

just as harmful as an increase.

 These unwanted and unsought-for interactions are adverse and

undesirable but there are other interactions that can be
beneficial and valuable.

 The mechanisms of both types of interaction, whether adverse

or beneficial, are often very similar,
 MECHANISMS OF DRUG
INTERACTION
I. PHARMACOKINETIC INTERACTIONS
I.I. DRUG ABSORPTION INTERACTION

 Drug interactions can affect drug absorption by:

 affecting the dissolution of the drug in the stomach.

 by influencing gastric emptying or intestinal blood flow.

 by inhibition of active transport processes.

 Drug dissolution in the stomach can be modulated by:

 gastric pH changes

 complexation or chelation of the drug.

I.I. DRUG ABSORPTION INTERACTION

A. Effects of changes in gastrointestinal pH

 The degree of absorption of an ionizable drug from the stomach

or duodenum depends on the pKa of the drug and the pH of the
environment

 In general, alkalinizing agents decrease the absorption of weak

acids. E.g. NSAIDS, Vitamin K antagonist, oral penicillin.

 Conversely, acidifying agents affect the absorption of weak

bases. E.g. propoxyphene and reserpine.
I.I. DRUG ABSORPTION INTERACTION
A. Effects of changes in gastrointestinal pH
Examples:
Tetracycline + Sodium bicarbonate

Tetracycline + Cimetidine

 Drugs that are hydrolyzed in the stomach are also

sensitive to changes in gastric pH.
 E.g. increasing gastric pH facilitates the absorption of

penicillin.
I.I. DRUG ABSORPTION INTERACTION

B. Chelation and complexation

 Some drugs can interact to form complexes that are
poorly absorbed.
 Tetracyclines can form complexes with calcium,
magnesium, iron, or aluminum ions leading to a
decreased absorption of the antibiotic.

 Cholestyramine can form poorly absorbed complexes

with drugs containing carboxylic acids or hydroxyl
groups like warfarin, NSAIDs and sulfonamides.

 Kaolin can form complex with digoxin.

I.I. DRUG ABSORPTION INTERACTION

C. Changes in gastrointestinal motility

 Gastric emptying controls the length of time that a drug

remains in the stomach.

 Compared to the duodenal mucosa, the gastric mucosa is

not a major site for drug absorption.

 Increasing the rate of gastric emptying increases the rate

of drug absorption which can result in adverse or toxic
effects due to exaggerated tissue concentrations of the
drug.
I.I. DRUG ABSORPTION INTERACTION
I.I. DRUG ABSORPTION INTERACTION

C. Changes in gastrointestinal motility

Examples:

Acetaminophen + Propantheline = Absorption rate of APAP

Acetaminophen + Metoclopramide = Absorption rate of APAP

Acetaminophen + Pethidine/Diamorphine = Absorption rate of

APAP
I.I. DRUG ABSORPTION INTERACTION

C. Changes in gastrointestinal motility

 Additionally, the presence of food in the stomach can

affect the absorption of many drugs.

 Food can reduce or delay the absorption of some drugs,

while not affecting or increasing the absorption of other
drugs.
I.I. DRUG ABSORPTION INTERACTION

D. Induction or inhibition of drug active transport.

 One significant example of this type of drug interaction is

the inhibition of folic acid uptake by phenytoin.
I.2. DRUG DISTRIBUTION INTERACTION

A. Protein-binding interactions

 Drug interactions affecting drug distribution arise from

effects on drug binding in plasma and tissues.

 Two drugs can compete with each other for the same
protein binding site, displacing the drug with the lower
affinity from the binding site.

 Noncompetitive or allosteric drug interaction due to a

drug-induced conformational change in the binding site
can also lead to the displacement of the bound drug.
I.2. DRUG DISTRIBUTION INTERACTION

A. Protein-binding interactions

 Albumin is the most important protein involved in the

binding of acidic drugs in plasma and interstitial fluids.

 A variety of acidic drugs bind to albumin at two different

sites while some drugs bind to both sites.

 Effective displacers for albumin bound drugs: salicylic

acid, phenylbutazone, sulfonamides.
I.2. DRUG DISTRIBUTION INTERACTION
I.2. DRUG DISTRIBUTION INTERACTION

A. Protein-binding interactions

 Examples of a drug interaction largely on protein binding:

 sulfaphenazole + tolbutamide = hypoglycemic
effects

 Warfarin + Trichloroacetic acid = anticoagulant

effects
I.3. DRUG BIOTRANSFORMATION INTERACTION

 It is the most common drug interactions as most drugs

are eliminated by metabolism.

 Drug metabolism generally takes place in the liver,

although other organs, such as the intestines and lungs,
can also be important.

 Two types:
 Enzyme Inhibition- decreases metabolism

 Enzyme Induction- increases metabolism

I.3. DRUG BIOTRANSFORMATION INTERACTION

A. Enzyme induction
 Leads to an elevation of unbound clearance if metabolism
is the major component of clearance and clearance is not
limited by hepatic blood flow.

 Decreases the duration of action of a drug through

increasing metabolic elimination.

 If the metabolite of a drug is the active therapeutic agent,

then induction increases the effect, and sometimes
adverse effects are observed.
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION

A. Enzyme induction

 Many drugs induce their own metabolism upon repeated

administration.
 mechanism involved in the development of tolerance

to some drugs.

 Some inducing agents can also produce physiological

changes that can affect drug metabolism.
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION

B. Enzyme inhibition
 Results in a decrease in unbound clearance.

 Three basic types of enzyme inhibition:

1. Competitive- inhibitors compete with substrates for
the same binding site on the enzyme.
2. Noncompetitive- inhibitors bind to the enzyme at
different sites than the substrate.
3. Uncompetitive- inhibitors bind reversibly to the
enzyme-substrate complex to form an inactive
ternary complex.
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.3. DRUG BIOTRANSFORMATION INTERACTION
I.4. DRUG EXCRETION INTERACTION

 The renal tubular secretion of drugs is often mediated by

active transport systems for weak acids and weak bases.

 Meaning, two drugs that are transported by the same

system can compete with each other.

 probenecid inhibits the tubular secretion of the

penicillins, prolonging their activity.
I.4. DRUG EXCRETION INTERACTION

 The urinary excretion of drugs involves glomerular

filtration, tubular reabsorption, and tubular secretion.

 Drug interactions affecting excretion can occur during

tubular reabsorption and secretion.

 Because only the unionized form of a drug is reabsorbed

in the renal tubule, agents affecting urinary pH can
modulate tubular reabsorption.
 Thiazide diuretics and the carbonic anhydrase inhibitor
acetazolamide can raise urinary pH, which facilitates the excretion
of weak acids.
 MECHANISMS OF DRUG
INTERACTION
II. PHARMACODYNAMIC INTERACTIONS
2.1. ADDITIVE OR SYNERGISTIC INTERACTIONS

 It is common to use the terms ‘additive’, ‘summation’,

‘synergy’ or ‘potentiation’ to describe what happens if two
or more drugs having the same pharmacological effect are
given together and the effects can be additive.

 For example, alcohol depresses the CNS and, if taken in

moderate amounts with normal therapeutic doses of any
of a large number of drugs (e.g. anxiolytics, hypnotics,
etc.), may cause excessive drowsiness.
 2.1. ADDITIVE OR SYNERGISTIC INTERACTIONS

 Additive effects can occur with both the main effects of

the drugs as well as their adverse effects, thus an additive
‘interaction’ can occur with antimuscarinic, antiparkinson
drugs (main effect) or butyrophenones (adverse effect)
that can result in serious antimuscarinic toxicity.

Side-effects of antimuscarinics
include constipation,
transient bradycardia(followed
by tachycardia, palpitation and
arrhythmias), reduced bronchial secretions,
urinary urgency and retention, dilatation of
the pupils with loss of accommodation,
photophobia, dry mouth, flushing and
dryness of the skin.
2.2. ANTAGONISTIC OR OPPOSING
INTERACTION

 In contrast to additive interactions, there are some pairs

of drugs with activities that are opposed to one another.

 For example the coumarins can prolong the blood clotting

time by competitively inhibiting the effects of dietary
vitamin K.

 If the intake of vitamin K is increased, the effects of the

oral anticoagulant are opposed and the prothrombin time
can return to normal, thereby cancelling out the
therapeutic benefits of anticoagulant treatment.
2.3. DRUG OR NEUROTRANSMITTER INTERACTION

 A number of drugs with actions that occur at adrenergic

neurones can be prevented from reaching those sites of
action by the presence of other drugs.

 The tricyclic antidepressants prevent the re-uptake of

noradrenaline (norepinephrine) into peripheral adrenergic
neurones.

 Thus, patients taking tricyclics and given parenteral

noradrenaline have a markedly increased response
(hypertension, tachycardia)
2.3. DRUG OR NEUROTRANSMITTER INTERACTION

 Similarly, the uptake of guanethidine (and related drugs

guanoclor, betanidine, debrisoquine, etc.) is blocked by
‘chlorpromazine, haloperidol, tiotixene’, a number of
‘amfetamine-like drugs’ and the ‘tricyclic antidepressants’
so that the antihypertensive effect is prevented.

 The antihypertensive effects of clonidine are also

prevented by the tricyclic antidepressants.

 One possible reason being is that the uptake of clonidine

within the CNS is blocked
DRUG-HERB INTERACTION
DRUG-HERB INTERACTION

 The most well known and documented example is the

interaction of St John’s wort (Hypericum perforatum)
which induces CP450

 There have also been isolated reports of other herbal drug

interactions, attributable to various mechanisms, including
additive pharmacological effects.
DRUG-DIETARY, LIFESTYLE
AND ENVIRONMENTAL
FACTORS INTERACTION
DRUG-FOOD INTERACTION

 It is well established that food can cause clinically important

changes in drug absorption through effects on gastrointestinal
motility or by drug binding.

 In addition, it is well known that tyramine (present in some

foodstuffs) may reach toxic concentrations in patients taking
‘MAOIs’.

 With the growth in understanding of drug metabolism

mechanisms, it has been increasingly recognised that some
foods can alter drug metabolism.

 Currently, grapefruit juice causes the most clinically relevant of

these interactions.
DRUG-FOOD INTERACTION
DRUG-FOOD INTERACTION

A. Cruciferous vegetables and charcoal-broiled meats

 Cruciferous vegetables, such as brussels sprouts,

cabbage, and broccoli, contain substances that are
inducers of drug metabolism.

 Chemicals formed by ‘burning’ meats (charcoal-broiled)

additionally have these properties.
DRUG-FOOD INTERACTION

A. Grapefruit juice
 In general, grapefruit juice inhibits intestinal CYP3A4, and
only slightly affects hepatic CYP3A4.

 Naringin in grapefruit juice can inhibit the metabolism of

dihydropyridine calcium antagonists, cyclosporin, and
caffeine.

 Grapefruit juice + felodipine = increases in felodipine

blood concentration and decreases in diastolic blood
pressure
DRUG-FOOD INTERACTION

 Nutrition itself can modulate the metabolism of drugs and

xenobiotics as many essential cofactors and constitutive
compounds are obtained from food.

 High in protein and low carbohydrate diet enhances the

metabolic disposition of antipyrine, theophylline, and
phenacetin.

 Low protein diet can decrease the phase I clearance of

many drugs.
DRUG-LIFESTYLE INTERACTION

A. Tobacco

 Cigarette smoke contains some 3000 chemicals, some of

which are inducers and inhibitors of drug metabolism.

 Some of the inhibitors include carbon monoxide, nicotine,

cadmium, and cyanide.

 The predominant effect of cigarette smoking is enzyme

induction, principally due to nicotine and the polycyclic
aromatic hydrocarbons formed during combustion
DRUG-LIFESTYLE INTERACTION
DRUG-LIFESTYLE INTERACTION

A. Ethanol

 Acute administration of ethanol inhibits both phase I and

phase II enzymes involved in drug biotransformation.

 Chronic ethanol consumption leads to enzyme induction

that can affect the disposition of a number of drugs.

 Ethanol has pharmacodynamic interactions with sedatives

and other drugs.
DRUG-DISEASE AND
GENETIC FACTORS
INTERACTION
DRUG-DISEASE INTERACTION

A. Liver Disease

 Liver disease can have profound effects on drug

metabolism.

 During liver disease there are changes in hepatic cell mass

and hepatic blood flow.

 Both of these effects contribute to a general decrease in

drug clearance.
DRUG-DISEASE INTERACTION
DRUG-GENETIC FACTORS INTERACTION

 Metabolic polymorphisms have been described for a

variety of enzymes, some of which are involved in drug
metabolism.

 These polymorphisms can lead to drug interactions and

toxicity in the affected individuals that are not seen in the
general population.

 Some drug interactions arise from polymorphisms in

enzymes that are not directly involved in drug metabolism
DRUG-GENETIC FACTORS INTERACTION

Examples:
 Diphenylhydantoin toxicity is increased in slow acetylators
of isoniazid compared to rapid acetylators

 Hemolysis is seen in response to a number of drugs in

people with a glucose-6-phosphate
dehydrogenase deficiency.

 Warfarin resistance is seen in individuals with abnormally

tight binding of vitamin K
BENEFICIAL DRUG
INTERACTIONS
BENEFICIAL DRUG INTERACTIONS

 Some of the enzyme inducing and inhibiting effects of

drugs can be used to therapeutic advantage.
 phenobarbital has been used to treat both
unconjugated and Neonatal hyperbilirubinemia, as this
drug induces glucuronosyl transferase.

 Multiple drug therapy that takes advantage of synergistic

or inhibitory effects of drug combinations is used to treat
many conditions.
 trimethoprim and sulfamethoxazole produces a
synergistic inhibition of bacterial folate synthesis.
BENEFICIAL DRUG INTERACTIONS

Other Examples:
 Penicillins and aminoglycosides are used in combination to
produce synergistic bacteriostatic effects.

 Probenecid is administered with penicillin to reduce renal

loss of the antibiotic.

 Carbidopa is coadministered with levodopa to inhibit dopa

decarboxy-lase in peripheral tissues, allowing more of the
drug to enter the brain.
BENEFICIAL DRUG INTERACTIONS

Other Examples:

 Diuretic combinations to prevent

potassium loss.

 Antacid combinations to reduce

constipation.
REFERENCE
 Baxter, K. (Ed). (2008). Stockley’s Drug
Interactions (8th ed). London, UK:
Pharmaceutical Press.

 Li, A. (Ed). (1997). Drug-drug

Interactions: Scientific and Regulatory
Perspective. San Diego, CA: Academic
Press.