DRUG INTERACTIONS
What is 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…”
 The outcome can be harmful if the interaction
causes an increase in toxicity of drug
 A reduction in efficacy due to interaction can
sometimes be just as harmful as 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
1.1. Drug Absorption Interaction
 Drug interactions can affect drug absorption by:
o Affecting dissolution of the drug in the
stomach
o By influencing gastric emptying or
intestinal blood flow
o By inhibition of active transport process
 Drug dissolution in the stomach can be
modulated by:
o Gastric pH changes
o Complexation or chelation of the drug
A. Effects of changes in gastrointestinal pH
 The degree of absorption of an ionisable drug
form the stomach or duodenum depends on the
pKa of the drug and pH of the environment
 In general, alkalizing agents decrease the
absorption of weak acids.
o Ex. NSAIDs, Vitamin K, antagonist, oral
penicillin
 Conversely, acidifying agents affect the
absorption of weak bases.
o Ex. Propoxyphene and reserpine
 Example:
 Tetracycline + NaHCO3
 Tetracycline + Cimetidine
 Drugs that are hydrolyzed in the stomach are also
sensitive to changes in gastric pH
o Ex. Increasing gastric pH facilitates
absorption of penicillin
B. Chelation and Complexation
 Some drugs can interact to form complexes that
are poorly absorbed
 Tetracyclines can form complexes with Ca, Mg,
Fe, or Al ions leading to decreased absorption of
antibiotic
 Cholestyramine can form poorly absorbed
complexes with drugs containing carboxylic acids
or hydroxyl groups like warfarin, NSAIDs, and
sulphonamides
 Kaolin can form complex with Digoxin
C. Changes in gastrointestinal motility
 Gastric emptying controls the length of time that
a drug remains in the stomach
 Compared to 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
Table 1. Effects of Drugs on Gastric Emptying
Increase Decrease
Metoclopramide Anticholinergics;
Atropine, TCA
Reserpine Central analgesic,
Morphine
Anticholinesterases Isoniazid
NaHCO3 Chloropramine
Phenytoin
Al(OH)3
Mg(OH)2
Examples:
 Acetaminophen + Propantheline – decrease
absorption rate of APAP
 Acetaminophen + Metoclopramide – increase
absorption rate of APAP
 Acetaminophen + Pethidine/Diamorphine –
decrease absorption rate of APAP
 Additionally, the presence of food in the stomach
can affect the absorption of many drugs
 Food can reduce or delay the absorption of some o Warfarin + Trichloroacetic acid: increase
drugs, while not affecting or increasing the anticoagulant effects
absorption of other drugs 1.3. Drug Biotransformation Interaction
D. Induction or Inhibition of Drug Active Transport  It is the most common drug interactions as most
 One significant example of this type of drug drugs are eliminated by metabolism
interaction is the inhibition of folic acid uptake by  Drug metabolism generally takes place in the
phenytoin liver, although other organs, such as intestines
1.2. Drug Distribution Interaction and lungs, can also be important
A. Protein Binding Interactions  2 types
o Enzyme inhibition – decreases
 Drug interactions affecting drug distribution arise
metabolism
from effects on drug binding in plasma and
o Enzyme induction – increases metabolism
tissues
 Two drugs can compete with each other for the A. Enzyme Induction
same protein binding site, displacing the drug  Leads to an elevation of unbound clearance if
with the lower affinity from the binding site metabolic elimination
 Noncompetitive or allosteric drug interaction due  If the metabolite of a drug is the active
to a drug-induced conformational change in the therapeutic agent, then induction increases the
binding site can also lead to the displacement of effect, and sometimes adverse effects are
bound drug observed
 Albumin is the most important protein involved Table 3. Major Enzyme-Inducing Agents in
in the binding of acidic drugs in plasma and Humans
interstitial fluids Barbiturates Phenylbutazone
 A variety of acidic drugs bind to albumin at 2 Glutethimide Griseofulvin
different sites while some drugs bind to both Meprobamate Rifampicin
sides Chlorpromazine Oral contraceptives
 Effective displacers for albumin bound drugs: TCA Ethanol
o Salicylic acid Phenytoin Organochlorine
o Phenylbutazone compounds
o Sulfonamides Primidone Cigarette smoking
Table 2. Binding of Acidic Drugs to Albumin Carbamazepine Cruciferous vegetables
Site 1 Site 2 Antipyrine Charcoal-broiled meat
Chlorothiazide Benzodiazepines  Many drugs induce their own metabolism upon
Furosemide Cloxacillin repeated administration
o Mechanism involved in the development
Indomethacin Dicloxacillin
of tolerance to some drugs
Naproxen Glibenclamide
Phenylbutazone Ibuprofen Some inducing agents can also produce physiological
Phenytoin Indomethacin changes that can affect drug metabolism
Sulfadimerhoxine Naproxen 1.3. Drug Biotransformation Interaction
Tolbutamide Probenecid B. Enzyme Inhibition
Valproate Tolazamide  Results in decrease in unbound clearance
Warfarin Tolbutamide  3 Basic Types of Enzyme Inhibition:
 Example of drug interaction largely on protein 1. Competitive – inhibitors compete with substrates
binding: for the same binding site on the enzyme
o Sulfaphenazole + tolbutamide: increase 2. Noncompetitive – inhibitors bind to the enzyme at
hypoglycemic effects different sites than substrate
3. Uncompetitive – inhibitors bind reversibly to the o Ethambutol
enzyme-substrate complex to form an inactive o Hydralazine
ternary complex o Oxazepam
Table 4. Toxic Effects Due to Inhibition of Drug o Phenazone
Metabolism o Propoxyphene
Inhibitor Inhibited Drug Toxic Effect o Tolbutamide
Dicumarol Chlropropamide Hypoglycemic  Increased
collapse o Carbamazepine
Phenytoin Vertigo, o Diazepam
anorexia o Dicumarol
Tolbutamide Hypoglycemic o Griseofulvin
collapse o Metoprolol
Phenylbutazone Chlorpropamide Hypoglycemic o Propranolol
collapse o Nitrofurantoin
Phenytoin Vertigo, brain o Alpha tocopheryl nicotinate
damage
1.4. Drug Excretion Interaction
Tolbutamide Hypoglycemic
collapse  The urinary excretion of drugs involve
Chloramphenicol Tolbutamide Hypoglycemic glomerular filtration, tubular re-absorption, and
collapse tubular secretion
Sulfaphenazole Tolbutamide Hypoglycemic  Drug interactions affecting excretion can occur
collapse during tubular reabsorption and secretion
Sulfamethizole Phenytoin Vertigo, brain  Because only the unionized form of drug is
damage reabsorbed in the renal tubule, agents affecting
Disulfiram Phenytoin Brain damage urinary pH can modulate tubular reabsorption
Table 5. Effect of Food on Drug Absorption o Thiazide diuretics and the carbonic
 Reduced anhydrase inhibitor acetazomatide can
o Ampicillin raise urinary pH, which facilitates the
o Aspirin excretion of weak acids
o Captopril  The renal tubular secretion of drugs is often
o Ethanol mediated by active transport systems for weak
o Penicillins acids and weak bases
o Tetracyclines  Meaning, 2 drugs that are transported by the
o Iron same system can compete with each other
o L-DOPA o Probenecid inhibits tubular secretion of
o Warfarin the penicillins, prolonging their activity
 Delayed Mechanisms of Drug Interaction
o Acetaminophen II. Pharmacodynamic Interactions
o Aspirin 2.1. Additive or Synergistic Interactions
o Cephalosporins
 It is common to use the terms “additive”,
o Sulfonamides
“summation”, or “potentiation” to describe what
o Diclofenac
happens if two or more drugs having the same
o Digoxin
pharmacological effect are given together and the
o Furosemide
effects can be additive
o Indoprofen
 For example, alcohol depresses the CNS and, if
o Tulmesoxide
taken in moderate amounts with normal
o Valproate
therapeutic doses of any of a large number of
 Unaffected
o Chlorpropamide
 drugs (e.g. anxiolytics, hypnotics, etc.), may cause
excessive drowsiness
 Additive effects can occur with both 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 that can result in
serious antimuscarinic toxicity)
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 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 neurons can be prevented from
reaching those sites of action by the presence of
other drugs
 The tricyclic antidepressants (TCAs) prevent the
re-uptake of noradrenaline (norepinephrine) into
peripheral adrenergic neurons
 Thus, patients taking tricyclics and given
parenteral noradrenaline have a markedly
increased response (hypertension, tachycardia)
 Similarly, the uptake of guanethidine (and related
drugs guanoclor, betanidine, debrisoquine, etc.) is
blocked by ‘chlorpromazine, haloperidol,
tiotixene’, a number of ‘amphetamine-like drugs’
and the ‘tricyclic antidepressants’ so that the
antihypertensive effect is prevented
 The antihypertensive effects of clonidine are also
prevented by the TCAs
 One possible reason being is that the uptake of
clonidine within the CNS is blocked
Drug-Herb Interaction
 The most well known and documented example
is the interaction of St. John’s wort (Hypericum
perforatum) which induces CP450
 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
recognized that some foods can alter drug
metabolism
 Currently, grapefruit juice causes the most
clinically relevant of these interactions
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
B. 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, cyclosporine, and caffeine
 Grapefruit juice + felodipine: Increases in
felodipine blood concentration and decreases in
diastolic blood pressure
 Nutrition itself can modulate the metabolism of
drugs and xenobiotics as may 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
C. Tobacco
 Cigarette smoke contains some 3000 chemicals, Methadone
some of which are inducers and inhibitors of drug Salicylates
metabolism Phenylbutazone
 Some of the inhibitors include carbon monoxide, Antipyrine
nicotine, cadmium, and cyanide Aminopyrine
 The predominant effect of cigarette smoking is Beneficial Drug Interactions
enzyme induction, principally due to nicotine and  Some of the enzyme inducing and inhibiting
the polycyclic aromatic hydrocarbons formed effects of drugs can be used to therapeutic
during combustion advantage
Table 5. Effect of Tobacco Smoking on Drug o Phenobarbital has been used to treat both
Biotransformation unconjugated and Neonatal
Increased Metabolic No effect hyperbilirubinemia, as this drug induces
Rate glucuronosyl transferase
Nicotine Diazepam
 Multiple drug therapy that takes advantage of
Phenacetin Meperidine synergistic or inhibitory effects of drug
Antipyrine Phenytoin combinations is used to treat many conditions
Theophylline Nortriptyline o Trimethoprim and sulfamethoxazole
Imipramine Warfarin produces a synergistic inhibition of
Pentazocine Ethanol bacterial folate synthesis
Propoxyphene Phenobarbital  Other examples:
Chlorpromazine o Penicillins and aminoglycosides are sused
D. Ethanol in combination to produce synergistic
 Acute administration of ethanol inhibits both bacteriostatic effects
phase I and phase II enzymes involved in drug o Probenecid is administered with
biotransformation penicillin to reduce renal loss of antibiotic
 Chronic ethanol consumption leads to enzyme o Carbidopa is co-administered with
induction that can affect the disposition of a levodopa to inhibit dopa decarboxy-lase
number of drugs in peripheral tissues, allowing more of the
 Ethanol has pharmacodynamics interactions with drug to enter the brain
sedatives and other drugs o Diuretic combinations to prevent K loss
Drug-Disease and Genetic Factors Interaction o Antacid combinations to reduce
constipation
A. Liver Disease
 “Understanding the mechanisms underlying drug
 Liver disease can have profound effects on drug
interactions is useful, not only in preventing drug
metabolism
toxicity, but also in devising safer, more effective
 During liver disease there are changes in hepatic
therapies for diseases”
cell mass and hepatic blood flow
 Both of these effects contribute to a general
decrease in drug clearance
Table 6. Effect of Liver Disease on Drug
Disposition
Significantly Reduced Minimally Affected
Diazepam Oxazepam
Meprobamate Lorazepam
Phenobarbital Chlorpromazine
Glutethimide Acetaminophen
Chlormethiazole Morphine
Meperidine