PREPARED BY BASHEERA V, ASSISTANT PROFESSOR, DEPARTMENT OF PHARMACY PRACTICE

DRUG INTERACTION
Drug interaction may be defined as an alteration in the effect of one drug by prior or
concurrent administration effect of another drug . apart from drug- drug interaction it also
include interaction with food, interaction with disease status .

Drug interaction is clinically more significant in patients with renal impairment, alcoholics,
patient receiving chronic medications or having metabolic abnormality. Drug interaction
become harmful to patient by increasing efficacy or toxicity, decreasing therapeutic effect of co
administered drug. Drugs like anticoagulants, oral hypoglycemic agents, cytotoxic drugs etc
shows large no of drug interaction.

MECHANISM OF DRUG INTERACTION

Classified in to two categories

1. Pharmacokinetic drug interaction

2. Pharmacodynamic drug interaction
PHARMACOKINETIC DRUG INTERACTION

Alteration in GI absorption

Drug interaction reduce total amount of drug absorbed reduces therapeutic activity of drug.

1. Alteration of pH
Many drugs are weak acid or weak alkali. The non ionized form of a drug is rapidly
absorbed than ionized form
Acidic drugs (aspirin) unionized at the stomach pH and get rapidly absorbed from
stomach. Basic drugs (amphetamine, quinine) unionized at intestinal pH and better
absorbed from intestine
2. Complexation and adsorption
Some substances bind with drug therapy preventing absorption of it. Eg- tetracycline
should not given with milk,antacid or iron or Ca containing preparations. Tetracycline

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combine with metal ions such as Fe2+. Al3+, Mg2+, Ca2+ etc to form complexes that are
poorly absorbed
3. Changes in gastric motility
A cathartic by increasing GI motility may increase the rate at which another drug passes
through GIT, shorten gastric emptying time and reduce absorption of drugs.
Eg- digoxin
4. Inhibition of GI enzymes
Phenytoin and OCP inhibit intestinal conjugate enzyme thus reduce absorption of folic
acid

Alteration in drug distribution

OR displacement interaction (displacement of drug from the protein binding site)

When two drugs that are capable of binding to proteins are administered concurrently , they
may bind at different sites on the proteins (non competitive displacement)-binding
characteristics of the one drug may altered OR bind at the same site on the proteins(
competitive displacement) the drug that has the greater affinity for the binding sites will
displace the other from plasma or tissue proteins.

The protein bound fraction is not biologically active. The bound drug is gradually released to
maintain the equilibrium and pharmacological response. The unbound or free form of drug is
metabolized and excreted.

Eg:- warfarin and phnylbutazone. Both are bound to albumin. Phenylbutazone have higher
affinity, so displace anticoagulant warfarin . Therefore increased risk of haemorrhage so
concurrent therapy avoided. Similarly mefenemic acid, chloralhydrate, nalidixic acid als displace
warfarin from protein binding site.

Alteration on metabolism

1. Stimulation of metabolism (enzyme induction)

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A drug may stimulate metabolism of another drug by increasing the activity of hepatic
enzymes (eg – cytochrome P450 micrsomal enzyme), so decrease in pharmacological
action of drug

INDUCING AGENT DRUG EFFECT

Rifampicin Oral contraceptive pregnancy
Phenytoin Tolbutamide Decreased hypoglycemia
Phenytoin Quinidine Reduced quinidine levels
Barbiturate Warfarin Decreased anticoagulant effect

2. Inhibition of metabolism
A drug inhibit microsomal enzyme production, may rise blood levels of other drug or its
toxic metabolites, causing intensified drug effect and prolonged drug action.

INDUCING AGENT DRUG EFFECT

Isoniacid, phenylbutazone Phenytoin Phenytoin intoxication
Allopurinol , nortryptiline Warfarin Haemorrhage
Phenylbutazone Tolbutamide Excessive hypoglycemia
MAO inhibitors Barbiturate Prolonged sedation

Alcohol – acute ingestion of intoxicating amount inhibit enzyme and chronic ingestion cause
enzyme induction

Alteration on excretion

1. Change in urinary pH
Any drug that will change urinary pH will alter excretion of weak acid or weak base.
Ionized form of drug excrete easily. Non ionized drug diffuse from urine back in to

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blood. Therefore acidic drug excreted in basic urine and basic drug excreted in acidic
urine.
Example for urinary acidifiers- ascorbic acid, PAS, ammonium chloride, calcium chloride,
phenylbutazone
Example for urinary alkalinisers- acetazolamide, potassium citrate, sodium citrate,
sodium bicarbonate
Drugs whose excretion enhanced in acidic urine- amphetamine, fenfluramine, quinidine,
pethidine, pracainamide
Drugs whose excretion enhanced in basic urine- barbiturates, streptomycin
2. Interference with urinary excretion
Competition for tubular transport between concurrently administered drugs commonly
interfere with urinary excretion
Example- penicillin and probencid
Probencid increase serum level of penicillin and prolong activity of penicillin by blocking
their tubular excretion

COMPETING DRUG PRIMARY DRUG EFFECT ON PRIMARY DRUG

Probencid Indomethacin, salicylates, PAS Toxicity of indometacin,
salicylates, PAS
Verapamil, quinidine digoxin Digoxin toxicity
Spironolactone Digoxin Digoxin
Salicylate, sulphonamide Methotrexate Bonemarrow suppression

PHARMACODYNAMIC INTERATION

1. Antagonistic effect
Drugs having opposite pharmacological action
Example- acetylcholine and nor adrenaline: acetylcholine lower HR and nor adrenaline
increases the HR

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Thiazide increases blood glucose levels. If it is administered to a diabetic patient who is

on insulin/ tolbutamide increased dose is necessary
Cholinergic drug pilocarpine ( eye problem) and Anticholinergic drug propantheline for
gastric problem
2. Synergestic effects
Drugs acting at the same site or influencing same physiological system cause synergestic
effect
Example- trimethoprim and sulphonamide- increased antimicrobial activity
Alcohol and CNS depressants- increased CNS depression
Oralhypoglycemic and salicylate/propranol – excessive hypoglycemia
Digitalis and propranolol- excessive bradycardia
3. Alteration of electrolyte level
Drug which cause alteration in fluid and electrolyte balance may modify the response of
tissue to drugs
Example:- diuretics and digoxin- diuretics cause potassium losing may cause
Hypokalemia and making the heart more sensitive to digoxin result in digoxin toxicity.
Diuretics and tubocurarine – Hypokalemia leads to tubocurarine toxicity result in
prolonged paralysis
Diuretics and phenylbutazone – phenylbutazone induce salt and water retension ,
antagonize the diuretic activity
4. Interaction involving adrenergic system
MAO inhibitors and sympathomimetics agents – MAO-Inhibiotors cause increased level
of nor epinephrine with in the adrenergic neurons. Sympathomimetics agents release
norepinephrine from stores. So exaggered response cause hypertension, cardiac
arrhythmia
5. Alteration of receptor site interaction
a) Drug interacting at same receptor
Morphine antagonized by nalophine
b) Drug interaction at different receptor

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Adrenaline and theophylline – adrenaline activate adenyl cyclase and increase 3,5
cAMP cause bronchial smooth muscle relaxation . where as theophylline inhibit PDE
and increase 3,5 cAMP leads to bronchial s.m relaxation .

DRUG- DRUG INTERACTION WITH REFERENCE TO ANALGESICS

ANALGESIC DRUG INTERACTING DRUG EFFECT

Salicylates urine alkalinizer Excretion of salicylates , Seum level of
salicylate reduces
Salicylates urine acidifiers Excretion decreased, Setum level
increased
Salicylate indomethacin Salicylate inhibit GI absorption of
indomethacin, Serum level of
indomethacin reduced
Salicylate heparin Aspirin inhibit platet function , disturb
haemostatic mechanism, Chance of
bleeding high
Salicylate probencid Compete for same binding site on plasma
protein, Probencid activity decreased
Phenylbutazone antidiabetic Serum tolbutamide increased Excessive
hypoglycemia
Phenylbutazone anticoagulants Serum warfarin increases Avoid combn

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DRUG- DRUG INTERACTION WITH REFERENCE TO CARDIVASCULAR DRUGS

CARDIOVASCULAR DRUG INTERACTING DRUG EFFECT
Digitalis Antacid Absorption of digitalis reduced
Digitalis Cimetidine Cimetidine Inhibit metabolism of
digitalis leads to cardiotoxicity by
digitalis
Digitoxin Barbiturates Promote metabolism of digitoxin to
digoxin. Digoxin half life is less than
digitoxin, leads to underdigilisation
Digitalis Sympathomimetics Increased ectopic pacemaker activity .
leads to cardiac arrhythmia
Digitalis Quinidine Increased serum digoxin level
Amiodarone Oral anticoagulant Amiodarone reduce metabolism of oral
anticoagulant , increased activity
Propranolol Antidiabetic Propranolol inhibit release of glucose
from liver glycogen, so reduction in
dose of antidiabetic required to prevent
excessive hypoglycemia
Guanethidine Tricyclic anti depressants Inhibit uptake of guanethidine, so avoid
TCA
Methyldopa Amphetamine Decrease action of methyldopa
Captopril salicylate Inhibit action of captopril

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DRUG- DRUG INTERACTION WITH REFERENCE TO GASTRO INTESTINAL DRUGS

GI DRUG INTERACTING DRUG EFFECT
Antacid Aspirin Less GI irritation and better absorption of
aspirin
Antacid Bisacodyl Premature disintegration of bisacodyl, GI
irritation and vomiting
Antacid Isoniacid Decrease INH absorption
Antidiarroeal (kaolin digoxin Adsorption of digoxin, decreased
and pectin) absorption of digoxin
Cathartics Slowly absorbed drugs Decrease absorption of drugs
Antiemetics Levodopa/ethanol/acet Reduce motility of GIT, increase absorption
aminophen of GIT

DRUG- DRUG INTERACTION WITH REFERENCE TO HYPOGLYCEMIC AGENTS

HYPOGLYCEMIC DRUG INTERACTING DRUG EFFECT
Antidiabetic agent alcohol Alcohol has hypoglycemic effect, so severe
hypoglycemia and coma occurs
Tolbutamide Rifampicin Decrease hypoglycemic effect
tolbutamide phenylbutazone Increased hypoglycemic action
Antidiabetic OCP Impairedglucose tolerance , decraesd
hypoglycemic action
Soluble insulin Protamine zinc insulin If these two mixed in same syringe onset
of soluble insulin delayed due to its
conversion to long acting protamine zinc
insulin

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DRUG- DRUG INTERACTION WITH REFERENCE TO VITAMINS

VITAMIN INTERACTING DRUG EFFECT
vit B12 chloramphenicol Chloramphenicol cause erythrocyte
maturity, so less respond to vit B12
Vit A Mineral oil Oil impair GI absorption of vit A
Vit B6 Levodopa Vit B6 increase metabolism of
levodopa, decreased amount of
levodopa reaches brain
Vit D Phenytoin/phenobarbotal Drug stimulate vit D metabolism ,
results lower serum Ca levels,
development of rickets
Vitamin B complex OCP OCP cause deficiency of vit B12, vit C,
vit B6, folic acid by inhibition of
gastric enzyme responsible for its
absorption.

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DRUG- DRUG INTERACTION WITH REFERENCE TO DIURETICS

DIURETICS INTERACTING DRUG EFFECT
Thiazides Sulfonyl urea Thiazide antagonize the action of
ulfonyl urea; pt should be given
potassium supplemts
Thiazedes Antihypertensives Tiazid increase action of
antihypetensives; pt should be
watched for excessive hypotension
Potassium losing diuretics Cardiac glycosides Hypokalemia induced by diuretics
enhance digitalis effect and leads
to toxicity. Potassium replacement
therapy should be followed
Ethacrynic acid Aminoglycoside antibiotics Both are ototoxic, ethacrynic acid
increases renal toxicity of
aminoglycosides
Frusemide Phenytoin Decreased absorption of frusemide
Actazolamide/thaizide quinidine Diuretics make urine alkaline,
decreased excreation of quinidine ,
increased serum level of quinidine
Spironolactone Potassium chloride Spironolactone conserve
potassium. So Hyperkalemia occur
when K+ supplements given along
with it

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DRUG- FOOD INTERACTION

DRUG FOOD EFFECT

Digoxin High fiber diet Decrease abdorption of digoxin
Acetaminophen Alcohol Increased hepatotoxicity
MAO inhibitors Tyramine rich If tyramine containing food taken with
food(pickle,meat, curd, yeast MAO-inhibitors , it can leads to high BP
extract, beer,wine and
fermented foods)
Green leafy vegetables warfarin Warfarin inhit the action of vit K, pt must
(vitK) be counseled to avoid overconsuming
these food stuffs
Grape fruit juice Statins Grape fruit juice contain furanocoumarin
it increase the drug’s potency leads to
condition called rhabdomyolysis
Ca containing food Tetracycline Ca cause adsorption of tetracycline,
milk, yoghurt, cheese unable to effectively absorb antibiotic
Ethanol Folic acid Folic acid deficiency
Sugar Antidiabetic Block drug action
Food INH, tetracycline, amoxicillin, Reduce absorption of drugs
levodopa, rifampicin
Food Iron supplements Reduce absorption, in empty stomach
cause GI irritation
Food Nitrofurantoin, hydralazine, Increase absorption
carbamazepine, propranolol
High fat meals Griseofulvin Increase absorption
Green vegetables Antibiotics Reduce effect of drug
Caffeine Aspirin/indomethacin Increased action of drug

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