1.C. Drug Interaction-Session I

Pharmacology
Drug Interaction
By:
Mr. Shivsharan B. Dhadde
Drug interaction
• Drug-Drug Interactions (DDIs): This occurs when two or more drugs interact with
each other. The interaction may enhance or reduce the effectiveness of one or
both drugs or lead to new side effects.
• Drug-Food Interactions: Some drugs can interact with certain foods or beverages,
affecting their absorption, metabolism, or effectiveness. For example, grapefruit
juice can interfere with the metabolism of certain drugs.
• Drug-Condition Interactions: Certain medical conditions may affect how drugs are
metabolized or excreted, leading to potential interactions. For example, liver or
kidney disease can impact drug metabolism and elimination.
• Drug-Alcohol Interactions: The consumption of alcohol can interact with certain
medications, either enhancing or diminishing their effects and potentially causing
adverse reactions.
Drug interaction
• The modification is mostly quantitative

the response is either increased or decreased in intensity
• But sometimes it is qualitative

an abnormal or a different type of response is produced.
• The possibility of drug interaction arises whenever a patient concurrently receives more
than one drug, and the chances increase with the number of drugs taken.
Mechanism of Drug Interactions
Drug interactions can be broadly divided into

– Pharmacokinetic interactions
– Pharmacodynamic interactions
• In certain cases, however, the mechanisms are complex and may not be
well understood.
• Few interactions take place even outside the body when drug solutions are
mixed before administration.
Pharmacokinetic interactions
These interactions alter the concentration of the object drug at its site of action (and
consequently the intensity of response) by affecting its:
• Absorption
• Distribution
• Metabolism
• Excretion
Pharmacokinetic interactions
1 Alteration of absorption or first-pass metabolism
2 Displacement of plasma protein bound drug
Alteration of drug binding to tissues affecting

3
volume of distribution and clearance
4 Inhibition/induction of metabolism
5 Alteration of excretion
Interactions-Absorption of Drug
• Absorption of an orally administered drug can be affected by other concurrently

ingested drugs.
• This is mostly due to formation of insoluble and poorly absorbed complexes in the
gut lumen
• Some interactions can be minimized by administering the two drugs with a gap of
2–3 hours so that they do not come in contact with each other in the g.i.t.
• Some interactions can not be minimized even you administer with sufficient gap
between the drug.
Examples-Interactions-Absorption of Drug
• Calcium/iron salts, antacids or sucralfate forms insoluble and poorly absorbed complexes
with tetracyclines.
• Phenytoin absorption is decreased by sucralfate due to binding in g.i. lumen.
• Ketoconazole absorption is reduced by H2 blockers & PPI because they reduce gastric
acidity which promotes dissolution & absorption of ketoconazole.
• Ampicillin, tetracyclines, cotrimoxazole markedly reduce gut flora that normally
deconjugates oral contraceptive steroids secreted in bile as glucuronides & permits their
enterohepatic circulation.
• Contraceptive failure have been reported with concurrent use of these antibiotics due to
lowering of the contraceptive blood levels.
• Alteration of gut motility by atropinic drugs, tricyclic antidepressants, opioids & prokinetic
drugs-metoclopramide can affect drug absorption.
Interactions- Distribution of Drug
• These Interactions are primarily due to displacement of one drug from its binding
sites on plasma proteins by another drug.
• This initially raise the concentration of free and active form of drug in plasma that
may result in toxicity.
• Such effects are usually brief -free form of drug rapidly gets distributed,
metabolized & excreted.
• Clinical outcome of these interactions is significant when:

 Displacement extends to tissue binding sites as well
Is accompanied by inhibition of metabolism and/or excretion.
Examples- Interactions- Distribution of Drug
• Quinidine reduce the binding of digoxin to tissue proteins as

well as its renal and biliary clearance by inhibing the efflux
transporter P-glycoprotein
Resulting in nearly doubling of digoxin blood levels and toxicity.

Interactions- Metabolism of Drug
• Certain drugs affect the rate of metabolism of other drugs & thus affect the
bioavailability and the plasma half-life of the drug .
• Inhibition of drug metabolism may be due to competition for the same CYP450
isoenzyme or cofactor.
• Important inhibitors of metabolism of drugs:
Chloramphenicol, omeprazole, SSRIs,
HIV-protease inhibitors, cimetidine, ciprofloxacin,
metronidazole, macrolide antibiotics & azole antifungals
• A number of drugs induce microsomal drug metabolizing enzymes and enhance
biotransformation of several drugs.
• Important microsomal enzyme inducers:
Barbiturates, phenytoin, carbamazepine,
Rifampin, cigarette smoking, chronic alcoholism
Certain pollutants
Interactions- Excretion of Drug
• Interaction involving excretion are important mostly in case of drugs

actively secreted by tubular transport mechanisms.
• Probenecid inhibits:
Tubular secretion of penicillins and cephalosporins
Prolongs their plasma t½.
• Aspirin blocks the:
Uricosuric action of probenecid
Decreases tubular secretion of methotrexate.
• Change in urine pH can also affect excretion of weakly acidic or weakly
basic drugs.
• Diuretics, tetracyclines, ACE inhibitors and certain NSAIDs raise steady-

state blood levels of lithium by promoting its tubular reabsorption.
Pharmacodynamic interactions
• Pharmacodynamic interactions are those in which drugs influence each other’s

effects directly.
• Pharmacodynamic interactions can occur at:
– Receptor level - drugs interacting with the same protein
– Signaling level -affecting different signaling pathways or
– Effector levels - causing different pharmacological responses
• This may result in:

– Enhanced response (synergism),
– Attenuated response (antagonism) or
– Abnormal response.
• Clinical significance are in concurrent administration of synergistic or

antagonistic pair of drugs with adverse consequences.
Examples-Pharmacodynamic interactions
Drug interactions before administration
• Certain drugs react with each other and get inactivated if their solutions are
mixed before administration.
• In combined oral or parenteral formulations, the manufacturers take care
that such incompatibilities do not take place.
• In practice situations, these in vitro interactions occur when injectable drugs
are mixed in the same syringe or infusion bottle.
– Penicillin G or ampicillin mixed with gentamicin or another aminoglycoside
antibiotic.
– Thiopentone sodium when mixed with succinylcholine or morphine.
– Heparin when mixed with penicillin/ gentamicin/ hydrocortisone
– Noradrenaline when added to sodium bicarbonate solution.
Methods for detecting Drug interactions
Drug interactions are difficult to detect in the different stages of drug

development and in postmarketing surveillance.
Some methods for detecting drug interactions includes:
• Preclinical toxicity studies
• Adverse drug event reports from clinicians and patients
• In vitro evaluation of reversible and irreversible cytochrome P450
inhibition.
• Data mining studies using clinical databases.
Data mining studies using clinical databases
• Mining pharmacovigilance sources

• Spontaneous reporting systems
• Electronic health records
• Scientific literature
• social media resources
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Pharmacology

• The modification is mostly quantitative

• But sometimes it is qualitative

Drug interactions can be broadly divided into

1 Alteration of absorption or first-pass metabolism

2 Displacement of plasma protein bound drug

Alteration of drug binding to tissues affecting

• Absorption of an orally administered drug can be affected by other concurrently

• Clinical outcome of these interactions is significant when:

• Quinidine reduce the binding of digoxin to tissue proteins as

Resulting in nearly doubling of digoxin blood levels and toxicity.

• Interaction involving excretion are important mostly in case of drugs

• Diuretics, tetracyclines, ACE inhibitors and certain NSAIDs raise steady-

• Pharmacodynamic interactions are those in which drugs influence each other’s

• This may result in:

• Clinical significance are in concurrent administration of synergistic or

Drug interactions are difficult to detect in the different stages of drug

• Mining pharmacovigilance sources

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