Faculty of Pharmacy
Department of Pharmacology
5th year Pharmacy Students
Drug–Drug interaction
Dr. Hany El-Bassossy
http://www.staff.zu.edu.eg/helbassossy
Introduction
Definition:
A drug interaction is a situation in which a substance affects the
activity of a drug:
Introduction
Drug interactions should be avoided, due to the possibility of poor
or unexpected outcomes.
However, some drug interactions are useful, such as coadministering probenecid with penicillin (delayed excretion of
penicillin, less dose is needed).
 Co-administration of carbidopa with levodopa (Parkinson’s
disease), levodopa is metabolized in the peripheral tissues
outside the brain, which decreases the effectiveness of the
drug.
 Carbidopa inhibits the peripheral metabolism of levodopa, more
levodopa reach the brain, reduces the risk of side effects.
Types of interaction
Pharmacodynamic interaction
Modification of the pharmacological effect without altering
concentration (e.g. the co-administration of a receptor antagonist
and an agonist)
Pharmacokinetic interaction
Alteration of the concentration that reaches its site of action.
Pharmacodynamic interaction
Examples:
 Many diuretics lower plasma K+ conc, and thereby predispose to
digoxin toxicity.
 Sildenafil inhibits the isoform of phosphodiesterase (type V) that
inactivates cGMP; consequently, it potentiates organic nitrates,
which activate guanylate cyclase, and can cause severe
hypotension in patients taking these drugs.
 MAOI increase the amount of noradrenaline (norepinephrine)
stored in noradrenergic nerve terminals and interact dangerously
with drugs, such as ephedrine or tyramine, that release stored
noradrenaline.
Pharmacodynamic interaction
Examples:
 Warfarin competes with vitamin K, preventing hepatic synthesis
of various coagulation factors. If vitamin K production in the
intestine is inhibited (e.g. by antibiotics), the anticoagulant
action of warfarin is increased.
 The risk of bleeding, especially from the stomach, caused by
warfarin is increased by drugs that cause bleeding by different
mechanisms (e.g. aspirin , which inhibits platelet thromboxane A2
biosynthesis and which can damage the stomach.
Pharmacodynamic interaction
Examples:
 Sulfonamides prevent the synthesis of folic acid by bacteria and
other micro-organisms; trimethoprim inhibits its reduction to
tetrahydrofolate. Given together, the drugs have a synergistic
action of value.
 Histamine H1 receptor antagonists, such as promethazine,
commonly cause drowsiness as an unwanted effect. This is more
troublesome if such drugs are taken with alcohol.
Pharmacodynamic interaction
Examples:
 Non-steroidal anti-inflammatory drugs (NSAIDs, ibuprofen or
indometacin, inhibit biosynthesis of PGs, including renal
vasodilator PGE2, PGI2).
If administered to patients receiving:
 treatment for hypertension, they cause increase in blood
pressure.
 diuretics for chronic heart failure, they can cause salt and
water retention and hence cardiac decompensation
Pharmacokinetic interaction
Absorption:
 Gastrointestinal absorption is slowed by drugs that inhibit gastric
emptying, (atropine or opiates).
 Addition of adrenaline to local anaesthetic injections; the
resulting vasoconstriction slows the absorption of the
anaesthetic, thus prolonging its local effect.
 Colestyramine, a bile acid-binding resin, binds several drugs (e.g.
warfarin, digoxin), preventing their absorption if administered
simultaneously.
Pharmacokinetic interaction
Distribution:
 One drug may alter the distribution of another.
 Displacement of a drug from binding sites in plasma or tissues
transiently increases the concentration of free (unbound) drug,
but this is followed by increased elimination.
 Protein-bound drugs that are given in large enough dosage to act
as displacing agents include various sulfonamides and chloral
hydrate; trichloracetic acid, a metabolite of chloral hydrate,
binds very strongly to plasma albumin.
Pharmacokinetic interaction
Distribution:
 Displacement of bilirubin from albumin by such drugs in jaundiced
neonates, the undeveloped bilirubin metabolism premature liver,
allows unbound bilirubin to cross the immature BBB and cause
kernicterus.
 Phenylbutazone displaces warfarin and inhibits metabolism of the
pharmacologically active (S) isomer, prolonging prothrombin time
and resulting in increased bleeding.
 Quinidine, verapamil and amiodarone displace digoxin from tissuebinding sites and reduce its renal excretion; they consequently
can cause severe dysrhythmias through digoxin toxicity.
Pharmacokinetic interaction
Metabolism:
 Phase 1 (oxidation, reduction, or hydrolytic reactions) leading to
drug inactivation.
 Phase 2, in which enzymes form a conjugate of the phase 1
product to produce a metabolite with improved water solubility
and increased molecular weight, thereby facilitating drug
elimination
Pharmacokinetic interaction
Metabolism:
 Enzyme induction
 e.g. by barbiturates, ethanol or rifampicin.
 The inducing agent is normally itself a substrate for the
induced enzymes, resulting in tolerance.
 It is clinically important in starting treatment with
carbamazepine. low initial dose to avoid toxicity (because
liver enzymes are not induced initially) and gradually
increased (as it induces its own metabolism)
Pharmacokinetic interaction
Metabolism:
 Enzyme induction
 Enzyme induction is exploited therapeutically by administering
phenobarbital to premature babies to induce
glucuronyltransferase, thereby increasing bilirubin conjugation
and reducing the risk of kernicterus
Pharmacokinetic interaction
Metabolism:
 Enzyme inhibition
 P450 system, slows the metabolism and increases the action
of other drugs metabolised by the enzyme
 non-sedating antihistamine terfenadine and imidazole
antifungal (ketoconazole) and other drugs that inhibit the
CYP3A subfamily of P450 enzymes
 This can result in prolongation of the QT interval on the
electrocardiogram and a form of ventricular tachycardia in
susceptible individuals
 Grapefruit juice reduces the metabolism of terfenadine and
other drugs, including ciclosporin and several calcium channel
antagonists
Pharmacokinetic interaction
Metabolism:
 Enzyme inhibition
 The therapeutic effects of some drugs are a direct
consequence of enzyme inhibition (e.g. the xanthine oxidase
inhibitor allopurinol, used to prevent gout)
 Xanthine oxidase metabolises several cytotoxic and
immunosuppressant drugs, as mercaptopurine, the action of
which is thus potentiated and prolonged by allopurinol
 Disulfiram, an inhibitor of aldehyde dehydrogenase used to
produce an aversive reaction to ethanol, also inhibits
metabolism of other drugs, including warfarin
Pharmacokinetic interaction
Haemodynamic effects:
 Variations in hepatic blood flow influence the rate of inactivation
of drugs that are subject to extensive presystemic hepatic
metabolism (e.g. lidocaine , propranolol)
 A reduced cardiac output reduces hepatic blood flow, so negative
inotropes (e.g. propranolol) reduce the rate of metabolism of
lidocaine by this mechanism
Pharmacokinetic interaction
Drug excretion:
 Inhibition of tubular secretion
 Probenecid was developed to inhibit penicillin secretion and
thus prolong its action. It also inhibits the excretion of other
drugs, including zidovudine.
 Other drugs have an incidental probenecid-like effect and
can enhance the actions of substances that rely on tubular
secretion for their elimination.
Pharmacokinetic interaction
Drug excretion:
 Alteration of urine flow and pH
 Diuretics tend to increase the urinary excretion of other
drugs, but this is seldom clinically important. .
 Conversely, loop and thiazide diuretics indirectly increase the
proximal tubular reabsorption of lithium (which is handled in
a similar way as Na+), and this can cause lithium toxicity in
patients treated with lithium carbonate for mood disorders.
 The effect of urinary pH on the excretion of weak acids and
bases is put to use in the treatment of poisoning with
salicylate but is not a cause of accidental interactions.
Sites of interaction
1. Interaction at GIT
 Change in gastric pH
 Chelation in GIT
 GIT motility
 Membrane alteration, ex antineoplastic drugs
2. Pharmacokinetic interaction
 Induction ex barbiturates and coumarins/steroid H/ nicotine
 Inhibition ex MAOI or tricyclic antidepressants
Sites of interaction
3. Interaction at the plasma proteins
ex. Warfarin and phenylbutazone
bilirubin and sulphonamides/aspirin
Sites of interaction
4. Interaction at receptors

Enhancement
 Additive
 Summation, ex aspirin and codeine
 Membrane alteration, ex antineoplastic drugs
 Potentiation ex salicylates and pentobarbitone
 Synergism ex alcohol and barbiturates
5. Antagonism

Pharmacological (competitive or non-competitive),
(reversible or irriversible)

Physiological ex histamine and adrenaline on broncheal
muscles

Chemical ex Heparin and protamine sulphate
Sites of interaction
6. Drug interactions at the kidney

Competition for active renal tubular secretion
ex Penicillin and pronecid
Salicylate and uric acid

Change in urine pH
ex acidic pH more exretion of basic drugs