Drug-Drug interaction

INTRODUCION
• Drug interaction refers to an adverse drug response produced by
the administration of a drug or co exposure of the drug with
another substance, which modifies the patient’s response to drug.

• Some drug interaction are intentional in order to provide

improved therapeutic response or to decrease adverse drug
effects.

• A precipitant drug is the drug, chemical, or food element causing

the interaction and an object drug is the drug affected by the
interaction.

MECHANISM OF DRUG INTERACTION

PHARMACOKINETIC INTERACTION

• It occur when the absorption, distribution or elimination of the

drug is affected by another drug, chemical, or food element.

Absorption
 Drug interaction can affect the rate and the extent of
systemic drug absorption from the absorption site, resulting in
increased or decreased drug bioavailability.

 The most common drug absorption site is in the

gastrointestinal tract. However, drug bioavailability from other
absorption sites such as skin can be affected by drug interaction.
 For examples, epinephrine, a vasoconstrictor, will decrease the
percutaneous absorption of lidocaine, a local anesthetic agent.

 Altered absorption

• Chelation and complex formation alter absorption of drug.

• Examples : cations in antacids bind to sodium polystyrene

sulfonate, causing reduced renal clearance of bicarbonate,
resulting in systemic acidosis.

 Altered pH

• Some drugs need specific pH for absorption.

• Examples: H-2 blockers and antacids increases gastric pH.

The dissolution of drugs like ketoconazole and omeprazole
are reduced causing decreased drug absorption.

 Altered intestinal flora

• Examples: 40% or more of the administered digoxin is
metabolized by intestinal flora but use of antibiotics like
erythromycin reduces bacterial inactivation of digoxin.
 Altered GI motility
• Example: propantheline decreases the gastric emptying time
of acetaminophen , delaying its absorption from the small
intestine.
 Inhibition of drug metabolism in intestinal cells
• MAO-Is ( eg: tranylcypromine) inhibit metabolism of
tyramine containing foods in the intestine, leading to
hypertension caused by high tyramine levels.
Distribution
 The distribution of the drug may be affected by plasma protein
binding and displacement interaction or tissue and cellular
interactions.
 The most likely bound drug is capable of displacing the other.
The free drug concentration is increased by displacement by
another drug with higher affinity.
Examples:
i) valproic acid displaces phenytoin from plasma protein binding
sites and reduces hepatic phenytoin clearance by inhibiting the
liver’s metabolism of phenytoin,
ii) quinidine reduces digoxin clearance and displace digoxin from
tissue binding sites, leading to a higher plasma digoxin
concentration and reduced distribution volume.
Metabolism
• Drug metabolism can be affected by enzyme induction, enzyme
inhibition, substrate competition for the same enzyme and
changes in hepatic blood flow.
 Enzyme induction: A drug may induce the enzyme that is
responsible for the metabolism of another drug or even
itself. E.g. phenytoin increases the hepatic metabolism of
theophylline leading to decrease it’s level and reducing it’s
action and vive versa.
 Enzyme inhibition : It is decrease of the rate of metabolism
of drug by another one which lead to increase in the
concentration of the drug and leads to toxicity. Inhibition of
the enzyme may be due to the competition on it’s binding
site. So, the onset of action is short maybe within 24 hour.
 E.g. erythromycin inhibit the metabolism of astemizole
leading to increase concentration of the anti histamine
causing life threatening cardio toxicity.
Excretion
• Alteration on excretion of drugs
 Change in active tubular secretion: e.g. probenecid
blocks the active tubular secretion of penicillin and
some cephalosporin antibiotics
 Tubular reabsorption : e.g. antacids increases
salicylates clearance and decrease it’s action.
Pharmacodynamic interaction
• It occurs when the pharmacodynamics effect of the drug is altered
by another drug, chemical, or food element, producing an
antagonistic, synergistic, or additive effect.

 Antagonistic interaction: It means that the effect of two

chemicals is actually less than sum of the effect of two drug
taken independently. Example: spironolactone antagonize
the mineralocorticoid effect of carbenoxolone through an
effect of aldosterone receptor and carbenoxolone also
antagonize competitively the renal electrolyte handling
effects of spironolactone.

 Synergistic action: It means that the effect of two chemicals

taken together is greater than the sum of their separate
effects at the same doses. examples: NSAIDs and warfarin
increases risk of more thinning of blood.
  Additive effect: It means the effect of two chemicals is equal
to the sum of the effect of two chemicals taken separately.
e.g. paracetamol and ibuprofen increases analgesic
property.

Potential drug interaction

• Multiple drug therapy, including both prescription and OTC
medication can potentially lead to drug interactions. The more
drugs used by patients, the greater potential for a drug interaction
in the patient.

• Multiple prescribers: patients can be seen by different prescribers

who prescribe interacting medication

• Patient compliance: patient need to follow proper instruction for

taking medication.

• Older patients are at more risk than younger ones because they
might have physiological and pathophysiological condition that
lead to altered body composition, altered GI transit time,
decrease protein binding, decrease drug clearance etc.

Clinical significance
• Not all drug interaction are clinically significant or cause an
adverse effect. In some cases interacting drugs can be prescribed
such as cimetidine and an antacid might be prescribed to the
patient , but the patient should be instructed not to take medicine
at the same time.
 • Combination drug therapy can have beneficial effects. Eg:
trimethoprim and sulfamethoxazole- combination antibiotic for
increased efficacy in UTI.

Management of drug interaction

• Review the patient profile, including drug history and patient risk
factors.

• Determine the probability of a clinically significant drug

interaction.

• Suggest a different drug if there is a high probability for a clinically

significant drug interaction. For example: acetaminophen can be
used for headache instead of aspirin for a patient on
anticoagulant therapy.

• Carefully instruct the patient as to the timing of the medication.

Example: the antacid and H-2 blocker should not be given at the
same time.

• Monitor the patient for adverse events. Sulfonamide can prolong

prothrombin time in patient given warfarin therapy. The
prothrombin time should be monitored in these patients.

• Reevaluate the patient profile and drug history when changing

drug therapy. E.g.: when discontinuing the diuretics of a
congestive heart failure patient on digoxin, a review of the profile
may reveal a potassium supplement that should be discontinued
as well.
Other recommendations for drug interaction

Drugs Effects Recommendation

Calcium therapy + Chronic aluminium Use alternative

aluminium hydroxide antacid antacid. Especial
hydroxide intake can cause care should be
osteomalacia taken with people
with calcium
deficiency

Lincomycin + kaolin Reduced GI Space dosed by 2-3

absorption of hour
lincomycin by up to
90%

Dicoumarol,warfari Chronic laxative Periodic long term

n + laxatives administration may monitoring of
cause loss of anti prothrombin times
coagulant control in all suspected
patients

Thiazide diuretics + Decreased Space doses by 2-3

colestyramine absorption and hour
effect of diuretics
Digoxin + Greatly reduced Space doses by
colestyramine absorption of about 8 hour.
digitalis alkaloids
with concurrent
administration

Drugs Effects recommendation

Chlorpropamide, Introduction of Warn patient

tolbutamide + oral salicylate against high dose
salicylates therapy can result or chronic
in a hypoglycemic salicylate therapy.
reaction With long term
salicylate therapy
patient should be
monitored.

Dicoumarol, Possible elevated This combination is

warfarin + blood levels of best avoided
indomethacin anticoagulant with
risk of
hemorrhage. Risk
 of GI bleeding.

Warfarin + nalidixic Possible Combination

acid hypothrombinemia administration
with associated should be used
hemorrhage risk with care and
patient coagulation
monitored

Oral anticoagulant + Increased Best to avoid

naproxen anticoagulant concurrent
effect and risk of GI administration.
bleeding Monitor patients.