THERAPEUTIC

PROBLEMS
ROLL NO.-18 TO 34
 PROBLEM-1
• A 35 YEAR OLD MALE WAS PRESCRIBED
CISAPRIDE,TERFENADINE AND
ERYTHROMYCIN TOGETHER FOR SORE
THROAT.NEXT DAY HE WAS ADMITTED IN
CARDIAC CASUALTY WITH ARRYTHMIA.

• A) WHAT HAPPENED TO THE PATIENT ?

• B) HOW THIS CAN BE PREVENTED ?
ERYTHROMYCIN
 belongs to macrolide group of antibiotics.
 It interferes with aminoacyl translocation, preventing the transfer of
the tRNA bound at the A site of the rRNA complex to the P site of
the rRNA complex.
 CYP3A4 enzyme inhibitor.

CISAPRIDE
 It is a prokinetic drug.
 Acts by 5 − 𝐻𝑇4 agonism which promotes Ach release from the
myenteric plexus.
 Metabolized by CYP3A4 enzyme.

TERFENADINE
 Second generation antihistaminic.
 Also metabolized by CYP3A4 enzyme.
• The patient suffered from arrythmia and was admitted into the casualty.
• This probably occurred as a result of drug-drug interaction that occurs when
TERFENADINE and CISAPRIDE are co-administered with a potent CYP3A4
inhibitor such as ERYTHROMYCIN.

ERYTHROMYCIN

NORCISAPRIDE
CISAPRIDE (INACTIVE METABOLITE)

CYP3A4
TERFENADINE FEXOFENADINE
• TERFENADINE and CISAPRIDE has been known to cause polymorphic
ventricular tachycardia (torsades de pointes) at higher concentration or when
it was co-administered with CYP3A4 inhibitors (eg., azole antifungals,
macrolide antibiotics, antidepressants, HIV protease inhibitors) in this case
ERYTHROMYCIN.
• This toxicity is due to blockade of delayed rectifier 𝐾 + channels in the heart at
higher concentration.
• Leading to prolongation of QT interval and predisposes to
arrythmia/ventricular fibrillation.
• This can be prevented by replacing ERYTHROMYCIN with
AZITHROMYCIN which also belongs to same class of antibiotics.
• AZITHROMYCIN in not an CYP3A4 inhibitors and hence it
prevents the drug interaction and hence their toxicity.
• Otherwise, use any other class of antibiotics.

• Cisapride was suspended from marketing in India from March 2011.

PROBLEM 2

• A 45 YEAR OLD MALE EPILEPTIC PATIENT

STABLE ON CARBAMAZEPINE WAS PRESCRIBED
CLAROTHROMYCIN FOR THROAT INFECTION.
WHAT WILL HAPPEN AND WHY?
CLARITHROMYCIN
Belongs to macrolide group of antibiotics
Like Erithromycin also inhibits CYP3A4 enzyme.
Acts by interfering with aminoacyl translocation, preventing the transfer of the tRNA bound at
A site of the rRNA complex to the P site of the rRNA complex.

CARBAMAZEPINE
Belongs to antiepiletic drugs
Act by prolongation of Na+ channel inactivation
Substrate as well as inducer of CYP3A4 and CYP2C9.
• The patient was prescribed clarithromycin while he was on
carbamazepine.
• As clarithromycin is CYP3A4 enzyme inhibitor, it will inhibit the
metabolism of carbamazepine.
• As a result there will be an increase in concentration of
carbamazepine in the blood, producing dose related adverse effects.
• Carbamazepine can cause dose related neurotoxicity – sedation ,
dizziness , vertigo, diplopia and ataxia.
• Vomiting, diarrhoea and worsening of seizures.
• This situation can be prevented by decreasing the dose by
30 to 50 percent during such drug combination.
• Also serum levels of carbamazepine should be monitored
within 3 to 5 days of starting clarithromycin.
• Alternatively, azithromycin could become drug of choice as
it does not inhibit CYP3A4 enzyme thus not causing any of
the ADR.
THANK YOU