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Dr. T.R.RAMANUJAM. M.D.,

  • QUESTION: CISAPRIDE INTERACTION FATAL ? IF SO WHAT IS ITS SIGNIFICANCE ? ANSWER: YES

    Cisapride is one of the frequently used prokinetic agent used in a variety of GIT disorders by virtue of its effects of its 5 HT receptor agonism. With afew exceptions , most of the drug interactions with cisapride are as a consequence of its increase in plasma concentration. Cisapride is metabolised in the liver by an isoenzyme of Cyt P 450 known as CYP3A4. However, isolated cases of QtT prolongation syndrome and ventricular arrhythmias have ben reported in aptients receiving cisapride alone.

    Inhibition of the above isoenzyme CYP3A4 has serious consequences when cisapride is administered with drugs like:
    · Macrolide antimicrobials  
      (Erythromycin,Clasrithromycin,Roxithromycin etc.,)
    · Antifungal azole - ketoconazole, itraconazole,
      miconazole, fluconazole etc.,
    · Troleandomycin

    The product information was updated to include a warning about the risks of administering cisapride concurrently with the above agents. This includes the seriousness of the occurrence of cardiac arrhythmias as a result of the interaction . It also state that to minimize the potential for the adverse effect , the maximum dose of cisapride should not exceed 40mg/day in a patient with normal hepatorenal function as recommended by the UK committee of Safety of Medicines and the Medicine Control Agency.


    Indications of Cisapride are:

    1. Symptoms of mucosal lesions associated with GE reflux
    2. Symptomatic dyspepsia and non-ulcer dyspepsia
    3. Diabetic gastroparesis
    4. Chronic idopathic constipation
    5. Irritable Bowel Syndrome (IBS)
    6. Colonic hypomotility
    7. Aspiration syndromes
    8. Cystic fibrosis in children
    9. Systemic sclerosis
    10. Autonomic neuropathy


    Deaths have occurred as a result of drug interactions. Four patients died and further 16 were resuscitated after cardiopulmonary arrest. Mosst patients had been taking drugs that inhibit CYP3A4 enzyme systems or had other risk factors that predispose the patient for cardiac adverse effects. The major culprit in all the above cases had been CYP3A4 inhibition, the consequences of which is increase in plasma concentration of Cisapride.


    CARDIOVASCULAR ADVERSE EFFECTS- RISKS ASSOCIATED WITH -IN 86 PATIENTS:
Risk Factors  No. of Patients
1. Concurrent Imidazole & Macrolide
Antimicrobials 
32
2. History of I.H.D(Ish Heart Dis)  22
3. Renal Impairment  14
4. Electrolyte imbalance  11
5. L.T use of medication assoc with arrhythmia or
prolonged QT interval
(Amiodarone & Phenothiazine)
7
Other drugs like HIV protease inhibitors like Nefazodone, 
Probably Nelvinafir, and some selective serotonin reuptake inhibitors(SSRI) etc., inhibit CYP3A4 enzyme systems. In case of oral anticoagulants like warfarin and acenocoumarol , cisapride potentiate oral anticoagulants leading to hypoprothrombinemia in one case . Therefore the caution is necessary in patients with oral antiocoagulants when cisapride required to be added to the regimen by close monitoring.

CISAPRIDE ALTERS DRUG ABSORPTION:

The absorption of Morphine, Diazepam, alcohol, and L-dopa are increased by cisapride. Oral cimetidine but not rtanidtidine increased the bioavailability of cisapride but cisapride decreased the oral bioavailability of both cimetidine and ranitidien. Cisappride increased the sedation of Morphine, diazepam, and depressant effect of alcohol.

Antimuscarinica ( including atropine )and opioids antagonize the effects sof cispride on GIT. 
Cisapride have an unpredictable effect omn the absorption of drugs like digoxin and cyclosporin ( narrow margin TI)


BENEFICIAL DRUG INTERACTION WITH CISAPRIDE:

Improved visuo manual coordination and decreased gait disability had been observed in patients receiving concomitant L-Dopa and cisapride. However, this combination may result in an increased likelihood of L-dopa associated adverse effects. 

CAUTION:
In patients with hepatic & renal impairment.

NEWER AGENTS SIMILAR TO CISAPRIDE UNDER STUDY ARE:

Alizpride, Betanopride, and Zacropride.
Both clobepride and cinitapride are prokinetics and as well antiemetics unlike cisapride.

CISAPRIDE IS NOT AN ANTIEMETIC:

PROKINETIC &ANTIEMETICS - A COMPARISON OF METOCLOPRAMIDE, DOMPERIDONE AND CISAPRIDE.
METOCLOPRAMIDE  DOMPERIDONE  CISAPRIDE
Potent antiemetic  Moderate. Antiemetic  Not an antiemetic
Prokinetic  Prokinetic  only a prokinetic
Direct effect on CTZ thro'DA R antagonism5HT3 antagonism Ltd. entry into CNSDA antagonism  No DA antagonism5HT4 agonism
Sign hyperprolactinemia& EP effects Hyperprolactinemaia No EP effects  No hyperprolactinemia No EP effects
Periph thro rel of Ach atMyenteric region Periph thro' D2 antagonism Periph thro' rel of Achmyenteric region 
Inhibititon or receptive
Relaxation, increases
Antral& duodenal contr
Incr gastr emptying rate
Incr LES pr & Inhibit GE
Reflux
No effect on Gastr Secr.
No effect on Col. motility
Increased Gast motilityLowers LES pr. Inhibit GE reflux ? No effect oncol. motility Incr Gastr motilityIncr LES prInhibit GE reflux
INCREASES COLONICMOTILITY
Perip effcts antagonisedBy atropine &antimuscarin. Atropine & antimuscarinicsDo not antasgonise Antagonised by atropine& antimuscarinics
¯ Bioavail of digoxin     ­ Bio avail Parcetam, 
aspirin Alter of Int del 
of food & adj of Insulin
dose
No DI with drugs used in parkinsonism Ldopa,Bromocryp ¯ abs of diazep,alcohol
Bioavailability 75%  15%  30-40%
10-15mg before food 20-40mg before food  5-20mg with food
Pot antiemetic in chem ind vomiting. Not useful in motion sickness  Mild- mod antiemetic In diabeticx gastroparesisGE reflux ? Not an antiemetic In diab gastroparesis in colon idio constipAspir syndrome, Cyst fibros in children Dangerous DI with Macrolide,azoles, anticoagulants CNSdepressants
Key- LES Lower esophageal sphincter, GE- Gastroesophageal
EP-Extrpyramidal system, DA- Dopamine receptor, POT- potent
Ind- induced
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