Thursday, September 9, 2010

Isosorbide mononitrate Vs dinitrate - what to use?

This post is due to the question asked by one of my clever interns. What is the difference between the nitrates, and how can we apply that in practice based on the evidence we have.
We use three intrates- nitroglycerine, isosorbide mononitrate(ISMN), isosorbidedinitrate(ISDN). They are used widely for stable & unstable angine , heartfailure, and acute MI.  ISMN & ISDN both have to be denitrified to nitric oxide and cause vasodilation of venules and arteioles.

ISDN - has extensive first pass metabolism in the liver, and its half life is 40 min. Its major metabolites are isosorbide 2 mononitrate & isosorbide 5 mononitrate with half lives of 2 & 4 hrs respectively.
In a study done on pts with tid dose of ISDN with a 14 hr drug free interval, the excercise capacity improved after the first dose. Another study with same dose showed antianginal effects decreased progressively after the 2nd & 3rd dose likely due to tolerance. There is a sustained release ISDN when used at the max dose of 80mg bid ..causes tolerence,but when administered less than 12 hrs apart with a long drug free period...the antianginal effect was ok. One of the major studies of black pts with heart failure A-HEFT trial showed mortality benefit in adding ISDN with hydralazine.This made ACC to include ISDN in their 2009 guidelines for heart failure.

ISMN - doesn't undergo first pass hepatic metabolism.half life is around 4-6 hrs.It is primarily used in the management of chronic stable angina. It is not FDA-approved for treating heart failure. Standard formulations are 20 & 40 mg ..and again when given in an eccentric fashion(less than 12 hrs between daytime doses)...tolerance seems to be less.There is an extended release ISMN given once a day which also gives antianginal efect.

Soooo...... ISMN is preferred for angina as its once daily administration, and does better with compliance. Its better to give the drug in the morning during the time pts are active..and leave them drug free during sleep.
ISDN is recommended for heart failure (especially useful in black people..along with hydralazine), and has to be given in n eccentric fashion ( 8 hrs apart i.e- at 9am & 5pm...and so a 16hr drug free interval) to prevent tolerance. If adherence is an issue..then ISMN can be used in an off label fashion.
Also its safe to taper slowly ..when stopping nitrates..to prevent rebound.

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