3.11 Drugs Used for Angina – Nitrates

In this topic we will look at organic nitrates and explore their use in a clinical setting.

Introduction – Organic Nitrates

The organic nitrates are effective dilators of (predominantly) veins and arteries and are used to treat angina pectoris. Organic nitrates can be classed into two broad groups:

• Short acting rapid onset nitrates: glyceryl trinitrate and isosorbide dinitrate
• Longer acting slower onset nitrates: isosorbide mononitrate.

Short and long acting nitrates are both used to manage angina, but are used at different times. The short acting – rapid onset sublingual glyceryl trinitrate and isosorbide dinitrate are used to manage acute symptoms of unstable angina or for the prevention of symptoms of angina. The longer acting nitrates isosorbide mononitrate (and controlled release isosorbide dinitrate and glyceryl trinitrate patch) are used to prevent symptoms of chronic angina. The order of relative duration of action of the different nitrates can be remembered by the number of nitrate groups in the preparation:

• trinitrate (3) is short acting
• dinitrates (2) slightly longer acting
• mononitrates (1) long acting.

Endogenous (naturally produced) nitric oxide is produced by vascular endothelial cells (other cells too but they are less important at the moment) and has a range of important functions. One of these functions is to mediate relaxation of vascular smooth muscle. Nitric oxide (NO) moves from the endothelial cell and enters the smooth muscle cell where it binds with soluble guanylyl cyclase which converts GTP to cGMP. cGMP activates Protein Kinase G which phosphorylates myosin and causes smooth muscle relaxation.

The organic nitrates donate a nitrate group where it is converted to nitric oxide by s-nitrosothiol to nitric oxide. Nitric oxide (NO) binds with soluble guanylyl cyclase which converts GTP to cGMP. cGMP activates Protein Kinase G which phosphorylates myosin and causes smooth muscle relaxation.

At therapeutic doses of nitric oxide, the dilation of veins predominates over arteries.  The vasodilatation of veins (+++ lots) and arteries (+ a bit) has 2 major effects:

It is the reduction in ventricular pre-load and resultant reduction of myocardial oxygen demands that explains its benefit in stable angina (pectoris), rather than it’s dilation of the coronary arteries.

Side effects include orthostatic hypotension, headache, flushing, palpitations, hypotension and peripheral oedema. Patients can build a tolerance to nitrates with continuous exposure. This can be avoided by ensuring patients have nitrate-free period of at least 8-hours in each 24-hour period.

Kinetics. Most organic nitrates have low oral bioavailability as they undergo extensive first pass metabolism. The one exception is isosorbide mononitrate which has quite high oral bioavailability. Because the bioavailability of the other organic nitrates are low, they are typically administered by sublingual tablet or spray, patch or infusion.