Nitrates

•	Pathophysiology.
•	Principles of drug therapy.
•	Individual drugs.

Mechanism of action

1.	The nitrates and nitrites are denitrated in smooth muscle to release nitric oxide (NO).

2.	NO activates guanylate cyclase and increase the synthesis of cyclic GMP.

3.	A cGMP-dependent protein is stimulated and this leads to the dephosphorylation of the light chain of myosin and resulting in smooth muscle relaxation.

Pharmacokinetics

1.	The nitrates are generally well absorbed through oral and intestinal mucosal and the skin and are used by these routes.

2.	They are subject to extensive and rapid metabolism in the liver at first-pass after absorption from the gut. 

3.	They are first denitrated to mononitrates and then conjugated with glucuronic acid.

4.	Preparations and routes of administration:

Compound	Route/preparation	Duration of action	
Amyl nitrate	Inhalation in crushable glass capsule	10 min (onset 10s)	
Glyceryl trinitrate	•	Sublingual

•	Percutaneous
•	Oral sustained release	•	30 min (onset 1 min)
•	5 hr
•	8 – 12 hr	
Isosorbide dinitrate	•	Sublingual
•	Chewable
•	Oral sustained release	•	1 hr
•	2 – 3 hr
•	6 – 12 hr	
Isosorbide-5-mononitrate	•	Oral	•	12 hr	

Effects on Heart

1.	The nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure.

2.	The basic action of the nitrates is to relax all smooth muscles, the relaxation being more in veins than in arteries.

3.	Venodilation and venous pooling:

a.	reduces venous return to the heart resulting in a reduction in ventricular end-diastolic herat pressure and heart size.

b.	improve subendocardial perfusion.

4.	Arteriolar dilatation reduces peripheral resistance and myocardial workload and further reducing myocardial demand for oxygen.

5.	The nitrates relieve anginal symptoms by reducing the myocardial demand for oxygen and improving myocardial perfusion rather than by increasing coronary blood flow.

6.	Apart from angina pectoris, the nitrates may be used for relieving esophageal spasm managing heart failure and for controlling postoperative hypertension.

Adverse effects

1.	Dizziness: due to postural hypotension.

2.	Palpitations: due to compensatory increase in heart rate.

3.	Throbbing headache: due to meningeal artery pulsations.

4.	Methaemoglobinaemia at high doses.

5.	Tolerance:

a.	More likely with high doses of nitrates with longer half-life giving a steady