Nitrates cause the relaxation of vascular smooth muscle resulting in:
Peripheral pooling and reduced venous return
Reduced left ventricular and diastolic pressure (preload)
Reduced systemic vascular resistance (afterload)
Reduced myocardial energy and oxygen requirements
Relaxes spasm of coronary arteries
Mechanism of Action
GTN is converted by mitochondrial aldehyde dehydrogenase to nitric oxide, it activates the enzyme guanylate cyclase. This induces a cascade of protein kinase-dependent phosphorylation events in smooth muscles. This leads to dephosphorylation of the myosin light change of smooth muscles, causing relaxation and increased blood flow in veins, arteries and cardiac tissue
Side effects can include: tachycardia, bradycardia, hypotension, methaemaglobinaemia, muscle twitching and decreased PaO2.
The use of GTN in someone who has suffered a right ventricular MI can result in severe hypotension. This is due to the reduction in preload when using GTN. If the pumping ability of the right ventricle is affected, the flow from the right ventricle becomes preload dependent. A reduction in venous return (preload) with the use of GTN will diminish flow from the right ventricle into the pulmonary circulation and diminish left ventricular filling, leading to a large reduction in cardiac output.
Precautions include: inferior MI, cerebral vascular disease, risk of hypotension and syncope, intoxication and phosphodieseterase 5 inhibitor medication
Drug interaction may occur with non-depolarising muscle relaxants and narcotics.
The concurrent use of nitrates with alcohol, antihypertensive, other drugs causing hypotension and vasodilators (including sildenafil, tadalafil and vardenafil) may result in enhanced orthostatic hypotensive effects.
The overdose dosage is approx. 105mg/kg
An overdose can have a variety of hemodynamic effects, including syncope, dyspnoea, decreased heart rate and palpitations. Neurological manifestations include seizures, coma and death.
GTN is absorbed, after a sublingual dose of GNT, peak concentration is reached in 4.4 minutes and measured to be 2.56 ng/ml. Bioavailability is approx. 40% but is dependent on factors such as mucosal metabolism and hydration status
The volume of distribution is 3L/kg
The enzyme mitchonchondrial aldehyde dehydrogenase is known to cause the bioactivation of GTN. It is metabolised to nitrate , 1,2-glyceryl dinitrate, and 1,3 glyceryl dinitrate. Nitrate is then metabolised to nitric oxide.
Both dinitrates are subsequently metabolised to mononitrates that are not active on the blood vessels, and to glycerol and carbon dioxide.
Metabolism is the main route in which GTN is eliminated from the body. Liver metabolism to 1,2-dinitro derivative is excreted by the kidneys.
GTN increased cGMP causing smooth muscle relaxation and vasodilation. It effects arteries and veins at lower concentrations causing decreased preload and stroke volume along with reduced blood pressure which reduces cardiac output and myocardial oxygen demand
With higher doses, dilation of the arteries occurs, resulting in a reduction in arterial pressure which, coupled with venous pooling when standing, often results in postural hypotension and dizziness.
As both cardiac output and arterial pressure are reduced, the oxygen demand by the myocardium is also reduced.
Nitrates also dilate normal coronary and coronary collateral vessels. The resultant increased coronary perfusion, and hence oxygen delivery, ensures more efficient distribution of blood to ischemic areas of the myocardium. The organic nitrates do not significantly change contractility or heart rate.
Duration of action
Sublingual tablet: 1-3 minutes
Sublingual spray: 2-4 minutes
IV infusion pump: Immediate
Transdermal patch: >4 hours
Duration of action:
Smooth muscle can develop a tolerance to its effects especially when given as an IV infusion or long acting preparation.