NITRATES

Demitrost Laloo

What are nitrates?

Prodrugs that are sources of nitric oxide (NO)

Drugs include: Glyceryl trinitrate

(nitroglycerin), isosorbide mononitrate and

isosorbide dinitrate

History

Nitroglycerin was first synthesized in 1846 by

Sobrero

Alfred Nobel devised a process to stabilize the

nitroglycerin and patented a specialized

detonator in 1863

In 1857, T. Lauder Brunton of Edinburgh

administered amyl nitrite by inhalation and

noted that anginal pain was relieved within 30-

60 secs

William Murrell surmised that the action of

nitroglycerin mimicked that of amyl nitrite

Chemistry

polyol esters of nitric acid

characterized by a sequence of carbon–

oxygen–nitrogen (—C—O—NO2)

Organic nitrates of low molecular mass

(nitroglycerin) are moderately volatile, oily

liquids

high-molecular-mass nitrate esters

(e.g.,isosorbide dinitrate, and isosorbide

Mechanism of action

Organic nitrates lead to the formation of the reactive gaseous free radical NO and related NO-containing compounds

NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP, activate PKG, and modulate the activities of cyclic nucleotide phosphodiesterases

In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca2+ concentration in the cytosol, and relaxation

Proposed mechanisms underlying bioactivation of

organic nitrates

Effects of nitrates

promote relaxation of vascular smooth muscle

Low concentrations of nitroglycerin

preferentially dilate veins more than arterioles

decreases venous return, leading to a fall in left

and right ventricular chamber size and end-

diastolic pressures

Systemic arterial pressure may fall slightly

Higher doses of organic nitrates cause:

Further venous pooling and may decrease

arteriolar resistance as well, thereby decreasing

blood pressure and cardiac output

Causing pallor, weakness, dizziness, and

activation of compensatory sympathetic reflexes

Reduces myocardial O₂ demand

decreasing both preload and afterload

Dilating coronary arteries and thereby increasing coronary blood flow

mechanisms not entirely clear

Most hypotheses : dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for ~90% of the overall coronary vascular resistance

Limits platelet aggregation/adhesion

Other effects

Bronchial smooth muscle is relaxed irrespective of the preexisting tone

The muscles of the biliary tract, including those of the gallbladder, biliary ducts, and sphincter of Oddi, are effectively relaxed

Smooth muscle of the GI tract, including that of the esophagus, can be relaxed and its spontaneous motility decreased

Relaxes ureteral and uterine smooth muscle

Therapeutic uses

Mainly used in:

Stable angina pectoris

CCF

Unstable angina pectoris and NSTEMI

Acute myocardial infarction

Prinzmetal angina

Others :

Portal hypertension

Asthma and as a diuretic (obsolete)

Portal HTN

Nitroglycerin has been used in combination with vasopressin to control acute variceal bleeding. The rate of infusion of nitroglycerin is 50 to 400 μg/min, provided that the systolic blood pressure > 90 mmHg

Nitrates are no longer recommended, either alone or in combination with a ß blocker, for primary prophylaxis to prevent first variceal bleeds

For secondary prophylaxis (to prevent varicealrebleeding), isosorbide mononitrate may be added to a beta blocker if the beta blocker alone has not resulted in an appropriate decrease in HVPG

Adverse effects

Headache

Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop

High doses of organic nitrates causes postural hypotension, facial flushing, and tachycardia

Prolonged therapy causes endothelial dysfunction

Interactions

Phosphodiesterase V inhibitors such as

sildenafil, tardenafil, and vardenafil potentiate

the action of the nitrates.

To preclude the dangerous hypotension that

may occur, this combination is contraindicated.

Tolerance

Tolerance to the actions of nitrates develops rapidly and blood vessels become desensitized to vasodilation

Reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO: True vascular tolerance

Activation of mechanisms extraneous to the vessel wall: Pseudotolerance

Multiple mechanisms have been proposed to account for nitrate tolerance

PETN is the only organic nitrate in clinical use, which is devoid of induction of oxidative stress and related side-effects such as endothelial dysfunction and nitrate tolerance

Strategies to prevent Tolerance

Tolerance can be overcome by providing a

daily “nitrate-free interval” to restore sensitivity

to the drug

This interval is typically 10 to 12 hours, usually

at night, because demand on the heart is

decreased at that time

Other strategies

Sulfhydryl Group Donors

N-acetylcysteine and L-methionine

Antioxidants

ACE Inhibitors and Angiotensin-1 Receptor Blockers

Hydralazine

Carvedilol

Statins

Nitrates is also…

Found in groundwater and soil

Use as preservatives in processed food

Drinking water that contains high levels of nitrates can be toxic to humans especially infants

Causes Methemoglobinemia , also known as ‘Baby Blue Syndrome’ in infants

Excess nitrates ingestion also implicated in cancer, thyroid hypertrophy

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