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

oxygennitrogen (CONO2)

Organic nitrates of low molecular mass

(nitroglycerin) are moderately volatile,
oily liquids

high-molecular-mass nitrate esters

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 O demand

Dilating coronary arteries and thereby increasing

coronary blood flow

decreasing both preload and afterload

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 g/min,
provided that the systolic blood pressure > 90 mmHg

Nitrates are no longer recommended, either alone or

in combination with a blocker, for primary
prophylaxis to prevent first variceal bleeds

For secondary prophylaxis (to prevent variceal

rebleeding), 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 sideeffects 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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