Nitrates are prodrugs that release nitric oxide (NO) in the body. Common nitrate drugs include nitroglycerin and isosorbide mononitrate. Nitrates were first synthesized in the 1840s and are used to treat conditions like angina by relaxing smooth muscle and dilating blood vessels. They reduce blood pressure and myocardial oxygen demand. However, tolerance to nitrates develops rapidly due to desensitization of vascular smooth muscle. Providing a daily nitrate-free period can help overcome tolerance. Nitrates are also found naturally in soil and water and excess nitrates can cause methemoglobinemia or be linked to cancer.

1. NITRATES
Demitrost Laloo

2. What are nitrates?
 Prodrugs that are sources of nitric oxide (NO)
 Drugs include: Glyceryl trinitrate
(nitroglycerin), isosorbide mononitrate and
isosorbide dinitrate

3. 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

4. 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

6. 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

7. Proposed mechanisms underlying bioactivation of
organic nitrates

8. 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

9.  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

10.  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

11. 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

12. 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)

15. 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 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

16. 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

17. 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.

18. 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

20. 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

21. Other strategies
 Sulfhydryl Group Donors
 N-acetylcysteine and L-methionine
 Antioxidants
 ACE Inhibitors and Angiotensin-1 Receptor
Blockers
 Hydralazine
 Carvedilol
 Statins

22. 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

23. THANK YOU