Nitrates
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NITRATES
Demitrost Laloo
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What are nitrates?
Prodrugs that are sources of nitric oxide (NO)
Drugs include: Glyceryl trinitrate
(nitroglycerin), isosorbide mononitrate and
isosorbide dinitrate
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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
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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
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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
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Proposed mechanisms underlying bioactivation of
organic nitrates
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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
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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
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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
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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
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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)
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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
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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
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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.
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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
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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
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Other strategies
Sulfhydryl Group Donors
N-acetylcysteine and L-methionine
Antioxidants
ACE Inhibitors and Angiotensin-1 Receptor Blockers
Hydralazine
Carvedilol
Statins
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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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THANK YOU