• NITRATES

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 1.NITRATES
O2NO ONO2
ONO ONO 2
amyl nitrite glyceryl trinitrate
(nitroglycerin)
O 2NO H
O O2NO ONO 2

O O2NO ONO2
H ONO2
Isosorbide dinitrate Erythrityl tetranitrate

O 2NO ONO2

O 2NO ONO2
pentaerythritol tetranitrate

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Organic Nitrates
✓ Organic nitrates & nitrites are
simple nitric & nitrous esters of
glycerol.
✓ These agents cause a rapid
decrease in myocardial oxygen Requires normal
demand leading to rapid vascular
resolution of symptoms. endothelium

✓ Nitrates are effective for all

Diffuses to local
types of angina. vascular smooth
muscle
✓ Activation of guanylate cyclase
increases cGMP activating a
cGMP kinase leading to
dephosphorylation of myosin
light chains decreasing
contractile force.

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Mechanism of Action of Nitrovasodilators
Nitrates become denitrated by glutathione S-transferase
to release

Nitric Oxide
activates

Guanylate Cyclase*

converts

GTP
cGMP
activates

cGMP-dependent protein kinase

Activation of PkG results in phosphorylation

of several proteins that reduce intracellular calcium
causing smooth muscle relaxation
 Mechanism of Action(angina)

Nitrates decrease myocardial oxygen demand:

1. The primary effect is a reduction in venous tone which
results in venous pooling decreasing venous return
(decreased preload).
2. Arteriolar tone is less effectively reduced resulting in a
decrease in Peripheral Vascular Resistance (PVR)
(decreased afterload ) and decreased blood pressure.
3. #s 1 & 2 decrease myocardial wall stress reducing O2
demand.
4. Dilation of coronary vessels or exerts a ~minor effect on
increasing O2 supply.
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Nitric Oxide and Vasodilation
endothelial derived relaxing factor (EDRF) – nitric oxide (NO)

Intracellular Membrane Bound

Ca++ Stores Ca++ C.M.
Guanylate Cyclase
Ca++
NO
GTP

Ca++ Soluble
NO
Synthetase
NO Guanylate Cyclase
+
Citrulline GTP
PDE
cGMP GMP
Arginine
Ion Channels
cGMP-Dependent PK
PDEase Activity
Nitrate vasodilators in Angina Therapy

❑ Appear to alleviate anginal pain by restoring myocardial

oxygen supply/demand via

❑ decreasing myocardial work due to decreased afterload

and preload.

❑ Ischemic regions of heart may have improved blood flow to

subendocardial regions due to decreased preload that
decreases ventricular wall tension.

❑They have no direct effect on cardiac or skeletal

muscles.
Nitrate vasodilators in Angina Therapy

Drug Interactions
Nitrates are contraindicated in patients on sildenafil (Viagra®)
due to increased potential for hypotensive episode via PDE5
inhibition.

Therapeutic Use
Used in exertional and variant angina to restore myocardial
oxygen supply/demand.
Nitrates are used in congestive heart failure

Improve coronary blood flow after MI

Nitrates and other vasodilators in Hypertension

Activators of the
NO/guanylate cyclase pathway
a-Adrenoceptor Hydralazine
antagonists Nitroglycerin
Prazosin Nitroprusside Ca2+-channel blockers
Terazosin NO
Dihydropyridines
Ca2+

K+

Angiotensin II receptor K+-channel activators

antagonists Minoxidil
Losartan Diazoxide
Valsartan
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Pharmacokinetics:
The difference between nitrate preparations is mainly in
time of onset of action.
1. Nitroglycerin suffers marked 1st pass metabolism so
administration is sublingual (rapid absorption and onset
(<1 minute), t1/2 ~10 minutes.
❑ Occasionally as nitroglycerin is metabolized anginal
symptoms will return. Transdermal administration either
as patch or paste provides a depot of agent for a steady
availability.
❑ Nitro-Bid is an oral or topical preparation which saturates
the hepatic catabolic pathways allowing a prolonged
level of nitroglycerine**>
2. Isosorbide mononitrate & isosorbide dinitrate are
long acting nitrates that are relatively resistant to hepatic
catabolism t1/2 ~ 1 hour.
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 Pharmacokinetics of Nitrate Esters

Onset Duration of Action Metabolites

(min) (min)
Amyl nitrite 0.25 1
Nitroglycerin 2 30

Isosorbide dinitrate 3 60 Active

Erythrityl tetranitrate 15 180
Pentaerythritol tetranitrate 20 330

• Nitrate esters act fast! Think about the size of these molecules.
• They are rapidly metabolized in the liver (glutathione-nitrate
reductase). Yet, can be used in oral prophylactic therapy, especially
ISDN, ETN and PETN
• Number of nitrate groups does not linearly correspond to potency
• Nitrovasodilators decrease the blood pressure of patients!!

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Nitrate vasodilators in Angina Therapy

❑ Rapid onset of action after sublingual admin. due to by-pass of liver first
time through. Sublingual administration in acute attacks and
prophylaxis of acute attacks.

❑ Oral administration of nitrates has longer onset time but longer duration
of action.

❑ Transdermal delivery (NTG patch) onset time of ~1hour and duration of

4-8 hours.

❑ Tolerance to all nitrate compounds develops after prolonged use and

treatment has to be interrupted every ~8 hours.

❑ Tolerance may be due to decreased production of NO from nitrate

drugs or due to the production of oxygen free radicals (•O2-) which react
with NO to form peroxynitrates that are not vasodilators.
Effects of nitrates in generating NO• and stimulating guanylate
cyclase to cause vasodilation
 Tolerance

❑Tolerance can be avoided by providing a

“nitrate free” interval daily; for most angina
patients this is a night when myocardial
demand is low.
❑Use the least effective dose

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 Adverse effects:
1. The most common side effect of nitrates is
headache due to veno-dilation, patients whom
intermittently used nitrate preparation should
be asked about headaches after nitrate use

✓ Lack of headache often indicates degradation

of agent with a loss of therapeutic effect.

2. Postural hypotension & syncope particularly

with sublingual use.
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 Adverse effects:…
3. Tachycardia induced by decreased Peripheral
Vascular Resistance (PVR) may itself induce
anginal symptoms especially with unstable
symptoms.

4. Methemaglobinemia can occur with chronic use

of long term agents, this may occur when
sublingual use is combined with long acting
agents.

5. Withdrawal symptoms may occur (an indication

of tolerance) when nitrate agents are tapered or
discontinued, this may precipitate anginal attacks.
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A serious nitrate drug interaction
 NITRATES
CONTRAINDICATIONS

❑Previous hypersensitivity
❑Hypotension ( < 80 mmHg)
❑AMI with low ventricular filling
pressure
❑1st trimester of pregnancy
 THE END
FURTHER READING!

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