Drug Class 11: Organic and Inorganic Nitrates

Class 11: Nitrates

Glyceryl trinitrate (Nitroglycerin-Not preferred) (not a nitro compound)-Volatile, oily liquids with low molecular mass

Isosorbide dinitrate-High molecular mass nitrate esters, exist as solids at rtp

Isosorbide mononitrate-High molecular mass esters, exists as solids at rtp

Note: ***To have a pharmacological effect, the compounds above MUST BE REDUCED to form reactive free radical nitric oxide (NO), an active component (similar to a prodrug).

11.1 Mechanism of action:

-NO produced by reduction of these compounds. NO increases the cellular level of cGMP. Activates PKG and modulates activities of PDEs 2,3,5 (phosphodiesterases), responsible for the breakdown/hydrolysis of cGMP and cAMP.

-In smooth muscles, NO mediates increase in intracellular cGMP and activates PKG. This leads to reduced phosphorylation of myosin light chain and reduced calcium concentration in the cytosol causing vasodilation.

1.Provide exogenous source of nitric oxide (which mediates vasodilator effects). Predominantly venodilators. 

2. Reduce venous return and preload to the heart, thus reducing myocardial oxygen requirement.

3. Reduces afterload as arteriole resistance decreases.


-preferential dilation of veins over arterioles (Venodilation occurs).

-Venodilation results in a decrease of both left and right ventricular size and end diastolic pressures. Little change in systemic vascular resistance.

-Systemic arterial pressure may fall slightly, heart rate is unchanged or may increase slightly in response to a decrease in BP (baroreceptor reflex). 


-Causes venous pooling and also may decrease arteriolar resistance. Thus, systolic and diastolic blood pressure and cardiac output decreases.

-Causes pallor, weakness, dizziness, activation of compensatory sympathetic reflexes (baroreceptor reflex).

-Reflex tachycardia and peripheral arteriolar vasoconstriction tends to restore systemic vascular resistance.

-Coronary blood flow may increase transiently due to coronary vasodilation. However, it may decrease after due to cardiac output and blood pressure reduction of NO.

4. Cardiovascular effects (Effects on total and regional coronary blood flow)

-Ischemia is a powerful stimulus to coronary vasodilation and regional blood flow is adjusted by auto-regulatory mechanisms (i.e. if a region has low blood flow, body tries to compensate)

-In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation.

-Significant coronary stenoses disproportionately reduce blood flow to the subendocardial regions of the heart which are subjected to compression during systole.

Effects of Organic Nitrate: Tend to restore blood flow in these ischemic regions. The hemodynamic mechanisms responsible for effects on coronary blood flow appear to be due to ability of organic nitrates to cause dilation.

-It also prevents vasoconstriction of the large epicardial vessels (outer layer of the heart wall) without impairing autoregulation in small vessels.

-Results in an increase in blood flow distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation.

Vascular stealVascular steal

5. Cardiovascular effects: Effects on Myocardial Oxygen requirements

-Has Effects on systemic circulation. Thus, nitrates reduce myocardial oxygen demand.

Preload: Increasing venous capacitance with nitrates decreases venous return to the heart. It also decreases ventricular end-diastolic volume and pressure (preload). Thus, decreasing oxygen consumption.

Afterload: Decreases arteriolar resistance by vasodilating systemic vessels. Thus, myocardial work and oxygen consumption decreases.

∴ Organic nitrates decreases both preload and afterload as a result of dilation of venous capacitance and ateriolar vessels.

-Decrease in cardiac workload aids greatly.

Summary of the effects:

1. Decreases cardiac workload (Decreases both afterload and preload) (Increased venous capacitance, Decreased arteriolar resistance-Minor)

2. Decreases systemic arterial pressure (High doses)

3. Dilation of epicardial coronary arteries (aids in regional blood flow to ischemic regions)

4. Deterimental effects:

-At high doses of organic nitrates, blood pressure/cardiac output may be reduced to an extent where coronary flow is compromised.

-Reflex tachycardia and increased sympathetic tone may override the beneficial effect of organic nitrates on myocardial oxygen demand and aggrevate ischemia.


11.2 Possible Indications 

(a) Prevention and treatment of (stable) angina

(b) Chronic heart failure (isosorbide dinitrate with hydralazine)

(c) Acute heart failure associated with myocardial infarction and unstable angina (Glyceral trinitrate/GTN infusion)

-Can be used prophylatically if used immediately prior to exercise or stress.

***Sublingual tablets: Place one under tongue, do not swallow. May spit out or swallow what is left of the tablet to avoid adverse effects such as headache. Wait for 5mins. If angina persists put another under tongue and call ambulance.

11.3 Precautions

1. Hypovolemia-Contraindicated  [Hypotension might occur?]

2. Reduced intracranial pressure-Contraindicated

3. Treatment with sildenafil, tadalafil or vardenafil (PDE inhibitors) –Contraindicated

4. Anemia-Contraindicated if significant

***5. G6PD (Glucose 6 Phosphate dehydrogenase) deficiency-Risk of hemolytic anemia

6. Cardiovascular-Contraindicated in hypotension, hypertrophic obstructive cardiomyopathy, cardiac tamponade, aortic or mitral stenosis or cor pulmonale

7. Surgery-Remove nitrate patches before diathermy, defibrillation or cardioversion.

*Diathermy-The use of high frequency electric current to produce heat (Used to either cut or destroy tissue or to produce coagulation)

*Cardioversion-A medical procedure by which abnormal heart rates or cardiac arrhythmia is converted to normal rhythm using electricity or drugs.

8. Pregnancy-No data available. Assume Not safe

9. Breastfeeding-No data available

11.4 Adverse effects/Side effects

-Most are due to vasodilator effects.


1. Orthostatic/Postural Hypotension (Worsened by alcohol and/or if patient is standing), Headache, Flushing

2. Syncope/Fainting (Position head low to facilitate venous return)

3. Palpitations

4. Peripheral edema

5. Rashes (occasional)


*Contact dermatitis (topical), rebound angina


11.5 Crucial Points for counselling

*This medicine may make patient feel dizzy upon standing (postural hypertension). Get up gradually from sitting or lying to minimise this effect. Sit or lie down if necessary.

Note: Tolerance to nitrates occurs with frequent and continuous exposure (may occur within 24 horus).

*Avoid tolerance by ensuring a nitrate free period of at least 10-12 hours a day (AMH 2012).

11.6 Drug interactions

-Nitrates including sodium nitroprusside as well as amyl nitrite causes hypotension.

-If given with drugs that reduce BP (e.g. thiazides), additional hypertensive effects may occur.

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

-PDE 5 breaks down cGMP which itself causes smooth muscle relaxation and increased blood flow to the penis to assist erection.

-In the presence of a PDE 5 inhibitor, nitrates can drastically increase cGMP levels and reduce blood pressure greatly.

-Thus all 3 PDE 5 inhibitors are contraindicated.



11.7 Types of Nitrate agents

1. Glyceral trinitrate/GTN


  • Clinical Indications

***(a) Stable Angina

(b) Heart failure associated with acute Myocardial Infarction (USE as infusion!!!)

(c) Unstable angina [Accepted indication]  (USE as infusion!!!)

(d) Acute pulmonary edema (USE as infusion!!!)

  • Precautions

* Pregnancy-Safety is not established. CAT B2-AUS

  • Administration advice

Infusion: GTN adsorbs to plastics (PVC). Use glass infusion bottle and polyethylene giving set.


1. Patch administration -Apply to clean, dry skin on the chest area or upper arm. Fold the patch to prevent reuse.

2. Sublingual tablets/spray-Use during episodes of angina or before and activity expected to bring on angina

-Sit down or lie down before use as it may cause dizziness.


Sublingual tablets: Place one under tongue, do not swallow. May spit out or swallow what is left of the tablet to avoid adverse effects such as headache. Wait for 5mins. If angina persists put another under tongue and call ambulance.

-Store the tablets properly. Keep them in the original glass bottle away from moisture, heat and light. Do not carry tablets close to patient’s body (body temperature will affect degradation of tablets?)

-Write the date on the bottle when patient opens it. Discard any unused tablets 3 months later.

Sublingual sprays: Prime the spray before using it for the first time by pressing the nozzle 5 times, spraying it into the air. Prime it with 1 spray if it hasn’t been used for 7 days. Prime it with 5 sprays if it hasn’t been used for more than 4 months.

-When ready to use, aim the spray under the tongue and press the nozzle once, do not inhale the spray.

  • Pharmacokinetics of GTN 

    Absorption: Peak concentrations of GTN are found in plasma within 4 mins of sublingual administration of tablet.

    DOA: t1/2 of 1-3 mins.

    Metabolism: Avoids 1st pass metabolism/rapid entry

    OAA: More rapid if delivered sublingually.


  • Practice Points

-Sublingual GTN spray has a longer shelf life than tablets. It is useful for patients with infrequent angina.

-Ensure a nitrate free period of 10-12 hours each day when using a long acting glyceryl trinitrate patch (avoid tolerance)

-Do not stop IV infusion abruptly because of the potential for rebound symptoms.

  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

2. Isosorbide dinitrate (ISORDIL)

  • Clinical indications: 

(a) Prevention and treatment of angina

(b) Heart Failure (with hydralazine)

  • Precautions

-Pregnancy (CAT B1-AUS)


1. Sublingual tablets

-Use during episodes of angina or before an activity expected to bring about angina (exercise)

-Sit or lie down before use of the drug as it may cause dizziness

-Place the tablet under the tongue, do not swallow. After angina has been relieved, patient may spit out what is left of the tablet to avoid adverse effects such as headache.


  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

3. Isosorbide-5-mononitrate (IMDUR)

  • Clinical Indications: Prevention of angina
  • Precautions: CAT B2 (No data available)

****Counselling: Swallow whole, do not crush or chew tablet. Tolerance may develop, Advise patients to have a IMDUR free period. Twice daily dosing schedule permitted and maintains efficacy.

  • Practice points: 

-Take at the time of the day when angina is most frequent (e.g. at night for nocturnal angina or in the morning for daytime angina)

-Twice daily dosing with isosorbide mononitrate is NOT RECOMMENDED (no ISM free period-Tolerance may occur).

-Treatment with isosorbide mononitrate for treatment of acute episodes of angina is NOT RECOMMENDED because of its slow onset of action.

  • Pharmacokinetics

-Does not undergo significant first pass metabolism. Has good oral bioavailability after oral administation.

-Mononitrate has significantly longer half life than isosorbide dinitrate.

-Can be formulated as a plain tablet and sustained release preparation (both dosage forms have a longer DOA than the corresponding dosage forms)

Absorption: Sublingual administration produces maximal plasma concentations of the drug by 6 mins.

DOA: t1/2 of approx 45 mins

Metbaolism: Enzymatic denitration followed by glucoronide conjugation.

-Initial metabolites produced: isosorbide 2 mononitrate and isosorbide 5 mononitrate. Both metabolites have longer half lives (3-6 hours) and contribute to therapeutic efficacy.



  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.



*Developing Tolerance to organic nitrates

1. Transdermal patches of GTN (slow onset of action, continuous plasma nitrate concentration, peak effects occurring at 1-2 hours)

2. Sublingual organic nitrates (Continuous exposure to high doses to high doses of organic nitrates leads to decreased response)

Why does tolerance occur? Proposed mechanisms:

(a) Reduced capacity of the vascular smooth muscle to convert GTN to NO (active form)–>TRUE TOLERANCE

(b) Activation of mechanisms extraneous to the vessel wall–>PSEUDOTOLERANCE

(c) Inactivation of aldehyde dehydrogenase (involved in GTN biotransformation)

(d) Reactive intermediate formed during generation of NO from organic nitrates may damage and inactivate enzymes needed to form NO.

*Interrupt therapy for 8-12 hours a day to restore efficacy.

-Omit dosing at night in patients with exertional/stable angina. Adjust dosing intervals of oral/buccal preparations or by removing patches during ‘quiet’ periods.

-For patients who have paroxysmal nocturnal dyspnea (the sudden onset of shortness of breath at night), advise them to have have a organic nitrate free period during the ‘quiet’ periods of the day (i.e. not exercising)




*Comparison between the agents listed above:

-Nitrates vary in oral bioavailability. Formulations available, routes of administration and duration of effect.

This influences the choice of agent used to treat specific conditions.

Short acting nitrates:

  • Obviously, rapid onset but short-acting nitrates (sublingual GTN, sublingual isosorbide dinitrate) are useful in acute attacks of agina or preventing them when given immediately before an activity likely to induce angina.
  • Once sublingual tablets are opened, GTN tablets have a short shelf life of 3 months. Spray has a much longer shelf-life (2 years).
  • The spray may be particuarly useful for patients with infrequent symptoms.
  • Effects may be easier to adjust with sublingual tablets.

Long acting nitrates:

  • Long acting nitrates taken orally (isosorbide dinitrate, isosorbide mononitrate) and transdermal (GTN) are indicated for prevention of chronic angina.

IV Infusion of GTN:

  • IV infusion of GTN is appropriate/suitable in early management of acute MI and associated conditions (e.g. heart failure or persistent angina). Also, IV GTN can be used for unstable angina and acute pulmonary edema.
  • Isosorbide dinitrate is indicated for use in heart failure, in combination with hydralazine reduces mortality.


4. Sodium Nitroprusside (Refer to Drug Class 8: Vasodilators)

8.4 Sodium nitroprusside

240px-Sodium-nitroprusside-2DSodium Nitroprusside/SNP/Sodium nitroferricyanide

Mechanism of action:

1. Non-selective arteriolar and venous dilator

2.  SNP breaks down in circulation to release nitric oxide (NO)

3. NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP activates Protein Kinase G which activates phosphatases which inactivate Myosin light chains. Myosin light chains are involved in muscle contraction.

4. The end result is vascular smooth muscle relaxation, which allow vessels to dilate

5. In the human heart, nitric oxide reduces both total peripheral resistance as well as venous return, thus decreasing both preload and afterload.

*Due to this, it can be used in severe cardiogenic heart failure where it acts to increase cardiac output.

Clinical Indications: (a) Hypertensive emergency (b) Controlled hypotension during surgery to reduce bleeding (c) Acute Heart Failure

Precautions (All of them are contradicated for sodium nitroprusside use)

1. Compensatory hypertension (e.g. atrioventricular shunt or coarctation of the aorta- congenital condition whereby the aorta narrows in the area where the ductus arteriosus insets)


2. Vitamin B12 deficiency-CONTRAINDICATED!!! Refer to Vitamin Metabolic Biochemistry Lecture (Increased plasma homocysteine levels and increases damage to vessels. Adding nitroprusside will increase risk of thrombosis.)

3. Cerebral or coronary artery disease-CONTRAINDICATED!!!

4.  Congenital (Leber’s) optic atrophy-CONTRAINDICATED!!!

5. Tobacco amblyopia-CONTRAINDICATED!!!

6. Hypovolemia-CONTRAINDICATED!!!

7. Uncorrected anemia-CONTRAINDICATED!!!

Not contradicated but take extra caution

8. Increased intra-cranial pressure, encephalopathy-Risk of aggration

9. Hypothyroidism-Thiocyanate (degradation product of sodium nitroprusside). Inhibits both uptake and binding of iodine.

10. Hypothermia-Risk of aggravation

11. Pulmonary mpairment-May worsen hypoxemia

12. Renal impaired-Reduced excretion of thiocyanate concentrations during prolonged treatment.

13. Hepatic-Avoid use in severe impairment

14. Elderly-May require lower doses

15. Pregnant-Reserve for use in patients with hypertension not controlled by other agents. Short-term use for control of hypertensive crises may be safe provided that the pH and thiocyanate concentrations in maternal blood are monitored. Cat C-AUS

  • Side effects/Adverse effects

-Excessive hypotension or excessive cyanide accumulation

-Thiocyanate toxicity may also occur, especially with renal impairment


1. Nausea, Vomiting, Headache

2. Sweating, apprehension (Fear)

3, Restlessness

4. Muscle twitching

5. Retrosternal discomfort

6. Palpitations

7. Dizziness

8. Abdominal pain (with too rapid reduction in BP)


-Postural hypotension, Hypothyroidism, Paraesthesia, feeling of warmth, rash, flushing, increased intracranial pressure


-Thrombocytopenia, Methaemoglobinemia, Phlebitis (inflammation of veins usually in legs)


-Toxicity may occur, particularly with prolonged infusion or higher than recommended maximum dose. Toxicity is due to accumulation of thiocyanate or cyanide.

*Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light

*In normal renal function, cyanide accumulates with infusion rate of >2 micrograms/kg/min.

-Risk of toxicity is greater in renal impairment because of reduced excretion of thiocyanate.

-Thiocyanate toxicity causes confusion, psychosis, tinnitus, blurred vision, nausea, dyspnea, hypothyroidism and ataxia (lack of voluntary coordination of muscle movements)

Cyanide toxicity causes tachycardia, sweating, hyperventilation, headache, arrhythmias, metabolic acidosis, areflexia, coma, hypotension, pink colour of skin and mucous memranes, shallow breathing, dilated pupils and death.

  • Administration advice

-Dilute with glucose 5%, do not administer by direct injection!

-Infusion solution should be protected from light, e.g. with aluminium foil

-Final infusion concentration should be 50-100micrograms/ml (i.e. 50mg of sodium nitroprusside in 500-1000ml glucose 5%)

  • Practice points

-Monitor intra-arterial BP continuously during infusion and titrate infusion rate carefully to avoid excessive hypotension

-Abrupt withdrawl of sodium nitroprusside may cause rebound hypertension. Withdraw over at lesat 10-30 mins to avoid rebound.

-Usual duration of treatment should not exceed 72 hours because of cumulative thiocyanate toxicity and the possibility of cyanide toxicity; monitor thiocyanate concentrations.

  • Drug Interactions

-Nitrates (including sodium nitroprusside) as well as amyl nitrite causes hypotension. *Additional hypotensive effects may occur if administered with other anti-hypertensive agents.

*Administration with phosphodiesterase-5-inhibitors and nitrates is contraindicated.


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