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Nitroglycerin
Nitroglycerin Linda Wagner MLC Solutions, LTD Galena, USA Charlotte Kenreigh MLC Solutions, LTD Galena, USA ã 2007 Elsevier Inc. All rights reserved.
Introduction Nitroglycerin is an organic nitrate employed clinically for its action as a vasodilator. The rapid onset of action of the buccal, sublingual, and intravenous formulations has made nitroglycerin the drug of choice for acute episodes of angina pectoris secondary to coronary artery disease.
Nomenclature Name of the Clinical Form Related Names Source: EMTREE
Chemical Names CAS Number
Nitroglycerin Nitroglycerin; adesitrin; anginine; angiolingual; angised; angitrine; anogesic; antipressan; corditrine; coro nitro; deponit; deponit 10; diafusor; dinamite; gilustenon; glonoin; glycerol trinitrate; glyceryltrinitrate; gly trate; klavikordal; lenitral; longacting trinitrine; milisrol; millisrol; minitran; natirose; natispray; niong; niong retard; nirmin; nitracut; nitradisc; nitrangin; nitret; nitriderm tts; nitrilex; nitro; nitrobaat; nitrobid; nitrocaps; nitrocene; nitrocin; nitrocine; nitrocor; nitro corangin; nitroderm; nitroderm tts; nitrodisc; nitro dur; nitrodur; nitrodur 1; nitrodur 2; nitrofortin; nitrogard; nitro genasit; nitroglycerin; nitroglycerine; nitroglycerol; nitroglyn; nitrol; nitrolande; nitrolate; nitrolingual; nitrolingual retard; nitro mack; nitromack; nitro mack retard; nitromaz; nitromed; nitromex; nitromint; nitronal; nitronet; nitrong; nitrong mite; nitrong retard; nitropaste; nitro pflaster; nitro pflaster ratiopharm; nitroprol; nitroran; nitrorand; nitrospan; nitrostat; percutol; perglottal; perlinganit; reminitrol; s 917; solinitrina; susadrin; suscard; sustac; sustac forte; sustac oc; sustax; sustonit; transderm nitro; transdermnitro; transiderm nitro; transiderm nitro 10; transidermnitro; tridil; trinitran; trinitrin; trinitrina; trinitrine; trinitroglycerin; trinitroglycerol; trinitrol; trinitrolong; trinitrosan; venitrin; vernies; glyceryl trinitrate; cellegesic; glyceryl trinitrate tts; nit ret; nitroglycerin tts; nitroglycerine tts; pancoran; pancoran tts; rectogesic 1,2,3-propanetriol trinitrate 55-63-0
Basic Chemistry Chemical Structure
1
2
Nitroglycerin
Structure
Chemical Formula Properties Physical Properties
Molecular Weight Solubility
C3 H5 N3 O9
Nitroglycerin is a highly volatile white to pale yellow, thick, flammable explosive. When diluted is no longer explosive. Dilution of nitroglycerin with a suitable inert excipient, such as lactose, yields a white, odorless powder. When diluted with propylene glycol it yields a clear, colorless or pale yellow liquid. Nitroglycerin injection is a clear, practically colorless, nonexplosive solution. 227.085 Nitroglycerin is slightly soluble in water and is soluble in alcohol.
Human Pharmacokinetics The onset and duration of action of nitroglycerin is dependent on the formulation. Following i.v. administration, the onset of action is almost immediate, and the half-life is 1-4 min. Red blood cells and vascular walls are extrahepatic sites of metabolism. The clearance of nitroglycerin exceeds hepatic blood flow. Pharmacokinetic Properties Value Absorption Bioavailability
Distribution Volume of Distribution Plasma Protein Binding
Units Prep. and Route of Admin.
75; 60- % 75; 38.5
Transdermal; Transmucosal; Sublingual
Reference
Comments
Hutchinson and Shahan (2004)
The onset of action is within 2 min (transmucosal and sublingual), 30 min for ointment, and 1 hour with the oral extended release products. The hypotensive response to nitroglycerin occurs within 1-5 min.
200
l
McEvoy (2004)
60
%
McEvoy (2004)
Nitroglycerin Metabolism Plasma HalfLife Bio Half-Life
Clearance Routes of Elimination
1-4
min
McEvoy (2004) The effects of nitroglycerin last for variable lengths of time. The duration of action is 3-5 hrs (transmucosal), 30 min (sublingual), 3 hrs (ointment), and up to 12 hrs for the extended release preparation.
McEvoy (2004) Hydrolysis of nitroglycerin yields two major metabolites, 1,2 and 1,3-dinitroglycerin. These metabolites, which have longer half-lives than the parent compound, are less potent vasodilators.
Targets-Pharmacodynamics The primary pharmacologic response to nitroglycerin is relaxation of vascular smooth muscle and vasodilation. These effects are due to the breakdown of nitroglycerin at or near the plasma member of vascular smooth muscle cells resulting in the generation of nitric oxide. By activation of guanylate cyclase, nitric oxide increases the production of cyclic GMP that, in turn, causes vasodilation Hardman et al (2001), McEvoy (2004). Target Name(s): Guanylate cyclase
Therapeutics The vasodilation produced by nitroglycerin is useful in the management of angina pectoris secondary to coronary artery disease. In addition, intravenous nitroglycerin is used to control blood pressure in the perioperative and immediate postoperative settings. It is also used to produce controlled hypotension during surgical procedures. The intravenous preparation is employed for the management of congestive heart failure associated with acute myocardial infarction McEvoy (2004). Indications Value
Units
Prep. and Route of Admin.
Reference
Comments
Acute relief of an attack of angina pectoris due to coronary artery disease Dosage 1-2 Metered Nitroglycerin spray McEvoy (2004) Nitroglycerin is doses (0.4 sprayed onto or mg per under the tongue at spray) the onset of symptoms. No more than 3 doses should be administered over a 15 minute period.
3
4
Nitroglycerin Acute relief of an attack of angina pectoris due to coronary artery disease Dosage 0.3mg Sublingual tablet McEvoy (2004) The typical dose is 0.4 0.6 mg. A single tablet is dissolved under the tongue or in the buccal pouch at onset of symptoms. The dose may be repeated about every 5 minutes. No more than 3 doses should be administered over a 15 minute period. Prophylaxis of an attack of angina pectoris due to coronary artery disease Dosage 1-2 Metered Nitroglycerin spray McEvoy (2004) Nitroglycerin is doses sprayed onto or under the tongue 510 minutes prior to engaging in activity likely to precipitate an acute anginal attack. Prophylaxis of an attack of angina pectoris due to coronary artery disease Dosage 0.3mg Sublingual tablet McEvoy (2004) A single tablet is 0.6 dissolved under the tongue or in the buccal pouch 5-10 minutes prior to engaging in activity likely to precipitate an acute anginal attack. Prevention of angina pectoris due to coronary artery disease Dosage 0.2mg/h Transdermal McEvoy (2004) The initial dose should 0.8 infusion system be 0.2-0.4 mg/h. (patch) once daily The patch should be removed for 10-12 hrs each day to provide a nitratefree interval to avoid the development of tolerance. Prevention of angina pectoris due to coronary artery disease Dosage 2.5mg Sustained release McEvoy (2004) The initial dose is 2.5 13 tablet or capsule or 2.6 mg 3 or 4 times each day. The dose is titrated to maximal efficacy unless side effects intervene. Neither capsules nor sustained release tablets should be chewed. Prevention and treatment of angina pectoris secondary to coronary artery disease Dosage 1-3 mg Transmucosal McEvoy (2004) The tablet is placed between the lip and gum above the incisors or between the cheek and gum
Nitroglycerin every 3-5 hrs during waking hours. Prevention and treatment of angina pectoris secondary to coronary artery disease Dosage 1-5 inches Topical ointment McEvoy (2004) Begin with 1-2 inches every 8 hrs, then titrate the dose upward. The interval between applications may be shortened to 4 hrs if necessary. Angina pectoris unresponsive to organic nitrates or beta adrenoceptor antagonists, management of perioperative hypertension, congestive heart failure associated with acute myocardial infarction, production of controlled hypotension during surgical procedures Dosage Begin mg/min Continuous i.v. McEvoy (2004) There is no optimal at infusion maximum dose. The 50 dose should be titrated upward initially by 50 mg/min increments, increasing to 10 mg/ min increments if the desired effect is not obtained. Titration should be slowed once a partial blood pressure response is observed to allow adequate time for assessment.
Contraindications Nitroglycerin is contraindicated in those known to be hypersensitive to it or to other organic nitrates or to be hypersensitive to the adhesive for those using the transdermal system. It is contraindicated in those taking sildenafil, vardenafil, or tadalafil, and the i.v. formulation is contraindicated in patients with constrictive pericarditis, restrictive cardiomyopathy, and pericardial tamponade. The sublingual formulation is contraindicated in those with early myocardial infarction, severe anemia, or increased intracranial pressure McEvoy (2004). Adverse Effects Adverse effects associated with the use of nitroglycerin include hypotension, headache, flushing, transient dizziness, weakness, nausea and vomiting. Drug rash may be associated with the use of nitroglycerin, and there are reports of application-site irritation for those using the patch McEvoy (2004). Agent-Agent Interactions Agent Name
Mode of Interaction
Sildenafil
Sildenafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of sildenafil and nitroglycerin may therefore produce excessive hypotension.
5
6
Nitroglycerin Tadalafil
Vardenafil
Alcohol Calcium channel blockers Heparin
Tadalafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of tadalafil and nitroglycerin may therefore produce excessive hypotension. Vardenafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of vardenafil and nitroglycerin may therefore produce excessive hypotension. Alcohol may intensify the hypotensive effects of nitroglycerin. The combination of organic nitrates and calcium channel blockers may cause orthostatic hypotension. Intravenously administered nitroglycerin may antagonize the anticoagulant effect of heparin.
Pre-Clinical Research
Pharmacokinetics
Potency Value
Mouse LD50 30
Units
Organ/ Tissue
Prep. and Route of Admin.
mg/ kg
i.v.
LD50
115
mg/ kg
p.o.
Rat LD50
45
mg/ kg
i.v.
LD50
105
mg/ kg
p.o.
mg/ kg
i.v.
mg/ kg
p.o.
mg/ kg
p.o.
Rabbit LD50 23.2
LD50
1607
Guinea pig LD50 1450
Cell Line/ Type
Effects Exp. End Point
Reference
National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004)
Comments
Nitroglycerin Cat LD50
189
mg/ kg
i.v.
National Institute of Occupational Safety and Health (2004)
Dog LD50
19
mg/ kg
i.v.
National Institute of Occupational Safety and Health (2004)
Other Information – Web Sites National Institute of Occupational Safety and Health: http://www.cdc.gov/niosh/rtecs/ qx200b20.html
Book Citations National Institute of Occupational Safety and Health, 2004. The Registry of Toxic Effects of Chemical Substances. . Hardman, J.G., Limbird, L.E., Gilman, A.G., 2001. Drugs Used for the Treatment of Myocardial Ischemia. Hardman, J.G., Limbird, L.E., Gilman, A.G. (Ed.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Edition 10, pp. 845–9, Macmillan Publishing Co., New York, NY. McEvoy, G.K., 2004. McEvoy, G.K. (Ed.), AHFS Drug Information, 2004, pp. 1689–1691, American Society of Health-System Pharmacists, Inc., Bethesda, MD. Hutchinson, T.A., Shahan, D.R., 2004. Hutchinson, T.A., Shahan, D.R. (Ed.), DrugDexW System. MicroMedex, Edition 121. , Greenwood Village, CO..
7
Introduction Nitroglycerin is an organic nitrate employed clinically for its action as a vasodilator. The rapid onset of action of the buccal, sublingual, and intravenous formulations has made nitroglycerin the drug of choice for acute episodes of angina pectoris secondary to coronary artery disease.
Nomenclature Name of the Clinical Form Related Names Source: EMTREE
Chemical Names CAS Number
Nitroglycerin Nitroglycerin; adesitrin; anginine; angiolingual; angised; angitrine; anogesic; antipressan; corditrine; coro nitro; deponit; deponit 10; diafusor; dinamite; gilustenon; glonoin; glycerol trinitrate; glyceryltrinitrate; gly trate; klavikordal; lenitral; longacting trinitrine; milisrol; millisrol; minitran; natirose; natispray; niong; niong retard; nirmin; nitracut; nitradisc; nitrangin; nitret; nitriderm tts; nitrilex; nitro; nitrobaat; nitrobid; nitrocaps; nitrocene; nitrocin; nitrocine; nitrocor; nitro corangin; nitroderm; nitroderm tts; nitrodisc; nitro dur; nitrodur; nitrodur 1; nitrodur 2; nitrofortin; nitrogard; nitro genasit; nitroglycerin; nitroglycerine; nitroglycerol; nitroglyn; nitrol; nitrolande; nitrolate; nitrolingual; nitrolingual retard; nitro mack; nitromack; nitro mack retard; nitromaz; nitromed; nitromex; nitromint; nitronal; nitronet; nitrong; nitrong mite; nitrong retard; nitropaste; nitro pflaster; nitro pflaster ratiopharm; nitroprol; nitroran; nitrorand; nitrospan; nitrostat; percutol; perglottal; perlinganit; reminitrol; s 917; solinitrina; susadrin; suscard; sustac; sustac forte; sustac oc; sustax; sustonit; transderm nitro; transdermnitro; transiderm nitro; transiderm nitro 10; transidermnitro; tridil; trinitran; trinitrin; trinitrina; trinitrine; trinitroglycerin; trinitroglycerol; trinitrol; trinitrolong; trinitrosan; venitrin; vernies; glyceryl trinitrate; cellegesic; glyceryl trinitrate tts; nit ret; nitroglycerin tts; nitroglycerine tts; pancoran; pancoran tts; rectogesic 1,2,3-propanetriol trinitrate 55-63-0
Basic Chemistry Chemical Structure
1
2
Nitroglycerin
Structure
Chemical Formula Properties Physical Properties
Molecular Weight Solubility
C3 H5 N3 O9
Nitroglycerin is a highly volatile white to pale yellow, thick, flammable explosive. When diluted is no longer explosive. Dilution of nitroglycerin with a suitable inert excipient, such as lactose, yields a white, odorless powder. When diluted with propylene glycol it yields a clear, colorless or pale yellow liquid. Nitroglycerin injection is a clear, practically colorless, nonexplosive solution. 227.085 Nitroglycerin is slightly soluble in water and is soluble in alcohol.
Human Pharmacokinetics The onset and duration of action of nitroglycerin is dependent on the formulation. Following i.v. administration, the onset of action is almost immediate, and the half-life is 1-4 min. Red blood cells and vascular walls are extrahepatic sites of metabolism. The clearance of nitroglycerin exceeds hepatic blood flow. Pharmacokinetic Properties Value Absorption Bioavailability
Distribution Volume of Distribution Plasma Protein Binding
Units Prep. and Route of Admin.
75; 60- % 75; 38.5
Transdermal; Transmucosal; Sublingual
Reference
Comments
Hutchinson and Shahan (2004)
The onset of action is within 2 min (transmucosal and sublingual), 30 min for ointment, and 1 hour with the oral extended release products. The hypotensive response to nitroglycerin occurs within 1-5 min.
200
l
McEvoy (2004)
60
%
McEvoy (2004)
Nitroglycerin Metabolism Plasma HalfLife Bio Half-Life
Clearance Routes of Elimination
1-4
min
McEvoy (2004) The effects of nitroglycerin last for variable lengths of time. The duration of action is 3-5 hrs (transmucosal), 30 min (sublingual), 3 hrs (ointment), and up to 12 hrs for the extended release preparation.
McEvoy (2004) Hydrolysis of nitroglycerin yields two major metabolites, 1,2 and 1,3-dinitroglycerin. These metabolites, which have longer half-lives than the parent compound, are less potent vasodilators.
Targets-Pharmacodynamics The primary pharmacologic response to nitroglycerin is relaxation of vascular smooth muscle and vasodilation. These effects are due to the breakdown of nitroglycerin at or near the plasma member of vascular smooth muscle cells resulting in the generation of nitric oxide. By activation of guanylate cyclase, nitric oxide increases the production of cyclic GMP that, in turn, causes vasodilation Hardman et al (2001), McEvoy (2004). Target Name(s): Guanylate cyclase
Therapeutics The vasodilation produced by nitroglycerin is useful in the management of angina pectoris secondary to coronary artery disease. In addition, intravenous nitroglycerin is used to control blood pressure in the perioperative and immediate postoperative settings. It is also used to produce controlled hypotension during surgical procedures. The intravenous preparation is employed for the management of congestive heart failure associated with acute myocardial infarction McEvoy (2004). Indications Value
Units
Prep. and Route of Admin.
Reference
Comments
Acute relief of an attack of angina pectoris due to coronary artery disease Dosage 1-2 Metered Nitroglycerin spray McEvoy (2004) Nitroglycerin is doses (0.4 sprayed onto or mg per under the tongue at spray) the onset of symptoms. No more than 3 doses should be administered over a 15 minute period.
3
4
Nitroglycerin Acute relief of an attack of angina pectoris due to coronary artery disease Dosage 0.3mg Sublingual tablet McEvoy (2004) The typical dose is 0.4 0.6 mg. A single tablet is dissolved under the tongue or in the buccal pouch at onset of symptoms. The dose may be repeated about every 5 minutes. No more than 3 doses should be administered over a 15 minute period. Prophylaxis of an attack of angina pectoris due to coronary artery disease Dosage 1-2 Metered Nitroglycerin spray McEvoy (2004) Nitroglycerin is doses sprayed onto or under the tongue 510 minutes prior to engaging in activity likely to precipitate an acute anginal attack. Prophylaxis of an attack of angina pectoris due to coronary artery disease Dosage 0.3mg Sublingual tablet McEvoy (2004) A single tablet is 0.6 dissolved under the tongue or in the buccal pouch 5-10 minutes prior to engaging in activity likely to precipitate an acute anginal attack. Prevention of angina pectoris due to coronary artery disease Dosage 0.2mg/h Transdermal McEvoy (2004) The initial dose should 0.8 infusion system be 0.2-0.4 mg/h. (patch) once daily The patch should be removed for 10-12 hrs each day to provide a nitratefree interval to avoid the development of tolerance. Prevention of angina pectoris due to coronary artery disease Dosage 2.5mg Sustained release McEvoy (2004) The initial dose is 2.5 13 tablet or capsule or 2.6 mg 3 or 4 times each day. The dose is titrated to maximal efficacy unless side effects intervene. Neither capsules nor sustained release tablets should be chewed. Prevention and treatment of angina pectoris secondary to coronary artery disease Dosage 1-3 mg Transmucosal McEvoy (2004) The tablet is placed between the lip and gum above the incisors or between the cheek and gum
Nitroglycerin every 3-5 hrs during waking hours. Prevention and treatment of angina pectoris secondary to coronary artery disease Dosage 1-5 inches Topical ointment McEvoy (2004) Begin with 1-2 inches every 8 hrs, then titrate the dose upward. The interval between applications may be shortened to 4 hrs if necessary. Angina pectoris unresponsive to organic nitrates or beta adrenoceptor antagonists, management of perioperative hypertension, congestive heart failure associated with acute myocardial infarction, production of controlled hypotension during surgical procedures Dosage Begin mg/min Continuous i.v. McEvoy (2004) There is no optimal at infusion maximum dose. The 50 dose should be titrated upward initially by 50 mg/min increments, increasing to 10 mg/ min increments if the desired effect is not obtained. Titration should be slowed once a partial blood pressure response is observed to allow adequate time for assessment.
Contraindications Nitroglycerin is contraindicated in those known to be hypersensitive to it or to other organic nitrates or to be hypersensitive to the adhesive for those using the transdermal system. It is contraindicated in those taking sildenafil, vardenafil, or tadalafil, and the i.v. formulation is contraindicated in patients with constrictive pericarditis, restrictive cardiomyopathy, and pericardial tamponade. The sublingual formulation is contraindicated in those with early myocardial infarction, severe anemia, or increased intracranial pressure McEvoy (2004). Adverse Effects Adverse effects associated with the use of nitroglycerin include hypotension, headache, flushing, transient dizziness, weakness, nausea and vomiting. Drug rash may be associated with the use of nitroglycerin, and there are reports of application-site irritation for those using the patch McEvoy (2004). Agent-Agent Interactions Agent Name
Mode of Interaction
Sildenafil
Sildenafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of sildenafil and nitroglycerin may therefore produce excessive hypotension.
5
6
Nitroglycerin Tadalafil
Vardenafil
Alcohol Calcium channel blockers Heparin
Tadalafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of tadalafil and nitroglycerin may therefore produce excessive hypotension. Vardenafil inhibits phosphodiesterase type 5, the enzyme responsible for the metabolic degradation of cyclic GM P. Organic nitrates activate guanylate cyclase, which increases cyclic GM P. The combination of vardenafil and nitroglycerin may therefore produce excessive hypotension. Alcohol may intensify the hypotensive effects of nitroglycerin. The combination of organic nitrates and calcium channel blockers may cause orthostatic hypotension. Intravenously administered nitroglycerin may antagonize the anticoagulant effect of heparin.
Pre-Clinical Research
Pharmacokinetics
Potency Value
Mouse LD50 30
Units
Organ/ Tissue
Prep. and Route of Admin.
mg/ kg
i.v.
LD50
115
mg/ kg
p.o.
Rat LD50
45
mg/ kg
i.v.
LD50
105
mg/ kg
p.o.
mg/ kg
i.v.
mg/ kg
p.o.
mg/ kg
p.o.
Rabbit LD50 23.2
LD50
1607
Guinea pig LD50 1450
Cell Line/ Type
Effects Exp. End Point
Reference
National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004) National Institute of Occupational Safety and Health (2004)
Comments
Nitroglycerin Cat LD50
189
mg/ kg
i.v.
National Institute of Occupational Safety and Health (2004)
Dog LD50
19
mg/ kg
i.v.
National Institute of Occupational Safety and Health (2004)
Other Information – Web Sites National Institute of Occupational Safety and Health: http://www.cdc.gov/niosh/rtecs/ qx200b20.html
Book Citations National Institute of Occupational Safety and Health, 2004. The Registry of Toxic Effects of Chemical Substances. . Hardman, J.G., Limbird, L.E., Gilman, A.G., 2001. Drugs Used for the Treatment of Myocardial Ischemia. Hardman, J.G., Limbird, L.E., Gilman, A.G. (Ed.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Edition 10, pp. 845–9, Macmillan Publishing Co., New York, NY. McEvoy, G.K., 2004. McEvoy, G.K. (Ed.), AHFS Drug Information, 2004, pp. 1689–1691, American Society of Health-System Pharmacists, Inc., Bethesda, MD. Hutchinson, T.A., Shahan, D.R., 2004. Hutchinson, T.A., Shahan, D.R. (Ed.), DrugDexW System. MicroMedex, Edition 121. , Greenwood Village, CO..
7