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| | <StructureSection load='' size='340' side='right' scene='74/745476/Humanaldehydedehydrogenase/1'> | | <StructureSection load='' size='340' side='right' scene='74/745476/Humanaldehydedehydrogenase/1'> |
| | ==Structure== | | ==Structure== |
| - | The main ingredient of NitroDur is 1,2,3-propanetriol trinitrate, also known as <scene name='74/745476/Nitroglycerinmolecule/3'>Nitroglycerin</scene>. Nitroglycerin is a molecule that when broken down to nitric oxide binds to protein domains found in smooth muscle. These binding domains are often found in the form of dimers that require multiple NO molecules to bind as seen in <scene name='74/745476/2o0c_molecule/3'>Nitric Oxide bound to the domain of Nostoc cyanbacterial protein</scene>. The Nitric Oxide is often buried deep within the protein, that in conjunction with other molecular interactions triggers structural changes that activate proteins to serve their specific functions. In humans, NO binds to protein domains in this same fashion, as seen in <scene name='74/745476/Guanylate_cyclase/2'>Heterodimeric Catalytic Domain of Wild-type Human Soluble Guanylate Cyclase </scene>. | + | The main ingredient of NitroDur is 1,2,3-propanetriol trinitrate, also known as <scene name='74/745476/Nitroglycerinmolecule/3'>Nitroglycerin</scene>. Nitroglycerin is a molecule that when broken down to nitric oxide binds to protein domains found in smooth muscle. These binding domains are often found in the form of dimers that require multiple NO molecules to bind as seen in <scene name='74/745476/2o0c_molecule/3'>Nitric Oxide bound to the domain of Nostoc cyanbacterial protein</scene>. Nitric Oxide is often buried deep within the protein, that in conjunction with other molecular interactions, triggers structural changes that activate proteins to serve their specific functions. In humans, NO binds to protein domains in this same fashion, as seen in <scene name='74/745476/Guanylate_cyclase/2'>Heterodimeric Catalytic Domain of Wild-type Human Soluble Guanylate Cyclase </scene>. |
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| | ==Medication Details== | | ==Medication Details== |
| - | The medical delivery method for Nitroglycerin can come in the form of tablets (that dissolve under the tongue, or in the cheek), topical ointments, or patches <ref name="citation2">Tryzelaar, Dr. "Nitroglycerin (NTG)." Nitroglycerin (NTG). N.p., n.d. Web. 16 Oct. 2016”</ref>. Nitro-Dur delivers nitroglycerin to the body in the form of an acrylic patch <ref name="citation1">"NITRO-DUR® TRANSDERMAL DELIVERY SYSTEM." N.p., 3 Oct. 2014. Web. 16 Oct. 2016 </ref>. The NitroDur patch itself is composed of four layers that each serve a specific function in delivering an adequate dosage of nitroglycerin to the body. The exposed outermost layer of the patch is made up of aluminized plastic that is impermeable to nitroglycerin. This material prevents nitroglycerin from escaping through the back of the patch and directs the molecule to diffuse in the desired direction of toward the skin. The next layer consists of the actual nitroglycerin adsorbed in a mixture of lactose, colloidal silicon dioxide, and silicone medical fluid. The third layer is an ethylene-vinyl acetate copolymer layer that is selectively permeable to the desired nitroglycerin molecule. The final layer that functions to adhere the patch to the skin is composed of hypoallergenic silicone. <ref>"Transderm Nitro (Nitroglycerin): Side Effects, Interactions, Warning, Dosage & Uses." RxList. N.p., 30 Mar. 2009. Web. 12 Nov. 2016.</ref> | + | The medical delivery method for nitroglycerin can come in the form of tablets (that dissolve under the tongue, or in the cheek), topical ointments, or patches <ref name="citation2">Tryzelaar, Dr. "Nitroglycerin (NTG)." Nitroglycerin (NTG). N.p., n.d. Web. 16 Oct. 2016”</ref>. Nitro-Dur delivers nitroglycerin to the body in the form of an acrylic patch <ref name="citation1">"NITRO-DUR® TRANSDERMAL DELIVERY SYSTEM." N.p., 3 Oct. 2014. Web. 16 Oct. 2016 </ref>. The NitroDur patch itself is composed of four layers that each serve a specific function in delivering an adequate dosage of nitroglycerin to the body. The exposed outermost layer of the patch is made up of aluminized plastic that is impermeable to nitroglycerin. This material prevents nitroglycerin from escaping through the back of the patch and directs the molecule to diffuse in the desired direction of toward the skin. The next layer consists of the actual nitroglycerin adsorbed in a mixture of lactose, colloidal silicon dioxide, and silicone medical fluid. The third layer is an ethylene-vinyl acetate copolymer layer that is selectively permeable to the desired nitroglycerin molecule. The final layer that functions to adhere the patch to the skin is composed of hypoallergenic silicone. <ref>"Transderm Nitro (Nitroglycerin): Side Effects, Interactions, Warning, Dosage & Uses." RxList. N.p., 30 Mar. 2009. Web. 12 Nov. 2016.</ref> |
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| | == Function == | | == Function == |
| | The mechanism for nitroglycerin breakdown is disputed, but it is know that nitroglycerin eventually breaks down into nitric oxide. In more recent years, nitroglycerin has been found to be broken down with the help of aldehyde dehydrogenase 2 found in the mitochondria. <ref>Mayer, B., and Beretta, M. (2008) The enigma of nitroglycerin bioactivation and nitrate tolerance. News, views, and troubles. Br. J. Pharmacol. 155, 170-184 </ref> | | The mechanism for nitroglycerin breakdown is disputed, but it is know that nitroglycerin eventually breaks down into nitric oxide. In more recent years, nitroglycerin has been found to be broken down with the help of aldehyde dehydrogenase 2 found in the mitochondria. <ref>Mayer, B., and Beretta, M. (2008) The enigma of nitroglycerin bioactivation and nitrate tolerance. News, views, and troubles. Br. J. Pharmacol. 155, 170-184 </ref> |
| | There has been further proof showing that the breakdown of nitroglycerin permanently alters ALDH2 during <scene name='74/745476/Cys-302_of_aldh2_3/1'>Cys-302</scene> attack <ref name="citation23"> Lang, Barbara S., Antonius Cf Gorren, Gustav Oberdorfer, M. Wenzl, Cristina M. Furdui, Leslie B. Poole, Bernd Mayer, and Karl Gruber. "Vascular Bioactivation of Nitroglycerin: Reaction Mechanism Revealed by Crystal Structure of Aldehyde Dehydrogenase-2." BMC Pharmacology and Toxicology BMC Pharmacol Toxicol 13.Suppl 1 (2012): n. pag. Web. 1 Nov. 2016.</ref>. | | There has been further proof showing that the breakdown of nitroglycerin permanently alters ALDH2 during <scene name='74/745476/Cys-302_of_aldh2_3/1'>Cys-302</scene> attack <ref name="citation23"> Lang, Barbara S., Antonius Cf Gorren, Gustav Oberdorfer, M. Wenzl, Cristina M. Furdui, Leslie B. Poole, Bernd Mayer, and Karl Gruber. "Vascular Bioactivation of Nitroglycerin: Reaction Mechanism Revealed by Crystal Structure of Aldehyde Dehydrogenase-2." BMC Pharmacology and Toxicology BMC Pharmacol Toxicol 13.Suppl 1 (2012): n. pag. Web. 1 Nov. 2016.</ref>. |
| - | The mechanism that is believed to happen takes nitroglycerin (GTN), bound to aldehyde dehydrogenase 2 (ALDH2) through hydrogen bonds and van der waal interactions of the terminal nitrates, then Cysteine-302 (in ALDH2) attacks GTN to form a thionitrate intermediate while also releasing 1,2-glyceryl dinitrate (1,2-GDN) and a small amount of nitric oxide (NO). The thionitrate is then attacked by the surrounding Cysteines (Cys-301 or Cys-303), which forms a disulfide bond and nitrite. The nitrite is then released and converted into NO. It has also been found that daidzin will inhibit GTN breakdown through competitive inhibition because the binding sites of daidzin and GTN overlap <ref name="citation23"> </ref>. Once NO is released it is believed to activate <scene name='74/745476/Guanylate_cyclase/1'>guanylate cyclase </scene>, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to the dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and results in vasodilatation. <ref>"Nitrostat (Nitroglycerin) Drug Information: Clinical Pharmacology - Prescribing Information at RxList." RxList. N.p., n.d. Web. 30 Oct. 2016.</ref> | + | The mechanism that is believed to happen takes nitroglycerin (GTN), bound to aldehyde dehydrogenase 2 (ALDH2) through hydrogen bonds and van der waal interactions of the terminal nitrates, then Cysteine-302 (in ALDH2) attacks GTN to form a thionitrate intermediate while also releasing 1,2-glyceryl dinitrate (1,2-GDN) and a small amount of nitric oxide (NO). The thionitrate is then attacked by the surrounding cysteines (Cys-301 or Cys-303), which forms a disulfide bond and nitrite. Nitrite is then released and converted into NO. It has also been found that daidzin will inhibit GTN breakdown through competitive inhibition because the binding sites of daidzin and GTN overlap <ref name="citation23"> </ref>. Once NO is released, it is believed to activate <scene name='74/745476/Guanylate_cyclase/1'>guanylate cyclase </scene>, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to the dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and results in vasodilatation. <ref>"Nitrostat (Nitroglycerin) Drug Information: Clinical Pharmacology - Prescribing Information at RxList." RxList. N.p., n.d. Web. 30 Oct. 2016.</ref> |
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| | == Disease == | | == Disease == |
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| | ===Heart Disease=== | | ===Heart Disease=== |
| - | Nitroglycerin is commonly used to treat various conditions involving the heart. One way it's used is to increase the chances of detecting coronary artery disease when using MR coronary artery imaging (MRCA). This is done by increasing the vessel length making coronary artery disease more visible under MRCA <ref name="citation3">PMID: 27731913</ref>. Nitroglycerin is also used to treat heart disease and angina, which is classified as heart pain. Angina is caused by an inadequate supply of oxygen in the blood that flows to heart. To alleviate this problem, nitroglycerin is administered to widen the blood vessels reducing the heart's workload and thus oxygen demands from the oxygen poor blood supply <ref name="citation2"> </ref>. | + | Nitroglycerin is commonly used to treat various conditions involving the heart. One way it's used is to increase the chances of detecting coronary artery disease when using MR coronary artery imaging (MRCA). This is done by increasing the vessel length, making coronary artery disease more visible under MRCA <ref name="citation3">PMID: 27731913</ref>. Nitroglycerin is also used to treat heart disease and angina, which is classified as heart pain. Angina is caused by an inadequate supply of oxygen in the blood that flows to heart. To alleviate this problem, nitroglycerin is administered to widen the blood vessels reducing the heart's workload and thus oxygen demands from the oxygen poor blood supply <ref name="citation2"> </ref>. |
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| | ===Chronic Achilles Tendinopathy=== | | ===Chronic Achilles Tendinopathy=== |
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| | ===Raynaud’s Phenomenon=== | | ===Raynaud’s Phenomenon=== |
| - | The Raynaud's pehnomenon occurs due to vasoconstriction of the capillaries, veins, and arteries in external digits <ref name="citation2"> <ref>PMCID: PMC2860448</ref>. Symptoms of raynaud’s involves the fingers or toes turning pale, becoming numb, and then transitioning to a shade of purple or blue. These symptoms result from attacks that are characterized by spasms in the small blood vessels of the fingers and toes <ref>Haythornthwaite, Jenifer, Dr., and Fredrick Wigley, Dr. "Raynaud's, Finger and Skin Care." Scleroderma Education Program Chapter 2 Raynaud’s, Finger and Skin Care (n.d.): n. pag. Web. 16 Oct. 2016 </ref>. Patients who have been diagnosed with Raynaud’s phenomenon will occasionally need pharmacological therapy. While the nitro-dur patch is not specifically precribe, topical nitroglycerin ointment is used on these patients to decrease the occurrence and severity of vasospastic episodes <ref name="citation2"> </ref>. Nitroglycerin does this by expanding the blood vessels allowing better blood circulation <ref name="citation3"> </ref>.
| + | Raynaud's Phenomenon occurs due to vasoconstriction of the capillaries, veins, and arteries in external digits <ref name="citation2"> <ref>PMCID: PMC2860448</ref>. Symptoms of Raynaud’s involves the fingers or toes turning pale, becoming numb, and then transitioning to a shade of purple or blue. These symptoms result from attacks that are characterized by spasms in the small blood vessels of the fingers and toes <ref>Haythornthwaite, Jenifer, Dr., and Fredrick Wigley, Dr. "Raynaud's, Finger and Skin Care." Scleroderma Education Program Chapter 2 Raynaud’s, Finger and Skin Care (n.d.): n. pag. Web. 16 Oct. 2016 </ref>. Patients who have been diagnosed with Raynaud’s Phenomenon will occasionally need pharmacological therapy. While the NitroDur patch is not specifically prescribed, topical nitroglycerin ointment is used on these patients to decrease the occurrence and severity of vasospastic episodes <ref name="citation2"> </ref>. Nitroglycerin does this by expanding the blood vessels allowing better blood circulation <ref name="citation3"> </ref>. |
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| | == References == | | == References == |
| | <references/> | | <references/> |
|
Structure
The main ingredient of NitroDur is 1,2,3-propanetriol trinitrate, also known as . Nitroglycerin is a molecule that when broken down to nitric oxide binds to protein domains found in smooth muscle. These binding domains are often found in the form of dimers that require multiple NO molecules to bind as seen in . Nitric Oxide is often buried deep within the protein, that in conjunction with other molecular interactions, triggers structural changes that activate proteins to serve their specific functions. In humans, NO binds to protein domains in this same fashion, as seen in .
Medication Details
The medical delivery method for nitroglycerin can come in the form of tablets (that dissolve under the tongue, or in the cheek), topical ointments, or patches [1]. Nitro-Dur delivers nitroglycerin to the body in the form of an acrylic patch [2]. The NitroDur patch itself is composed of four layers that each serve a specific function in delivering an adequate dosage of nitroglycerin to the body. The exposed outermost layer of the patch is made up of aluminized plastic that is impermeable to nitroglycerin. This material prevents nitroglycerin from escaping through the back of the patch and directs the molecule to diffuse in the desired direction of toward the skin. The next layer consists of the actual nitroglycerin adsorbed in a mixture of lactose, colloidal silicon dioxide, and silicone medical fluid. The third layer is an ethylene-vinyl acetate copolymer layer that is selectively permeable to the desired nitroglycerin molecule. The final layer that functions to adhere the patch to the skin is composed of hypoallergenic silicone. [3]
Function
The mechanism for nitroglycerin breakdown is disputed, but it is know that nitroglycerin eventually breaks down into nitric oxide. In more recent years, nitroglycerin has been found to be broken down with the help of aldehyde dehydrogenase 2 found in the mitochondria. [4]
There has been further proof showing that the breakdown of nitroglycerin permanently alters ALDH2 during attack [5].
The mechanism that is believed to happen takes nitroglycerin (GTN), bound to aldehyde dehydrogenase 2 (ALDH2) through hydrogen bonds and van der waal interactions of the terminal nitrates, then Cysteine-302 (in ALDH2) attacks GTN to form a thionitrate intermediate while also releasing 1,2-glyceryl dinitrate (1,2-GDN) and a small amount of nitric oxide (NO). The thionitrate is then attacked by the surrounding cysteines (Cys-301 or Cys-303), which forms a disulfide bond and nitrite. Nitrite is then released and converted into NO. It has also been found that daidzin will inhibit GTN breakdown through competitive inhibition because the binding sites of daidzin and GTN overlap [5]. Once NO is released, it is believed to activate , resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to the dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and results in vasodilatation. [6]
Disease
Heart Disease
Nitroglycerin is commonly used to treat various conditions involving the heart. One way it's used is to increase the chances of detecting coronary artery disease when using MR coronary artery imaging (MRCA). This is done by increasing the vessel length, making coronary artery disease more visible under MRCA [7]. Nitroglycerin is also used to treat heart disease and angina, which is classified as heart pain. Angina is caused by an inadequate supply of oxygen in the blood that flows to heart. To alleviate this problem, nitroglycerin is administered to widen the blood vessels reducing the heart's workload and thus oxygen demands from the oxygen poor blood supply [1].
Chronic Achilles Tendinopathy
Chronic Achilles Tendinopathy is characterized by pain in the achilles tendon that is caused by tendon degradation [8]. A study conducted at an Australian University Hospital looked at the effect of topical glyceryl trinitrate (in the form of a NitroDur patch) on pain management and symptoms in chronic noninsertional Achilles tendinopathy. Study participants were given an active transdermal NitroDur patch, which delivered 1.25 mg of glyceryl trinitrate over 24 hours, or a placebo treatment patch. Over the course of 24 weeks, participants applied one fourth of the NitroDur patch to their most painful site on their body. Study results showed that the NitroDur patch was more effective than placebo in reducing pain caused by chronic noninsertional Achilles tendonitis [9].
Raynaud’s Phenomenon
Raynaud's Phenomenon occurs due to vasoconstriction of the capillaries, veins, and arteries in external digits [1]. Symptoms of Raynaud’s involves the fingers or toes turning pale, becoming numb, and then transitioning to a shade of purple or blue. These symptoms result from attacks that are characterized by spasms in the small blood vessels of the fingers and toes [10]. Patients who have been diagnosed with Raynaud’s Phenomenon will occasionally need pharmacological therapy. While the NitroDur patch is not specifically prescribed, topical nitroglycerin ointment is used on these patients to decrease the occurrence and severity of vasospastic episodes [1]. Nitroglycerin does this by expanding the blood vessels allowing better blood circulation [7].
References
- ↑ 1.0 1.1 1.2 1.3 Tryzelaar, Dr. "Nitroglycerin (NTG)." Nitroglycerin (NTG). N.p., n.d. Web. 16 Oct. 2016”
- ↑ "NITRO-DUR® TRANSDERMAL DELIVERY SYSTEM." N.p., 3 Oct. 2014. Web. 16 Oct. 2016
- ↑ "Transderm Nitro (Nitroglycerin): Side Effects, Interactions, Warning, Dosage & Uses." RxList. N.p., 30 Mar. 2009. Web. 12 Nov. 2016.
- ↑ Mayer, B., and Beretta, M. (2008) The enigma of nitroglycerin bioactivation and nitrate tolerance. News, views, and troubles. Br. J. Pharmacol. 155, 170-184
- ↑ 5.0 5.1 Lang, Barbara S., Antonius Cf Gorren, Gustav Oberdorfer, M. Wenzl, Cristina M. Furdui, Leslie B. Poole, Bernd Mayer, and Karl Gruber. "Vascular Bioactivation of Nitroglycerin: Reaction Mechanism Revealed by Crystal Structure of Aldehyde Dehydrogenase-2." BMC Pharmacology and Toxicology BMC Pharmacol Toxicol 13.Suppl 1 (2012): n. pag. Web. 1 Nov. 2016.
- ↑ "Nitrostat (Nitroglycerin) Drug Information: Clinical Pharmacology - Prescribing Information at RxList." RxList. N.p., n.d. Web. 30 Oct. 2016.
- ↑ 7.0 7.1 Heer T, Reiter S, Trissler M, Hofling B, von Knobelsdorff-Brenkenhoff F, Pilz G. Effect of Nitroglycerin on the Performance of MR Coronary Angiography. J Magn Reson Imaging. 2016 Oct 12. doi: 10.1002/jmri.25483. PMID:27731913 doi:http://dx.doi.org/10.1002/jmri.25483
- ↑ Chronic Achilles Tendon Injury: An Overview." Hospital for Special Surgery. N.p., 1 June 2011. Web. 30 Oct. 2016
- ↑ Hunte G, Lloyd-Smith R. Topical glyceryl trinitrate for chronic Achilles tendinopathy. Clin J Sport Med. 2005 Mar;15(2):116-7. PMID:15782065
- ↑ Haythornthwaite, Jenifer, Dr., and Fredrick Wigley, Dr. "Raynaud's, Finger and Skin Care." Scleroderma Education Program Chapter 2 Raynaud’s, Finger and Skin Care (n.d.): n. pag. Web. 16 Oct. 2016
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