Nitroglycerin (medication)

Last updated

Nitroglycerin
Nitroglycerin.svg
Nitrogylcerin (3D ball-and-stick model).png
Clinical data
Trade names Nitrol, others
AHFS/Drugs.com Monograph
MedlinePlus a601086
Routes of
administration 		sublingual, transdermal, by mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability <1%
Metabolism liver (rapid), red blood cells, vascular wall
Elimination half-life 3 minutes
Excretion In urine, in bile
Identifiers
  • 1,3-dinitrooxypropan-2-yl nitrate;

    [3-(nitrooxy)-2-[(nitrooxy)methyl]propyl] nitrate;

    1,2,3-trinitroxy propane
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
Formula C3H5N3O9
Molar mass 227.085 g·mol−1
3D model (JSmol)
  • C(C(CO[N+](=O)[O-])O[N+](=O)[O-])O[N+](=O)[O-]
  • InChI=1S/C3H5N3O9/c7-4(8)13-1-3(15-6(11)12)2-14-5(9)10/h3H,1-2H2 Yes check.svgY
  • Key:SNIOPGDIGTZGOP-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure (hypertension), anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. [1] [2] [3] [4] This includes chest pain from a heart attack. [1] It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein. [1]

Contents

Side effects and mechanism

Common side effects include headache and low blood pressure. [1] The low blood pressure can be severe. [1] It is unclear if use in pregnancy is safe for the foetus. [1] It should not be used together with medications within the PDE5 inhibitor family such as sildenafil due to the risk of low blood pressure. [1] Nitroglycerin is in the nitrate family of medications. [1] While it is not entirely clear how it works, it is believed to function by dilating blood vessels. [1]

History, society and culture

Nitroglycerin was written about as early as 1846 [5] [6] and came into medical use in 1878. [7] [8] [9] The drug nitroglycerin (GTN) is a dilute form of the same chemical used as the explosive, nitroglycerin. [9] Dilution makes it non-explosive. [9] In 2020, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions. [10] [11]

Medical uses

Three different forms of nitroglycerin: intravenous, sublingual spray, and the nitroglycerin patch. Nitro.JPG
Three different forms of nitroglycerin: intravenous, sublingual spray, and the nitroglycerin patch.

Nitroglycerin is used for the treatment of angina, acute myocardial infarction, severe hypertension, and acute coronary artery spasms. [1] [12] It may be administered intravenously, as a sublingual spray, or as a patch applied to the skin.

Angina

GTN is useful in decreasing angina attacks, perhaps more so than reversing angina once started, by supplementing blood concentrations of NO, also called endothelium-derived relaxing factor, before the structure of NO as the responsible agent was known. This led to the development of transdermal patches of glyceryl trinitrate, providing 24-hour release. [13] However, the effectiveness of glyceryl trinitrate is limited by development of tolerance/tachyphylaxis within 2–3 weeks of sustained use. Continuous administration and absorption (such as provided by daily pills and especially skin patches) accelerate onset of tolerance and limit the usefulness of the agent. Thus, glyceryl trinitrate works best when used only in short-term, pulse dosing. Glyceryl trinitrate is useful for myocardial infarction (heart attack) and pulmonary edema, again working best if used quickly, within a few minutes of symptom onset, as a pulse dose. [ citation needed ]It may also be given as a sublingual or buccal dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack. [14]

Other uses

Tentative evidence indicates efficacy of glyceryl trinitrate in the treatment of various tendinopathies, both in pain management and acceleration of soft tissue repair. [15] [16] [17] [18] [19]

GTN is also used in the treatment of anal fissures, though usually at a much lower concentration than that used for angina treatment. [2]

GTN has been used to decrease pain associated with dysmenorrhea. [3]

GTN was once researched for the prevention and treatment of osteoporosis; however, the researcher Sophie Jamal was found to have falsified the findings, sparking one of the largest scientific misconduct cases in Canada. [20]

Tolerance

After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as GTN— may develop in a patient, reducing its effectiveness. Tolerance is defined as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher doses of the drug to achieve the same effects,[ citation needed ] and was first described soon after the introduction of GTN in cardiovascular therapy. Studies have shown[ citation needed ] that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients' prognosis. [21] [ full citation needed ] These include endothelial and autonomic dysfunction. [22] [ full citation needed ]

The mechanisms of nitrate tolerance have been investigated over the last 30 years, and several hypotheses to explain tolerance have been offered, including:

  1. plasma volume expansion
  2. impaired transformation of GTN into NO or related species
  3. counteraction of GTN vasodilation by neurohormonal activation [23]
  4. oxidative stress [24] [ full citation needed ]

Recent evidence suggests[ weasel words ] that deleterious GTN-induced production of oxygen free radicals might induce a number of abnormalities, include those described above, so that the oxidative stress hypothesis might represent a unifying principle.

Adverse events

Glyceryl trinitrate can cause severe hypotension, reflex tachycardia, and severe headaches that necessitate analgesic intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance.

GTN also can cause severe hypotension, circulatory collapse, and death if used together with vasodilator drugs that are used for erectile dysfunction, such as sildenafil, tadalafil, and vardenafil. [25]

GTN transdermal patches should be removed before defibrillation due to the risk of explosion and/or burns, [26] [ verification needed ][ better source needed ] but investigations have concluded that GTN patch explosions during defibrillation were due to the breakdown voltage of the metal mesh in some patches. [27] [ non-primary source needed ]

Mechanism of action

GTN is a prodrug which must be denitrated, with the nitrite anion or a related species further reduced to produce the active metabolite nitric oxide (NO). Organic nitrates that undergo these two steps within the body are called nitrovasodilators, and the denitration and reduction occur via a variety of mechanisms. The mechanism by which such nitrates produce NO is widely disputed. Some believe[ weasel words ] that organic nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation. In recent years,[ when? ] a great deal of evidence has been produced[ citation needed ] that supports the conclusion that GTN's clinically relevant denitration and reduction produce 1,2-glyceryl dinitrate (GDN) and NO, and that this reaction is catalysed by mitochondrial aldehyde dehydrogenase (ALDH2 or mtALDH).

The NO produced by this process is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Among other roles, cGMP serves as a substrate for a cGMP-dependent protein kinase that activates myosin light chain phosphatase.[ clarification needed ] Thus, production of NO from exogenous sources such as GTN increases the level of cGMP within the cell, and stimulates dephosphorylation of myosin, which initiates relaxation of smooth muscle cells in blood vessels.

History

It was known almost from the time of the first synthesis of GTN by Ascanio Sobrero in 1846 that handling and tasting of nitroglycerin could cause sudden intense headaches, [5] [6] which suggested a vasodilation effect (as suggested by Sobrero). [28] Constantine Hering developed a form of nitroglycerin in 1847 and advocated for its dosing as a treatment of a number of diseases; however, its use as a specific treatment for blood pressure and chest pain was not among these. This is primarily due to his deep rooted focus in homeopathy. [29] [30]

Following Thomas Brunton's discovery that amyl nitrite could be used to treat chest pain, William Murrell experimented with the use of nitroglycerin to alleviate angina and reduce blood pressure, and showed that the accompanying headaches occurred as a result of overdose. Murrell began treating patients with small doses of GTN in 1878, and the substance was widely adopted after he published his results in The Lancet in 1879. [7]

The medical establishment used the name "glyceryl trinitrate" or "trinitrin" to avoid alarming patients, because of a general awareness that nitroglycerin was explosive. [31] [ verification needed ]

Overdoses may generate methemoglobinemia. [32]

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

<span class="mw-page-title-main">Amyl nitrite</span> Chemical compound

Amyl nitrite is a chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrite functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group. Like other alkyl nitrites, amyl nitrite is bioactive in mammals, being a vasodilator, which is the basis of its use as a prescription medicine. As an inhalant, it also has a psychoactive effect, which has led to its recreational use, with its smell being described as that of old socks or dirty feet. It is also referred to as banapple gas.

<span class="mw-page-title-main">Nitrate</span> Polyatomic ion (NO₃, charge –1) found in explosives and fertilisers

Nitrate is a polyatomic ion with the chemical formula NO−
3. Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble nitrate is bismuth oxynitrate.

<span class="mw-page-title-main">Nitroglycerin</span> Chemical compound

Nitroglycerin (NG), also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating glycerol with white fuming nitric acid under conditions appropriate to the formation of the nitric acid ester. Chemically, the substance is an organic nitrate compound rather than a nitro compound, but the traditional name is retained. Discovered in 1847 by Ascanio Sobrero, nitroglycerin has been used as an active ingredient in the manufacture of explosives, namely dynamite, and as such it is employed in the construction, demolition, and mining industries. It is combined with nitrocellulose to form double-based smokeless powder, which has been used as a propellant in artillery and firearms since the 1880s.

<span class="mw-page-title-main">Sildenafil</span> Drug for erectile dysfunction and hypertension

Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain symptoms in secondary Raynaud's phenomenon. It is unclear if it is effective for treating sexual dysfunction in females. It can be taken orally, intravenously, or through the sublingual route. Onset when taken orally is typically within twenty minutes and lasts for about two hours.

<span class="mw-page-title-main">Tendinopathy</span> Inflammation of the tendon

Tendinopathy is a type of tendon disorder that results in pain, swelling, and impaired function. The pain is typically worse with movement. It most commonly occurs around the shoulder, elbow, wrist, hip, knee, or ankle.

<span class="mw-page-title-main">Isosorbide dinitrate</span> Chemical compound

Isosorbide dinitrate is a medication used for heart failure, esophageal spasms, and to treat and prevent chest pain from not enough blood flow to the heart. It has been found to be particularly useful in heart failure due to systolic dysfunction together with hydralazine. It is taken by mouth or under the tongue.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

<span class="mw-page-title-main">Isosorbide mononitrate</span> Chemical compound

Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Nicorandil</span> Chemical compound

Nicorandil is a vasodilator drug used to treat angina.

A spasm of accommodation is a condition in which the ciliary muscle of the eye remains in a constant state of contraction. Normal accommodation allows the eye to "accommodate" for near-vision. However, in a state of perpetual contraction, the ciliary muscle cannot relax when viewing distant objects. This causes vision to blur when attempting to view objects from a distance. This may cause pseudomyopia or latent hyperopia.

<span class="mw-page-title-main">Diethylene glycol dinitrate</span> Chemical compound

Diethylene glycol dinitrate (DEGDN) is an explosive nitrated alcohol ester with the formula C4H8N2O7. While chemically similar to numerous other high explosives, pure diethylene glycol dinitrate is difficult to ignite or detonate. Ignition typically requires localized heating to the decomposition point unless the DEGDN is first atomized.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

A nitrovasodilator is a pharmaceutical agent that causes vasodilation by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.

Biological functions of nitric oxide are roles that nitric oxide plays within biology.

The classification of all headaches, including migraines, is organized by the International Headache Society, and published in the International Classification of Headache Disorders (ICHD). The current version, the ICHD-3 beta, was published in 2013.

<span class="mw-page-title-main">Transdermal analgesic patch</span> Medicated adhesive patch

A transdermal analgesic or pain relief patch is a medicated adhesive patch used to relieve minor to severe pain. There are many types of analgesic patches based on the main ingredients in the patches. These include patches containing counterirritants, which are used to treat mild to moderate pain, and patches containing opioids such as buprenorphine and fentanyl, used to relieve moderate to severe pain. Fentanyl is often used for opioid-tolerant patients. Nitroglycerin, also known as glyceryl trinitrate (GTN), a medication used for heart failure, high blood pressure, anal fissures, painful periods, and to treat and prevent chest pain, can also be found in patches. Beyond these are patches that contain drugs such as diclofenac and lidocaine and various other drugs. The main purpose of transdermal analgesic patches are to administer drugs in a more viable way to patients, as opposed to oral consumption or intravenous administration such as an injection.

William Murrell (1853–1912) was an English physician, clinical pharmacologist, and toxicologist. Murrell is best known for being one of the first to recognize the clinical benefits of glyceryl trinitrate for the management of patients with angina pectoris.

References

  1. 1 2 3 4 5 6 7 8 9 10 "Nitroglycerin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. 1 2 Fenton C, Wellington K, Easthope SE (2006). "0.4% nitroglycerin ointment: in the treatment of chronic anal fissure pain". Drugs. 66 (3): 343–9. doi:10.2165/00003495-200666030-00006. PMID   16526822. S2CID   46984485.
  3. 1 2 Morgan PJ, Kung R, Tarshis J (May 2002). "Nitroglycerin as a uterine relaxant: a systematic review". Journal of Obstetrics and Gynaecology Canada. 24 (5): 403–9. doi:10.1016/S1701-2163(16)30403-0. PMID   12196860.
  4. ↑ O'Leary ME, Hancox JC (May 2010). "Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias". British Journal of Clinical Pharmacology. 69 (5): 427–42. doi:10.1111/j.1365-2125.2010.03629.x. PMC   2856043 . PMID   20573078.
  5. 1 2 Sobrero A (1847). "Sur plusieur composés détonants produits avec l'acide nitrique et le sucre, la dextrine, la lactine, la mannite et la glycérine" [On several detonating compounds produced with nitric acid and sugar, dextrin, lactose, mannitol, and glycerine]. Comptes Rendus (in French). 24: 247–248. From p. 248: "Il faut toutefois être sur ses gardes en faissant cet essai, car il suffit d'en tenir une très-petite quantité (ce qu'on peut en prendre en y mouillant légèrement le bout du petit doigt) sur la langue pour en éprouver une migraine assez forte pendant pleusieurs heures. Cette action sur le corps humain a été constatée par plusieurs personnes dans mon laboratoire, et je l'ai éprouvée plusieurs fois sur moi-même avant que je fusse certain qu'elle a des propriétés toxiques." (It is always necessary to be on one's guard when making this test, for it suffices to take a very small quantity of it (which one can take by lightly wetting, in it, the tip of the little finger) on [one's] tongue in order to feel a quite strong headache for several hours. This action on the human body has been confirmed by several persons in my laboratory, and I tested it several times on myself before I was certain that it has toxic properties.)
  6. 1 2 Sobrero A (1849). "Sopra alcuni nuovi composti fulminanti ottenuti col mezzo dell'azione dell'acido nitrico sulle sostante organiche vegetali" [On some new explosive products obtained by the action of nitric acid on some vegetable organic substances]. Memorie della Reale Accademia delle Scienze di Torino. 2nd series (in Italian). 10: 195–201. From p. 198: " … basta il tenere una gocciolina di Piroglicerina sulla lingua, senza inghiottirla, perchè si provi tosto un violento dolore di capo, quale è quello di una forte emicrania, accompagnato da pulsazioni interne assai penose: nello stesso tempo provasi debolezza alle estremità inferiori. Questo effetto sentii io più volte, ed il provarono il signor prof. Valerico Cauda prepartore della mia scuola, ed altre persone ehe tentarono l'esperimento." ( … it suffices to hold a droplet of Piroglicerina [i.e., Sabrero's name for nitroglycerin] on [one's] tongue, without swallowing it, because one soon feels a violent pain in the head, which is a strong headache, accompanied by very painful internal throbbings; at the same time one would feel weakness in the lower extremities. This effect I felt many times, and it was felt by Prof. Valerico Cauda, who prepares lecture demonstrations at my school, and [by] other people who tried the experiment.)
  7. 1 2 Murrell W (1879). "Nitro-glycerine as a remedy for angina pectoris". The Lancet. 113 (2894): 80–81, 113–115, 151–152, 225–227. doi:10.1016/s0140-6736(02)42404-x. hdl:2027/uc1.b5295238. PMC   5901592 .
  8. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN   9783527607495. Archived from the original on 20 December 2016.
  9. 1 2 3 Ravina E (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 153. ISBN   9783527326693. Archived from the original on 20 December 2016.
  10. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  11. ↑ "Nitroglycerin - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  12. ↑ Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y (February 2008). "Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment". Journal of Cardiology. 51 (1): 2–17. doi: 10.1016/j.jjcc.2008.01.001 . PMID   18522770 . Retrieved 23 November 2016.
  13. ↑ "Nitro-Dur - FDA prescribing information, side effects and uses". drugs.com. Archived from the original on 1 April 2017. Retrieved 31 March 2017.
  14. ↑ "Nitroclycerin Oral Route and Sublingual Route". www.mayoclinic.org.
  15. ↑ Goldin M, Malanga GA (September 2013). "Tendinopathy: a review of the pathophysiology and evidence for treatment". The Physician and Sportsmedicine. 41 (3): 36–49. doi:10.3810/psm.2013.09.2019. PMID   24113701. S2CID   26907571.
  16. ↑ Andres BM, Murrell GA (July 2008). "Treatment of tendinopathy: what works, what does not, and what is on the horizon". Clinical Orthopaedics and Related Research. 466 (7): 1539–54. doi:10.1007/s11999-008-0260-1. PMC   2505250 . PMID   18446422.
  17. ↑ Assem Y, Arora M (January 2015). "Glyceryl trinitrate patches-An alternative treatment for shoulder impingement syndrome". Journal of Orthopaedic Translation. 3 (1): 12–20. doi:10.1016/j.jot.2014.11.001. PMC   5982354 . PMID   30035035.
  18. ↑ Bokhari AR, Murrell GA (February 2012). "The role of nitric oxide in tendon healing". Journal of Shoulder and Elbow Surgery. 21 (2): 238–44. doi:10.1016/j.jse.2011.11.001. PMID   22244067.
  19. ↑ Gambito ED, Gonzalez-Suarez CB, Oquiñena TI, Agbayani RB (August 2010). "Evidence on the effectiveness of topical nitroglycerin in the treatment of tendinopathies: a systematic review and meta-analysis". Archives of Physical Medicine and Rehabilitation. 91 (8): 1291–305. doi:10.1016/j.apmr.2010.02.008. PMID   20684913.
  20. ↑ Shuchman, Miriam (20 September 2016). "Misconduct saga rattles bone scientists". Canadian Medical Association Journal. 188 (13): 938–939. doi: 10.1503/cmaj.109-5314 . PMC   5026510 . PMID   27551032.
  21. ↑ Nakamura et al.[ full citation needed ]
  22. ↑ Gori et al.[ full citation needed ]
  23. ↑ Such activation is suggested to cause sympathetic activation, and release of vasoconstrictors such as endothelin and angiotensin II.
  24. ↑ Hypothesis of Munzel et al. (1995).[ full citation needed ]
  25. ↑ "Phosphodiesterase Inhibitors". CV Pharmacology. Archived from the original on 13 June 2017. Retrieved 3 April 2017.
  26. ↑ Scientific Committee on Occupational Exposure Limits (May 2008). Recommendation From the Scientific Committee on Occupational Exposure Limits for Glycerol Trinitrate (Nitroglycerin) [SCOEL/SUM/147] (Report). The Hague, NDL: Sociaal-Economische Raad. Archived from the original on 3 March 2016. Retrieved 30 March 2017.
  27. ↑ Liddle R, Richmond W (June 1998). "Investigation into voltage breakdown in glyceryl trinitrate patches". Resuscitation. 37 (3): 145–8. doi:10.1016/S0300-9572(98)00059-8. PMID   9715773.
  28. ↑ (Sobrero, 1849), pp. 198–199. On pages 198–199, Sobrero describes the results of administering nitroglycerin to a puppy, a mouse, and a guinea pig. After giving (orally) several centigrams of nitroglycerin to a puppy, the animal vomited, and within 7-8 minutes, it ceased to breath. Sobrero managed to revive it, but it convulsed. "L'apertura del suo corpo non diede a scorgere alterazione veruna al ventricolo. I vasi de cervello erano pieni di sangue, come rigonfii di sangue erano l'orocchietta destra de cuore e specialmente la vena cava superiore." (The opening of its body did not reveal any deterioration of the ventricle. The vessels of the brain were full of blood; similarly swollen with blood were the right auricle of the heart and especially the superior vena cava.) Administering nitroglycerin to a mouse and a guinea pig produced similar results.
  29. ↑ Hering C (1849). "Glonoine, a new medicine for headache, &c". American Journal of Homoeopathy. 4 (1): 3–5. Note: Hering renamed nitroglycerine "glonoine".
  30. ↑ Fye WB (January 1986). "Nitroglycerin: a homeopathic remedy". Circulation. 73 (1): 21–9. doi: 10.1161/01.cir.73.1.21 . PMID   2866851. See pp. 22–23.
  31. ↑ Sneader W (2005). Drug Discovery: A History. New York, NY: John Wiley & Sons. p. 433. ISBN   978-0471899808. Archived from the original on 8 September 2017.[ verification needed ]
  32. ↑ Kaplan KJ, Taber M, Teagarden JR, Parker M, Davison R (January 1985). "Association of methemoglobinemia and intravenous nitroglycerin administration". The American Journal of Cardiology. 55 (1): 181–3. doi:10.1016/0002-9149(85)90324-8. PMID   3917597.

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