The History of Glyceryl Trinitrate As a Prescription Drug

patches for transdermal delivery and in tablet form. It ARTICLE may also be injected. Th e history of glyceryl trinitrate as a prescription drug Anthony Butler Abstract A number of prescribed drugs possessing a nitro group (-NO2) are vasodilators and are used to relieve the symptoms of angina pectoris. Th e most widely prescribed drug in this group is glyceryl trinitrate (GTN). It was fi rst synthesized by an Italian chemist, Ascanio Sobrero, in 1847. Its clinical use was pioneered by phy- sicians including William Murrell and Sir Th omas Lauder Brunton, and it is now an established remedy for the condition. Its mode of action in vivo was a com- plete mystery until the discovery in the 1980s of nitric oxide (NO) as the naturally occurring messenger mol- ecule that triggers the process of vasodilation. However, exactly how the nitro group in GTN is converted into NO is still uncertain, although the general belief is that an enzyme is responsible. Introduction Th e nineteenth and twentieth centuries witnessed a Figure 1. Ascanio Sobrero. (Source: University of Torino surge in the number of new compounds made in the Archive) laboratory that were available for testing as possible drugs. Not only were the physical properties (colour, GTN was fi rst synthesised by an Italian, Ascanio So- crystal form, melting point and so on) of new com- brero (1812-1888) around 1847. (Figure 1). He was born pounds recorded, but the discoverer might do a few in the small town of Casale Monferrato in the Pied- simple tests to see whether the compound had any in- mont region of Italy and studied medicine at the near- teresting biological properties. It was quite common for by University of Torino (Turin). He found chemistry a chemist to taste the compound he had made, some- the most interesting part of the course and discontin- thing that would be unthinkable now. Normally, tast- ued the study of medicine. On making this decision ing did not lead anywhere, but in one instance at least he moved, in 1840, to Paris to study with the distin- it led to the development of one of the most frequently guished French chemist Th éophile-Jules Pelouze. Pe- prescribed drugs of all time: glyceryl trinitrate (GTN), louze appears not to have discovered anything of sig- also known as nitroglycerine. It is used to alleviate the nifi cance but is famous for being distinguished. Sobrero symptoms of angina pectoris, and having been used stayed there until the early part of 1843 when, to en- for over 130 years is unlikely to be replaced in the near hance further his chemical understanding, he moved future. How it was discovered and how its use was de- to Giessen to study with the great German chemist Jus- veloped is a tale that spans several countries in Europe. tus von Liebig. Th ere he studied the distillation and de- Angina pectoris is one of the commonest cardio- composition of guajaco (guiacum) resin, a component vascular diseases. Its most conspicuous symptoms are of many a masculine fragrance. However, he was there an agonising chest pain and breathlessness on exertion for only a few months when the opportunity to return or stress, but both disappear on resting. Th e risk fac- to his home city of Turin arose. He was appointed to the tors for stable angina are having an unhealthy lifestyle, post of assistant at the Arsenale and later became lec- including not exercising, smoking, being overweight, turer in applied chemistry at the Technical School and and having a history of heart disease. Its use is predict- started his work on the nitration of glycerine.1 ed to increase as the population ages and as the inci- Th ere are errors in some published accounts of So- dence of diabetes, hypertension and obesity increases. brero’s invention of GTN. For example, Sneader2 refers GTN can be used as a spray for sublingual dosing, in to him as ‘Ascagne Sobrero, a French chemist’, both 6 PHARMACEUTICAL HISTORIAN · 2021 · Volume 51/1 Marsh and Marsh<sup>3 and Fant4 appear to suggest that credit to Sobrero for the invention of GTN, the latter he made GTN while working with Pelouze in Paris, felt he deserved more recognition. Nobel reappears in while a Wikipedia entry5 states that Pelouze supervised our story later in a somewhat humbler role. this work at the University of Turin. Th e truth emerged during the centennial celebrations for Sobrero’s birth in Biological action of GTN 1912. In Paris he had witnessed the production of gun- Although a full account7 was given in Italian in 1849, cotton by the action of fuming nitric acid on cotton. the fi rst announcement of the invention and proper- Pelouze had tried the same reaction using glycerine in ties of GTN was given in an article in the French sci- place of cotton, but the result was oxidation to give ox- entifi c journal Comptes rendus8 in February 1847. It is alic acid and carbon dioxide. described as an extract from a letter to Pelouze. As was Th ere are easier ways to make oxalic acid. It was at the custom of the time, Sobrero tasted the material he the Technical School in Turin, without any supervi- had made. He placed a ‘very small quantity’ (ce qu’on sion by Pelouze, that Sobrero attempted the nitration peut en prendre en y mouillant) on his tongue, and the of glycerine using – not concentrated nitric acid – but result was a severe headache that lasted several hours. It a mixture of concentrated nitric and sulphuric acids, had the same eff ect on other members of the laboratory which is a nitrating rather than an oxidising agent. He staff . Th is observation was not without signifi cance, al- obtained a compound that reminded him of olive oil though there were many twists and turns on its journey and he called it pyroglycerine, but today we know it as to becoming a treatment for angina pectoris. glyceryl trinitrate. Its systematic name is 1,2,3-trini- Th e fact that GTN caused headaches when ingested troxypropane. He soon came to realise that it was a haz- was of great interest to homeopaths. During the Victo- ardous material, exploding with considerable violence, rian era homeopathy was a popular form of medicine, and he was injured during one experiment. He delayed and when one considers the nauseating and ineff ective making any announcement of his discovery because of medicines prescribed at that time, giving a patient a the hazards involved in the manipulation of GTN. De- solution so dilute that it contained nothing was an at- termining its chemical structure was not without diffi - tractive option. One essential principle of homeopathy culties, but it is now known to be as shown (Figure 2). was similia similibus curantur (like cures like). If GTN caused headaches then it must also be a cure for them. Th e full story of GTN in homoeopathic medicine is re- counted in detail by Fye.9 As a preliminary to its homeopathic use as a treatment for headaches, it underwent the process of Prüfung or ‘proving’ by the prominent homeopath Constantine Hering, under the guidance of Samuel Hahnemann himself, the founder of homeopathic medicine. It was renamed Glonoine and given to a number of believers who reported on its eff ect. Hering Figure 2. Chemical structure of glyceryl trinitrate reported the results10 and concluded that it ‘will cure headaches and other complaints’, but there are no re- Dynamite ports if it having been used in this way. Although ho- Some years later, when information about GTN was meopathy is now largely discredited, the case of GTN generally available, it was taken up by the Swedish ex- represents a benefi cial crossover from homeopathic to plosives entrepreneur, Alfred Nobel. He incorporated allopathic prescribing, as its ‘proving’ provided useful it into a diatomaceous earth (kieselguhr) to give dyna- information on its biological activity and toxicity. mite. Th is proved far safer to handle than GTN itself, although Nobel’s younger brother, Emil, and a student (C.E. Hertzman) were killed by an explosion during the early testing of dynamite in 1864. According to his bi- ographer, this event preyed on Nobel’s mind all his life, although he rarely spoke of it.6 Dynamite is used exten- sively in civil engineering, and Nobel deeply regretted Figure 3. Chemical structure of isoamyl nitrite its use in warfare. However, it is also one of the products that contributed to Nobel’s fortune and allowed him Amyl nitrite to establish the Nobel Prizes, the highest honour that At about the same time the French chemist Antoine Jé- any scientist can receive. Although Nobel always gave rôme Balard (1802-1876) produced what is known as PHARMACEUTICAL HISTORIAN · 2021 · Volume 51/1 7 amyl nitrite but is, in fact, iso-amyl nitrite (Figure 3). showed that inhaling amyl nitrite greatly lowered arte- He began life as an apothecary in Montpellier and end- rial tension in both animals and humans. Among the ed up as professor of chemistry at the Collège de France. young housemen in Edinburgh at that time was Th om- He is most famous for the discovery of bromine (also as Lauder Brunton (1844-1916) (Figure 4). discovered by Carl Jacob Löwig at around the same Brunton was a gifted physician as well as physiolo- time) but, in fact, the invention of amyl nitrite is just gist and noted that the severe pain of angina in his pa- as signifi cant. Th e biological eff ects of inhaling amyl tients could be alleviated by venesection.

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