Why is there a shortage of isosorbide mononitrate?

Euticals, Prince William Avenue, Sandycroft

Doctors and patients probably don't give too much thought to how the medicines they prescribe and take are produced. Cardiologists focus on clinical trials and evidence to guide practice but the actual manufacture of a medicine is something that we take for granted. Until that is we are informed that a particular medicine is just not available because of supply problems. This is the current situation with the drug isosorbide mononitrate (ISMO) which is used to treat patients with heart disease. The medicine is used to treat angina and heart failure and is very widely prescribed.

ISMO is a member of a family of medicines known as nitrovasodilators. These drugs work by releasing a chemical called nitric oxide which dilates the arteries and veins and is used to treat chest pain. The other medicines in this family include glyceryl trinitrate and isosorbide dinitrate. Glyceryl trinitrate, also known as GTN, is a supplied as a spray or a tablet to be placed under the tongue. Chemically GTN is the same as nitroglycerine, the explosive component of dynamite.

Nitroglycerine was discovered by Asciano Sobrero in 1847 in Turin. He made it by mixing nitric acid with glycerol and then slowly adding sulphuric acid. This reaction produced highly volatile and unstable liquid which was liable to explode.  In one of his early experiments Sobrero was badly scarred when a preparation exploded in his face. He is reported to have kept his discovery secret for a year before describing the chemical which he initially referred to as pyro-glycerine from the Greek meaning fire. Sobrero also reported that nitroglycerin had a sweet aromatic taste and when he placed a trace of it on his tongue it gave rise to a violent, pulsating headache, accompanied by weakness of the limbs.

Sobrero counselled against producing nitroglycerine it because he considered it too dangerous to be of any practical use however his discovery was developed as an explosive by Alfred Nobel. Nobel combined liquid nitroglycerine with sand in tubes and invented “Dynamite”. He successfully patented this invention and became very wealthy. In 1888 a French newspaper mistook the death of his brother Ludvig for his, headlining his obituary "The merchant of death is dead” the article when on to say “Dr Alfred Nobel, who made his fortune by finding a way to kill the most people as ever before in the shortest time possible, died yesterday." Nobel became troubled by his posthumous reputation and he subsequently changed his will, bequeathing most of his fortune to the establishment of a series of prizes, so that no future obituary writer would have any doubt as to his yearning for peace and progress.”

But what of the medical use of nitroglycerine. The physician William Murrell had observed the severe pounding headache after he touched the moist cork from a bottle of nitroglycerine to his tongue.  A moment after he experience a violent pulsation in his head. Murrell decided to test the substance on a series of 35 individuals some of whom also received a placebo as a control in the experiment. He found those who took the nitroglycerine experienced same symptoms. It was obvious to Murrell that nitroglycerin produced impressive effect and together with other observations he thought the substance might be useful in treating patients with angina. He tested his theory by his experimental observation describing the case of William A in December 1877. Aged sixty-four William A complained of intense pain in the chest excited by the slightest exertion. Murrell ordered the patient to take 1% nitroglycerine solution in half an ounce of water three times a-day. One week later he reported that there had been a very great improvement with the attacks considerably reduced in frequency and when they did occur much less severe.  He also found that if taken during an attack then it would reduce the length and severity and it had always succeeded. This is how nitroglycerine became the part of the standard treatment for angina. In later life Alfred Nobel himself suffered from angina. In 1890 his physician recommended nitroglycerine is a remedy but he declined it. In this letter to his assistant Ragnar Sohlman he wrote: 'My heart trouble will keep me here in Paris for another few days at least, until my doctors are in complete agreement about my immediate treatment. Isn't it the irony of fate that I have been prescribed nitroglycerine, to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public.“

So the nitrovasodilators used to treat patients are high explosives. This is not a problem for patients because only a tiny amount of chemicals are present in medicines. But imagine you are manufacturing the substances then the amounts involved are much greater and therefore the risk of explosion very high. Although there are many different generic manufacturers of ISMO tablets all of them in the UK rely on one company Euticals to supply the API (active pharmaceutical ingredient) and this is where the current problem with the supply of ISMO lies.

In November 2012 three workers at the Euticals plant in Wales were hospitalised following a chemical spill of isosorbide dinitrate. This led to an inspection by the Health and Safety Executive and a large amount of explosive isosorbide dinitrate was discovered - not surprising in a factory that was making the chemical which is a byproduct of the manufacture of ISMO. The factory was shut down so that the isosorbide dinitrate could be chemically treated before removal from the site and made safe. This resulted in the manaufacture of ISMO stopping and the UK production of this medication effectively ceasing without warning.

Problems with toxicity of nitroglycerine in factory workers is not a new phenomenon. In the 1940's it was very common for munition workers to complain of monday morning headache because of the powerful vasodilator action of nitroglycerine which was absorbed from their skin when handling explosives. This effect wore off quite quickly during the working week due to tolerance developing. At the weekend the workers were resensitised and some even smeared nitroglycerine paste into their cap bands so that they would have a constant exposure and thus remain tolerent to the effects thus avoiding the monday morning headache.

With regards to the current problems it is thought that the supply of ISMO will not re-start until the summer of this year and so currently patients who were receiving ISMO are being offered alternative formulations which still contain the same basic ingredient but in a slow release formulation.

Powerpoint Presentation on the History of Nitroglycerine as a Treatment for Angina

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