Quarryman's headache: clues to drug discovery

Chemist Ascanio Sobrero

@HealthMed Glyceryl trinitrate - GTN (discovered by Italian chemist Ascanio Sobrero in 1846-1847) - is widely used to prevent or reduce angina, a key warning symptom of coronary heart disease. 

An early clue that GTN might have medicinal properties came from the observation that handling the chemical could result in severe headache. GTN is also known as nitroglycerine, an important component in early explosives.  Workers in early munitions factories developed vascular headaches. And quarrymen handling nitroglycerine-based explosives were also at risk of such severe headaches that resignation may have been preferrable to recurrent onset of these severe symptoms. 

This lead to trials of GTN in angina by Dr William Murrell, with publication of results in 1879 in the UK medical journal The Lancet, followed by increasing popularity in use of GTN as treatment. 

The major beneficial effects of GTN are due to relaxation of veins, so reducing the filling pressure in the heart. This in turn, through Starling's Law of the Heart, reduces the work of the main pumps of the heart, the ventricles. Nitric oxide is a vasodilator made in the body by the cells that line blood vessels, endothelial cells: work on this pathway resulted in the award of the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott, Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system". 

Anti-anginal effects of GTN result from the dilator response of veins to the additional nitric oxide generated from the GTN by vascular enzymes (including mitochondrial aldehyde dehydrogenase). And this effect on veins occurs at a lower concentration of the drug than needed to relax arteries. Headache as an unwanted side effect of the drug is due to an increase in blood flow in arteries in the head.  The chance of arterial headache developing can thus be minimised by spitting out any remaining GTN once angina has settled.

Footnote

There had been an earlier report in The Lancet in 1867 by Dr T. Lauder Brunton from Edinburgh on use of an organic nitrite, amyl nitrite, to treat angina. There is now evidence that nitrite may act as a chemical signal, independent of its vasodilator and other effects through conversion to nitric oxide.

William Murrell's 1879 Lancet paper.

Murrell W. Nitro-glycerine as a remedy for angina pectoris. Lancet 1879; i: 80-81.

More on the dynamite story

Shift work and cardiovascular risk

@HealthMed It is well-known that shift workers have increased risk factors for serious heart disease, for example as reported in Knuttson's 1986 Lancet paper on papermill workers. They are more likely to smoke and tend to have higher blood pressure, cholesterol and weight and be more likely to have diabetes than  workers whose work pattern is confined to the daytime. They are also more likely to have insomnia, itself an independent risk factor for cardiovascular disease. Clinical pharmacologist Daniel Hackem from Ontario and his colleagues from Norway, Sweden and the USA had now raised further public and health professional interest in this disease link in a paper published in the British Medical Journal.

They looked at 34 previous studies of over 2 million shiftworkers. Together, there were over 17,000 heart events, over 6000 heart attacks and almost 2000 strokes. They concluded that stroke risk was around 5% higher and coronary event risk 24% higher in the shift-workers. Surprisingly, despite their large dataset, the researchers found no associated increase in mortality.

They take care to point out, as with any other observational study, that this is not necessarily a cause and effect relationship. People who take on shift work may be different in some unconnected way that puts up risk of vascular disease. Lower socio-economic status is an obvious important confounder. The work itself may be more stressful, at the same time as their being fewer other staff members in support 'out of hours'. Shift workers may also take more caffeine to try to stay alert during often long shifts.

Nonetheless there are several key messages reinforced by this report.

Shift-workers are more likely to have an excess of a wide range of cardiovascular risk factors. They  should therefore be encouraged to seek regular medical advice and their employers to raise awareness of these health risks and to support their staff in seeking regular medical advice. Shift-workers should also be supported in ensuring a healthy lifestyle despite the constraints on exercise and diet of unsocial hours of work.

Clinical pharmacologists and other health professionals should make sure to take a good occupational health history, including identifying whether a patient does shift work. They should make sure particular  care is taken to identify and reduce severity of cardiovascular risk factors in shift workers, supported by effective regular advice on healthy lifestyle. And where drug treament is indicated, prescribing treatment targets should be adjusted to take account of the increased cardiovascular risk to be prevented.

Employers should also make sure that patterns of shift work follow international guidance regarding avoiding abrupt shift changes, maximum shift duration and ensuring sufficient staff are working 'out of hours' to ensure that work is done both safely for employers' outcomes as well as their workers' health.