Trimetazidine (TMZ) is a small molecule drug that is taken orally. It was invented in the 1960s by entrepreneurial French doctor, Jacques Servier, and patented and marketed by the company – Laboratoires Servier – he founded in the 1950s. TMZ belongs to a class of compounds called piperazines. The initial patents on the class of compounds seem to focus on a possible role in increasing blood flow. However, further studies suggest that its mechanism may be nothing to do with physiology (blood flow increases), but instead have a more biochemical role (inhibiting metabolic pathways). The drug was targeted as a possible treatment for angina.
Why does changing blood flow and oxygen metabolism matter in angina? Well angina is chest pain caused by decreased blood flow to the heart muscles. Accompanying the blood is of course the oxygen that is needed to fuel the heart contractions. Lack of oxygen is obviously a problem for the heart. Angina is common and treatable (hence the historic interest from pharmaceutical companies).
An acute angina attack is treated differently to long term (chronic) symptoms.
In an acute attack the goal is to increase blood flow to the heart. A class of drugs called “nitrates” are used. You are probably familiar with people reaching for their nitrate sprays or tablets when suffering an attack. Interesting the compound most commonly used is glycerol trinitrate. This is more commonly known as TNT – the explosive invented by Alfred Nobel. Intriguingly Nobel suffered from angina and was offered the TNT he invented as a treatment. He refused at the time, but it later became a standard treatment. About a hundred years after Nobel died the biological mechanism of action of TNT was discovered. TNT releases a gas called nitric oxide in the blood stream that relaxes smooth muscles and increases blood flow, easing the pain of an angina attack. For this work, in 1998, three scientists were awarded the prize that Nobel himself founded.
Chronic angina is treated by lowering the oxygen requirement for the heart, making it better able to cope with reduced blood flow. The standard treatments here are beta blocker drugs which lower the heart rate and therefore reduce the hearts demand for oxygen.
[As an aside beta blockers are banned in sports such as archery, shooting golf and ski jumping where lowering your heart rate and/or calming your nerves may be performance enhancing; in certain circumstances athletes with angina can get a Therapeutic Use Exemption (TUE) to enable their use in competition].
So why is TMZ used as a treatment for angina? Like beta blockers it is taken chronically, not to increase blood flow, but instead - it is claimed – to reduce the oxygen cost of a heart contraction. So what is its mechanism of action?
TMZ is suggested to inhibit a specific metabolic pathway; hence its appearance on the WADA list as a “metabolic modulator”. To understand how it works we need to know that there are different routes for getting useful chemical energy from the food that we eat. Three different pathways exist for fats (fatty acids) carbohydrates (glucose) and proteins (amino acids). Proteins are only a minor source of energy so we can focus on fats and carbohydrates.
The amount of chemical energy (ATP) made per molecule of oxygen consumed is measured as a P/O ratio. For a carbohydrate such as glucose this is about 2.3, whereas for a fatty acid such as palmitic acid, the number is 2.1. The difference is subtle and for those who are interested comes about because glucose can generate additional ATP via a pathway called glycolysis that is not available to fatty acids which use a process called beta oxidation instead.
It is hypothesized that TMZ inhibits an enzyme (called 3-ketoacyl coenzyme A thiolase) in the beta oxidation pathway. The heart then adjusts to use more energy via the carbohydrate (glycolytic) route. This results in less oxygen being consumed to produce the same amount of useful chemical energy (ATP). So TMZ could be useful as a treatment for angina, a condition where less oxygen is delivered to the heart muscle.
It is worth mentioning that, whilst TMZ inhibits the enzyme 3-ketoacyl coenzyme A thiolase in the test tube (in vitro), it is not completely proven that this is its major effect in the body (in vivo). TMZ can also have, for example, more direct effects on oxygen consumption in mitochondria and/or activate nitric oxide production. It can also potentially protect the heart by inhibiting cardiac fibrosis, and thus preventing thickening and inflexibility in the heart valves.
Personally, I have some suspicions about a model where TMZ works chronically via significantly altering the balance between fat and carbohydrate metabolism in the heart. These are already under tight hormonal control via insulin, thyroid hormones, growth hormone and cortisol and hormonal changes might counter any chronic effects of TMZ.
In terms of side effects, TMZ is generally well tolerated. The major concern is that in some patients it seems to trigger Parkinson Disease symptoms, such as shaking, slow movement, muscle stiffness and other motor disorders. This concern is serious enough that TMZ is not licensed at all in the USA and is only approved in Europe for treating angina – and then only as add-on to existing treatments in patients who are not adequately controlled by or who are intolerant to other medicines. In fact, when the European Medicines Agency last looked at TMZ, a minority report argued for it being completely withdrawn from use.
Of course, drug prescription is always a cost-benefit analysis. So, the chance of side effects can be tolerated if the efficacy is very high. The further reading below puts both sides of these arguments.
We shall see in the next blog if TMZ really does affect the efficiency of cardiac metabolism and what effect this might have for an athlete.
1 A paper that discusses the mechanism of action of TMZ and its possible use in treating angina and other diseases
2 A paper that describes the differences in efficiency of fat and carbohydrate oxygen metabolism.
This is a complex paper for biochemical aficionados only! But as this topic is covered so badly (and usually incorrectly!) in most text books, I felt the need to present the views of a genuine expert on this topic
3 A recent clinical trial suggesting TMZ may not be beneficial in some patients with angina
4 The European Medicine Agency report on whether – and how – TMZ should be used clinically