How fumaric acid works
From a chemical point of view, fumaric acid is a dicarboxylic acid with four carbon atoms. It is used in the pharmaceutical industry for the production of drug salts (e.g. clemastine fumarate). Its esters (= compounds formed from organic acids and alcohols by splitting off water), the so-called fumarates, are used medically for the treatment of multiple sclerosis (MS) and psoriasis.
Fumaric acid & multiple sclerosis
Multiple sclerosis is an inflammatory disease of the insulating layer around the nerve pathways in the human body. The nerves in the brain and spinal cord are particularly affected. Because the insulation of the nerves is gradually broken down, the often densely packed nerve bundles fail and malfunction – similar to an electric cable.
As far as the cause of the disease is concerned, experts assume that in most cases the body’s own immune system attacks the insulation layer and causes it to break down or that the body has problems building up this very complex protective layer around the nerves.
One of these drugs contains an ester of fumaric acid called dimethyl fumarate, which was developed so that the active ingredient can be better absorbed through the intestinal wall into the blood. The compound monomethyl fumarate, which is actually active, is first formed in the body – dimethyl fumarate is therefore a prodrug (precursor of a drug).
The active ingredient is used in the treatment of a specific form of the disease – relapsing-remitting MS. In this case, the disease occurs in relapses. Between relapses, the symptoms of MS disappear completely or partially.
Diroxime fumarate, another ester of fumaric acid, is another derivative of this drug class whose active metabolite is also monomethyl fumarate. As less methanol is formed in the body when diroxime fumarate is activated, it is hoped that this will result in better tolerability in the gastrointestinal tract.
Treatment with fumaric acid also results in fewer inflammatory messengers being released by the immune system, which ultimately inhibits the progression of the disease.
Fumaric acid & psoriasis
Psoriasis is a non-contagious, inflammatory skin disease in which reddened, scaly patches of skin, usually the size of the palm of your hand, form on the knees and elbows. These areas are often very itchy.
The inflammatory process leads to increased new skin formation, but the skin cells are still too attached to each other to be removed evenly. This causes the typical scales to form. Experts believe that an increased number of immune cells can also be found in the affected areas, which is partly responsible for the inflammatory reaction.
This assumption is supported by the increased risk of inflammatory joint changes (so-called psoriatic arthritis) in the further course of the disease. It shows that psoriasis is a systemic disease, whereby the skin changes only reflect the visible part of the disease.
Absorption, breakdown and excretion
After ingestion, fumarates are rapidly converted by enzymes into their active form monomethyl fumarate. The original substances are not detectable in the blood.
Around 60 percent of the active substance is exhaled as carbon dioxide. The rest is excreted mainly via the kidneys in the urine.
When is fumaric acid used?
The derivatives of fumaric acid are used to treat
- adult patients with relapsing-remitting multiple sclerosis
- adult patients with moderate to severe psoriasis for whom external (topical) treatment, for example with creams, is not sufficient and systemic therapy (e.g. with tablets) is necessary
Due to its anti-inflammatory effect, it is used on a long-term basis.
How fumaric acid is used
Higher doses are used for the treatment of MS than for the treatment of psoriasis:
Multiple sclerosis patients start with 120 milligrams of dimethyl fumarate twice a day. After one week, the dose is increased to 240 milligrams twice a day.
For diroxime fumarate, the starting dose is 231 milligrams twice a day. After one week, the dose is increased to the recommended maintenance dose of 462 milligrams twice a day.
Lower dosages are used for the treatment of psoriasis. There is also a low-dose “starter pack”. To reduce the risk of side effects, the dose is slowly increased from one to three tablets a day over three weeks.
In the second, stronger pack, the dose is increased by one tablet a week for six weeks. If the full therapeutic effect is achieved earlier, the dose does not need to be increased any further. Here too, it is advisable to take the tablets during or immediately after a meal.
What are the side effects of fumaric acid?
The most common side effects (in more than one in ten people treated) are a feeling of heat and gastrointestinal complaints such as abdominal pain, indigestion and nausea. These may only occur initially, but can also reappear briefly during treatment with fumaric acid.
Other side effects of fumaric acid (in one in ten to one hundred patients) include changes in the blood count, itching, skin rash and increased protein excretion in the urine (an indication of kidney problems).
What should be considered when taking fumaric acid?
Contraindications
Fumaric acid and its derivatives must not be taken in the following cases of multiple sclerosis:
- Hypersensitivity to the active substance or any of the other ingredients of the medicine
Contraindications for the treatment of psoriasis (for which only dimethyl fumarate is approved) are
- hypersensitivity to the active substance or any of the other ingredients of the medicine
- severe diseases of the gastrointestinal tract
- severe liver or kidney dysfunction
- Pregnancy and breastfeeding
Interactions
As fumaric acid and its derivatives can have a negative effect on kidney function, no other active substances with similar side effects should be taken during treatment. These include, for example, methotrexate (rheumatism and cancer medication), retinoids (acne medication) and ciclosporin (immunosuppressant, for example after organ transplantation).
The simultaneous consumption of alcohol with an alcohol content of more than 30 percent can accelerate the rate of dissolution and thus lead to increased gastrointestinal side effects.
Age restriction
As there is insufficient experience of use in children and adolescents under the age of 18, it is not recommended in these cases.
Pregnancy and breastfeeding
Medicines containing fumarates for the treatment of psoriasis are contraindicated during pregnancy and breastfeeding, as there is only limited experience of their use. In addition, animal studies have shown fertility-threatening and fertility-damaging effects (reproductive toxicity).
According to experts, prednisolone or ciclosporin are the drugs of choice for severe courses of psoriasis. In multiple sclerosis, interferon beta-1a or interferon beta-1b and glatiramer acetate are recommended as immunomodulating basic therapeutics during pregnancy and breastfeeding.
How to obtain medication with fumaric acid
All preparations containing fumaric acid and its derivatives are available on prescription in Germany, Austria and Switzerland.
How long has fumaric acid been known?
Fumaric acid was first discovered in the fungus Boletus pseudoignarius and was extracted in its pure form from the common fumitory (a plant from the poppy family) in 1832. The common fumitory was already used in ancient times as a medicinal plant to treat cramps in the digestive tract and gall bladder, constipation and skin conditions.
Based on this experience, a psoriasis therapy with fumaric acid was developed in the 1970s by the doctor Günther Schäfer. Fumaric acid was not approved for the treatment of MS until 2013, after the active ingredient and its derivatives had proven effective in clinical trials.
