Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2015 Publisher: Athlone Pharmaceuticals Limited, Ballymurray, Co. Roscommon, Ireland
Pharmacotherapeutic group: Vitamin B1, Plain
ATC code: A11DA01
Thiamine pyrophosphate (TPP), the coenzymatic form of thiamine, is involved in two main types of metabolic reactions: decarboxylation of α-ketoacids (e.g. pyruvate, α-ketoglutarate and branched-chain keto acids) and transketolation (e.g. among hexose and pentose phosphates). Therefore, the principal physiological role of thiamine is as a coenzyme in carbohydrate metabolism, where TPP is required for several stages in the breakdown of glucose to provide energy.
Apart from its metabolic role as a coenzyme, thiamine plays a role in neurotransmitter function and in nerve conduction.
In high doses, thiamine suppresses the transmission of neural stimuli and thus can have an analgesic effect.
Early stages of thiamine deficiency may be accompanied by non-specific symptoms that may be overlooked or easily misinterpreted. The clinical signs of deficiency include anorexia; weight loss; mental changes such as apathy, decrease in short-term memory, confusion and irritability; muscle weakness; and cardiovascular effects such as an enlarged heart.
Cardiac failure, muscle weakness, peripheral and central neuropathy are functional consequences of severe thiamine deficiency. Clinical manifestations of beriberi (severe thiamine deficiency) vary with age. Adults may present with dry (paralytic or nervous), wet (cardiac), or cerebral (Wernicke- Korsakoff syndrome) forms of beriberi.
Thiamine is rapidly absorbed in humans, largely in the proximal small intestine. There are two mechanisms, one by a carrier mediated transport at low physiological concentrations (<2μM), one by passive diffusion at higher concentrations. Absorption is typically high, but intestinal absorption in humans is rate limiting.
The average total amount of thiamine in an adult is approximately 30mg. In general the heart has the highest concentration (0.28-0.79mg per 100g), followed by kidney (0.24-0.58mg per 100g), liver (0.20-0.76mg per 100g), and brain (0.14-0.44mg per 100g). In the spinal cord and the brain, the thiamine level is about double that of peripheral nerves. The whole-blood thiamine content varies from 5 to 12μg per 100 ml, 90% of which is in the red cells and leukocytes. Leukocytes have a 10 fold higher concentration than red cells. Thiamine has a high turnover rate in the body and is not stored in large amounts for any period of time in any tissue. When intake is about 60μg per 100g body weight (or 42mg per 70kg) and the total body thiamine reaches 2μg/g (or 140mg per 70kg), a plateau is reached in most tissues.
Thiamine transport across the blood-brain barrier involves two different mechanisms. The saturable mechanism at the blood-brain barrier, however, differs from the energy-dependent mechanism described in the gut, and from the active transport system described in cerebral cortex cells, which may be dependent upon membrane-bound phosphatases.
The immunohistochemical distribution of TTP (thiamine triphosphate) suggests that it has a role in nerve conduction.
Thiamine is quickly converted to the diphosphate and to a smaller extent the triphosphate esters in the tissues. All thiamine in excess of tissue needs, as well as binding and storage capacity, is rapidly excreted in the urine in the free form. Stimulation of nerves causes the release of thiamine or the monophosphate with a concomitant decrease in the triand diphosphates.
Thiamine is excreted in the urine. The half-life of thiamine in the body is 10-20 days. In addition to free thiamine and a small amount of thiamine diphosphate, thiochrome, and thiamine disulfide, about 20 metabolites of thiamine have been reported in the urine of rats and humans but only six have been conclusively identified. The relative proportion of metabolites to thiamine excreted increases with decreasing thiamine intake.
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.
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