A Textbook of Clinical Pharmacology and Therapeutics

dinucleotide (NAD) and nicotinamide adenine dinucleotide
phosphate (NADP). Niacin can be generated in the body in
small amounts from tryptophan. Deficiency of niacin causes
pellagra, that can manifest clinically as a syndrome complex
which includes dementia, dermatitis and diarrhoea.
Uses
1. Niacin is used to treat and prevent pellagra. If oral
treatment is not possible, intravenous injections are
available.
2. Nicotinic acid (or nicotinic acid analogues, e.g. acipomox)
may be used to treat dyslipidaemia (Chapter 27), but
hypolipidaemic dosing is limited by
vasodilatation/flushing.
Adverse effects
In replacement therapy for pellagra, adverse effects are
uncommon. High doses (as used for hyperlipidaemia) cause
the following:
1. vasodilatation due to prostaglandin D 2 – this can be
reduced by premedication with aspirin;
2. nausea, vomiting and itching;
3. hyperglycaemia;
4. exacerbation of hyperuricaemia.
Pharmacokinetics
Both niacin and nicotinamide are well absorbed via the intestine
and are widely distributed to tissues. When the usual dietary
amounts are administered, a high proportion is excreted as
N-methyl nicotinamide and other metabolites. When increased
doses are administered, a higher proportion is excreted
unchanged in the urine.
VITAMIN B 6 (PYRIDOXINE)
Physiology
Vitamin B6 occurs naturally in three forms, namely pyridoxine,
pyridoxal and pyridoxamine. All three forms are converted
in the body into pyridoxal phosphate, which is an
essential cofactor in several metabolic reactions, including
decarboxylation, transamination and other steps in amino
acid metabolism. Pyridoxine is present in wheatgerm, yeast,
bran, rice and liver. Deficiency causes glossitis, seborrhoea, fits,
peripheral neuropathy and sideroblastic anaemia. Isoniazid
prevents the activation of pyridoxal to pyridoxal phosphate
by inhibiting the enzyme pyridoxal kinase, and slow acetylators
of isoniazid are at increased risk of developing peripheral
neuropathy for this reason (Chapters 14 and 44).
Use
Pyridoxine hydrochloride is given to patients at risk (e.g. alcoholics)
during long-term therapy with isoniazid to prevent
peripheral neuropathy, and in deficiency states. Large doses
are used in sideroblastic anaemia. Pyridoxine is also used to
treat certain uncommon inborn errors of metabolism, including
primary hyperoxaluria. Large doses are sometimes used
to treat premenstrual syndrome, and there is a lobby of enthusiasts
for this, despite a paucity of evidence.
Adverse effects
There have been reports of ataxia and sensory neuropathy following
administration of large doses (2 g/day) of pyridoxine
for more than two months.
VITAMIN C (ASCORBIC ACID)
VITAMIN C(ASCORBIC ACID) 267
Physiology
Ascorbic acid is present in large quantities in citrus fruits,
tomatoes and green vegetables. Vitamin C is essential to
humans, monkeys and guinea pigs which, unlike other mammals,
cannot synthesize it from glucose. Dietary lack of vitamin
C causes scurvy, which is characterized by bleeding gums
and perifollicular purpura. Ascorbic acid is involved in several
metabolic processes (Figure 35.2). It is a potent watersoluble
anti-oxidant. The nutritional status of vitamin C can
be assessed by measuring the intracellular leukocyte concentration,
but this is not routinely performed or available.
Uses
1. Ascorbic acid is used in the prophylaxis and treatment of
scurvy. (Perhaps the first recorded clinical trial involved
the distribution of citrus fruit to some, but not all, British
naval vessels and observation of the incidence of scurvy.
The Admiralty were (after some prevarication) convinced
and British sailors were subsequently provided with
limes – whence the term ‘limeys’.)
2. Ascorbic acid increases the absorption of orally
administered iron.
3. The reducing properties of ascorbate may be used in the
treatment of methaemoglobinaemia.
4. In scorbutic patients, wound healing is delayed and this is
restored to normal by administration of ascorbic acid.
Adverse effects
Ascorbic acid is non-toxic in low doses. However, administration
of �4 g daily raises the urinary excretion of oxalate. Large
Anti-oxidant
CYP450
drug-metabolizing
enzyme function
Collagen
biosynthesis
VITAMIN C
Folic acid
activation
Figure 35.2: Functions of vitamin C.
Steroid
metabolism
Mitochondrial
electron transport
chain function