A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

84 PHARMACOGENETICS
for Ry1R or undergo muscle biopsy to assess their predisposition
to this condition. Muscle from affected individuals is
abnormally sensitive to caffeine in vitro, responding with a
strong contraction to low concentrations. (Pharmacological
doses of caffeine release calcium from intracellular stores
and cause contraction even in normal muscle at sufficiently
high concentration.) Affected muscle responds similarly to
halothane or suxamethonium.
ACUTE PORPHYRIAS
This group of diseases includes acute intermittent porphyria,
variegate porphyria and hereditary coproporphyria. In each
of these varieties, acute illness is precipitated by drugs
because of inherited enzyme deficiencies in the pathway of
haem biosynthesis (Figure 14.5). Drugs do not precipitate
acute attacks in porphyria cutanea tarda, a non-acute porphyria,
although this condition is aggravated by alcohol,
oestrogens, iron and polychlorinated aromatic compounds.
Glycine succinyl CoA
ALA synthetase
-aminolevulinic acid (ALA)
Drug-induced exacerbations of acute porphyria (neurological,
psychiatric, cardiovascular and gastro-intestinal disturbances
that are occasionally fatal) are accompanied by
increased urinary excretion of 5-aminolevulinic acid (ALA)
and porphobilinogen. An extraordinarily wide array of drugs
can cause such exacerbations. Most of the drugs that have
been incriminated are enzyme inducers that raise hepatic ALA
synthetase levels. These drugs include phenytoin, sulphonylureas,
ethanol, griseofulvin, sulphonamides, sex hormones,
methyldopa, imipramine, theophylline, rifampicin and
pyrazinamide. Often a single dose of one drug of this type can
precipitate an acute episode, but in some patients repeated
doses are necessary to provoke a reaction.
Specialist advice is essential. A very useful list of drugs that
are unsafe to use in patients with porphyrias is included in the
British National Formulary.
GILBERT’S DISEASE
This is a benign chronic form of primarily unconjugated hyperbilirubinaemia
caused by an inherited reduced activity/lack of
the hepatic conjugating enzyme uridine phosphoglucuronyl
transferase (UGT1A1). Oestrogens impair bilirubin uptake and
aggravate jaundice in patients with this condition, as does protracted
fasting. The active metabolite of irinotecan is glucuronidated
by UGT1A1, so irinotecan toxicity is increased in
Gilbert’s disease.
Porphobilinogen (PBG)
Uroporphyrin
Coproporphyrin
PBG
deaminase
Hydroxymethylbilane
UPG III synthetase
Uroporphyrinogen (UPG) III
CO 2
Coproporphyrinogen (CPG) III
CPG
oxidase
Protoporphyrinogen (PPG)
PPG
oxidase
Protoporphyrin IX
UPG decarboxylase
Ferrochelatase
Deficient in
acute intermittent
porphyria
Deficient in
hereditary
coproporphyria
Deficient in
variegate
porphyria
Haem
Figure 14.5: Porphyrin metabolism, showing sites of enzyme
deficiency.
Case history
A 26-year-old Caucasian woman has a three-month history
of intermittent bloody diarrhoea and is diagnosed with
ulcerative colitis. She is initially started on oral prednisolone
30 mg/day and sulfasalazine 1 g four times a day with little
improvement in her colitic symptoms. Her gastroenterologist,
despite attempting to control her disease with increasing
doses of her initial therapy, reverts to starting low-dose
azathioprine at 25 mg three times a day and stopping her
sulfasalazine. Two weeks later, on review, her symptoms of
colitis have improved, but she has ulcers on her oropharynx
with a sore mouth. Her Hb is 9.8 g/dL and absolute neutrophil
count is 250/mm 3 and platelet count 85 000.
Question
What is the most likely cause of this clinical situation
Answer
The patient has haematopoietic toxicity due to azathioprine
(a prodrug of 6-MP). 6-MP is inactivated by the enzyme
thiopurine methyltransferase (TPMT). In Caucasians 0.3%
(one in 300) of patients are genetically deficient in this
enzyme because of polymorphisms in the gene (*3/*4 is
most common) and 11% of Caucasians who have a heterozygous
genotype have low levels of the enzyme. Patients
with absent or low TPMT expression are at a higher risk of
bone marrow suppression. In this patient, the azathioprine
should be stopped and her TPMT genotype defined. Once
her bone marrow has recovered (with or without
haematopoietic growth factors), she could be restarted on
very low doses (e.g 6.25–12 mg azathioprine daily).