A Textbook of Clinical Pharmacology and Therapeutics

lipoprotein (LDL) is impaired. LDL receptors are needed for
hepatic uptake of LDL and individuals with FH consequently
have very high circulating concentrations of LDL, and suffer
from atheromatous disease at a young age. Homozygotes
completely lack the ability to synthesize LDL receptors and
may suffer from coronary artery disease in childhood, whereas
the much more common heterozygotes have intermediate
numbers of receptors between homozygotes and healthy indi-
viduals, and commonly suffer from coronary disease in young
adulthood.β-Hydroxy-β-methylglutaryl coenzyme A (HMG
CoA) reductase inhibitors (otherwise known as statins, an
important class of drug for lowering circulating cholesterol lev-
els) function largely by indirectly increasing the number of
hepatic LDL receptors. Such drugs are especially valuable for
treating heterozygotes with FH, because they restore hepatic
LDL receptors towards normal in such individuals by increas-
ing their synthesis. In contrast, they are relatively ineffective in
homozygotes because such individuals entirely lack the genetic
material needed for LDL-receptor synthesis.

INHERITED DISEASES THAT PREDISPOSE

TO DRUG TOXICITY

GLUCOSE-6-PHOSPHATE DEHYDROGENASE

DEFICIENCY

Glucose-6-phosphatase dehydrogenase (G6PD) catalyses the
formation of reduced nicotinamide adenine dinucleotide phos-
phate (NADPH), which maintains glutathione in its reduced
form (Figure 14.4). The gene for G6PD is located on the
X-chromosome, so deficiency of this enzyme is inherited in a
sex-linked manner. G6PD deficiency is common, especially in
Mediterranean peoples, those of African or Indian descent and
in East Asia. Reduced enzyme activity results in methaemoglo-
binaemia and haemolysis when red cells are exposed to oxidiz-
ing agents (e.g. as a result of ingestion of broad beans (Vicia
faba), naphthalene or one of several drugs). There are over 80
distinct variants of G6PD, but not all of them produce haem-
olysis. The lower the activity of the enzyme, the more severe is
the clinical disease. The following drugs can produce haemol-
ysis in such patients:

1. analgesics – aspirin;
   2.antimalarials – primaquine,quinacrine,quinine;
   3.antibacterials – sulphonamides, sulphones,
   nitrofurantoin, fluoroquinolones: ciprofloxacin
   4.miscellaneous – quinidine,probenecid.

Patients with G6PD deficiency treated with an 8-aminoquino-
line (e.g. primaquine) should spend at least the first few
days in hospital under supervision. If acute severe haemolysis
occurs,primaquinemay have to be withdrawn and blood
transfusion may be needed. Hydrocortisoneis given intra-
venously and the urine is alkalinized to reduce the likelihood
of deposition of acid haematin in the renal tubules. The

high incidence of this condition in some areas is attributed

to a balanced polymorphism. It is postulated that the selec-

tive advantage conferred on heterozygotes is due to a protec-

tive effect of partial enzyme deficiency against falciparum

malaria.

METHAEMOGLOBINAEMIA

Several xenobiotics oxidize haemoglobin to methaemoglobin,

including nitrates, nitrites, chlorates, sulphonamides, sul-

phones, nitrobenzenes, nitrotoluenes, anilines and topical local

anesthetics. In certain haemoglobin variants (e.g. HbM, HbH),

the oxidized (methaemoglobin) form is not readily converted

back into reduced, functional haemoglobin. Exposure to the

above substances causes methaemoglobinaemia in individuals

with these haemoglobin variants. Similarly, nitrites, chlorates,

dapsoneandprimaquinecan cause cyanosis in patients with a

deficiency of NADH-methaemoglobin reductase.

MALIGNANT HYPERTHERMIA

This is a rare but potentially fatal complication of general

anaesthesia (Chapter 24). The causative agent is usually an

inhalational anaesthetic (e.g. halothane,isoflurane) and/or

suxamethonium. Sufferers exhibit a rapid rise in temperature,

muscular rigidity, tachycardia, increased respiratory rate,

sweating, cyanosis and metabolic acidosis. There are several

forms, one of the more common ones (characterized by

halothane-induced rigidity) being inherited as a Mendelian

dominant. The underlying abnormality is a variant in the

ryanodine R1 receptor (Ry1R) responsible for controlling

intracellular calcium flux from the sarcolemma. The preva-

lence is approximately 1:20 000. Individuals can be genotyped

INHERITEDDISEASES THATPREDISPOSE TODRUGTOXICITY 83

Methaemoglobin

GSH

Reduced glutathione

Glucose-

6-phosphate

Glucose-6-phosphate

dehydrogenase

6-phosphogluconate

NADP NADPH

GSSG

Oxidized glutathione

Haemoglobin

Figure 14.4:Physiological role of glucose-6-phosphate

dehydrogenase.