Clinical Pharmacology and Therapeutics

EXAMPLES OF ALLERGIC AND OTHER ADVERSE DRUG REACTIONS 69
predisposes to non-immune haemolysis (e.g. primaquine).
Immune mechanisms include the following:
1. Combination of the drug with the red-cell membrane,
with the conjugate acting as an antigen. This has been
shown to occur with penicillin-induced haemolysis, and
may also occur with chlorpromazine and sulphonamides.
2. Alteration of the red-cell membrane by the drug so that it
becomes autoimmunogenic. This may happen with
methyldopa, and a direct positive Coombs’ test develops
in about 20% of patients who have been treated with this
drug for more than one year. Frank haemolysis occurs in
only a small proportion of cases. Similar changes can take
place with levodopa, mefenamic acid and beta-lactam
antibiotics.
3. Non-specific binding of plasma protein to red cells, and
thus causing haemolysis. This is believed to occur with
cephalosporins.
Aplastic anaemia as an isolated entity is not common, but
may occur either in isolation or as part of a general depression
of bone marrow activity (pancytopenia). Examples include
chloramphenicol and (commonly and predictably) cytotoxic
drugs.
Agranulocytosis can be caused by many drugs. Several
different mechanisms are implicated, and it is not known
whether allergy plays a part. The drugs most frequently implicated
include the following:
• most cytotoxic drugs (Chapter 48);
• antithyroid drugs (methimazole, carbimazole,
propylthiouracil; Chapter 38);
• sulphonamides and sulphonylureas (e.g. tolbutamide,
glipizide; Chapter 37);
• antidepressants (especially mianserin; Chapter 20) and
antipsychotics (e.g. phenothiazines, clozapine; Chapter 20);
• anti-epileptic drugs (e.g. carbamazepine, felbamate;
Chapter 22).
SYSTEMIC LUPUS ERYTHEMATOSUS
Several drugs (including procainamide, isoniazid, hydralazine,
chlorpromazine and anticonvulsants) produce a syndrome
that resembles systemic lupus together with a positive antinuclear
factor test. The development of this is closely related
to dose, and in the case of hydralazine it also depends on the
rate of acetylation, which is genetically controlled (Chapter
14). There is some evidence that the drugs act as haptens, combining
with DNA and forming antigens. Symptoms usually
disappear when the drug is stopped, but recovery may
be slow.
VASCULITIS
Both acute and chronic vasculitis can result from taking
drugs, and may have an allergic basis. Acute vasculitis with
purpura and renal involvement occurs with penicillins,
sulphonamides and penicillamine. A more chronic form can
occur with phenytoin.
RENAL DYSFUNCTION
All clinical manifestations of renal disease can be caused by
drugs, and common culprits are non-steroidal anti-inflammatory
drugs and angiotensin-converting enzyme inhibitors (which
cause functional and usually reversible renal failure in susceptible
patients; Chapters 26 and 28). Nephrotic syndrome
results from several drugs (e.g. penicillamine, high-dose captopril,
gold salts) which cause various immune-mediated
glomerular injuries. Interstitial nephritis can be caused by several
drugs, including non-steroidal anti-inflammatory drugs
and penicillins, especially meticillin. Cisplatin, aminoglycosides,
amphotericin, radiocontrast media and vancomycin
cause direct tubular toxicity. Many drugs cause electrolyte or
acid-base disturbances via their predictable direct or indirect
effects on renal electrolyte excretion (e.g. hypokalaemia and
hypomagnesaemia from loop diuretics, hyperkalaemia from
potassium-sparing diuretics, converting enzyme inhibitors
and angiotensin II receptor antagonists, proximal renal
tubular acidosis from carbonic anhydrase inhibitors), and
some cause unpredictable toxic effects on acid-base balance
(e.g. distal renal tubular acidosis from amphotericin).
Obstructive uropathy can be caused by uric acid crystals consequent
upon initiation of chemotherapy in patients with
haematological malignancy, and – rarely – poorly soluble
drugs, such as sulphonamides, methotrexate or indinavir, can
cause crystalluria.
OTHER REACTIONS
Fever is a common manifestation of drug allergy, and
should be remembered in patients with fever of unknown
cause.
Liver damage (hepatitis with or without obstructive features)
as a side effect of drugs is important. It may be insidious,
leading slowly to end-stage cirrhosis (e.g. during chronic
treatment with methotrexate) or acute and fulminant (as in
some cases of isoniazid, halothane or phenytoin hepatitis).
Chlorpromazine or erythromycin may cause liver involvement
characterized by raised alkaline phosphatase and bilirubin
(‘obstructive’ pattern). Gallstones (and mechanical
obstruction) can be caused by fibrates and other lipid-lowering
drugs (Chapter 27), and by octreotide, a somatostatin analogue
used to treat a variety of enteropancreatic tumours,
including carcinoid syndrome and VIPomas (vasoactive intestinal
polypeptide) (see Chapter 42). Immune mechanisms are
implicated in some forms of hepatic injury by drugs, but are
seldom solely responsible.