A Textbook of Clinical Pharmacology and Therapeutics

EXAMPLES OFALLERGIC ANDOTHERADVERSEDRUGREACTIONS 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 chlorpromazineand 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 acidand 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
   chloramphenicoland (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 impli-
   cated 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,
chlorpromazineand anticonvulsants) produce a syndrome
that resembles systemic lupus together with a positive anti-
nuclear factor test. The development of this is closely related
to dose, and in the case of hydralazineit also depends on the
rate of acetylation, which is genetically controlled (Chapter
14). There is some evidence that the drugs act as haptens, com-
bining 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 suscep-

tible patients; Chapters 26 and 28). Nephrotic syndrome

results from several drugs (e.g. penicillamine, high-dose cap-

topril,gold salts) which cause various immune-mediated

glomerular injuries. Interstitial nephritis can be caused by sev-

eral drugs, including non-steroidal anti-inflammatory drugs

and penicillins, especially meticillin.Cisplatin, aminoglyco-

sides,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 con-

sequent upon initiation of chemotherapy in patients with

haematological malignancy, and – rarely – poorly soluble

drugs, such as sulphonamides, methotrexateorindinavir, 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 fea-

tures) as a side effect of drugs is important. It may be insidi-

ous, leading slowly to end-stage cirrhosis (e.g. during chronic

treatment with methotrexate) or acute and fulminant (as in

some cases of isoniazid,halothaneorphenytoinhepatitis).

Chlorpromazineorerythromycinmay cause liver involve-

ment characterized by raised alkaline phosphatase and biliru-

bin (‘obstructive’ pattern). Gallstones (and mechanical

obstruction) can be caused by fibrates and other lipid-lowering

drugs (Chapter 27), and by octreotide, a somatostatin ana-

logue used to treat a variety of enteropancreatic tumours,

including carcinoid syndrome and VIPomas (vasoactive intes-

tinal polypeptide) (see Chapter 42). Immune mechanisms are

implicated in some forms of hepatic injury by drugs, but are

seldom solely responsible.