acute porphyria and unsafe drugs

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Clinical features of acute porphyria
The clinical manifestations of an acute attack are very diverse and the condition may be indistinguishable from many other disorders. The common neurovisceral symptoms of acute porphyric attacks are listed in Table 12.5.7 and, of these, abdominal pain is the most common presenting symptom. The pain itself may be difficult to identify since it is usually constant but poorly localized and usually unassociated with tenderness. There may be an associated colicky component and later ileus with abdominal distension which may mimic a surgical emergency. Constipation is a characteristic symptom but diarrhoea with increased borborygmi can also occur. The patient is usually markedly distressed and tachycardia is the rule.
Development of pain in the limbs is a frequent feature, particularly in the upper thighs and also in other somatic muscles of the chest, lumbar region, shoulders, and neck. Ultimately, muscle weakness and respiratory paralysis may occur. The patient becomes restless or frankly disturbed or deluded as in a toxic confusional state. The inability of attending medical personnel to identify the cause of the pain and the distress associated with it often leads to alienation and an exaggeration of the patient’s complaints which may be difficult to diagnose; often a suggestion of hysterical conversion syndrome or worse, malingering, is made by attending staff. Hypertension, sweating, and tremor together with tachycardia indicate marked sympathetic overactivity, and cardiac arrhythmias may ensue. In about 10 per cent of severe attacks grand mal seizures develop, treatment of which may prolong the attack since many anticonvulsants are highly porphyrinogenic. With sustained attacks there may be signs of a peripheral neuropathy that is related to axonal degeneration, principally affecting motor nerves. Peripheral neuropathy in its early stages may not affect the limb and tendon reflexes but with time these will be decreased or absent. In prolonged porphyric attacks, an ascending muscle weakness rapidly affecting the respiratory muscles and diaphragm and with bulbar paralysis may lead to ventilatory failure and death, if lifesaving cardiorespiratory resuscitation and intensive care measures are delayed.
In a full-blown attack, mental symptoms including anxiety, sleeplessness, and depression are often prominent; the terrifying nature of the illness only aggravates the patient’s distress. If the porphyric attack is sustained as a result of failed diagnosis or inadequate management, progressive alienation, visual and auditory hallucinations, and frank paranoia with homicidal outbursts may occur. Such disturbances are difficult to contain within the environment of the busy acute hospital. Although seizures may be a presenting sign of the acute attack, they often occur in association with fulminant hyponatraemia resulting from the inappropriate secretion of antidiuretic hormone and other rapid disturbances of sodium metabolism, including excess renal excretion. Treatment of hyponatraemia due to this cause in the acute attack poses special difficulties (see below). The use of large volumes of hypotonic dextrose will aggravate the hyponatraemia—and seizures—and may induce fatal cerebral herniation due to severe brain oedema.

Diagnosis of the acute attack is suspected on the basis of the past history, including photosensitivity or the intermittent discolouration of urine. The passage of frank wine-coloured or permanganate-coloured urine is unusual but if present indicates a full-blown established attack. The family history is often informative, with a history of abdominal pain in first-degree family members, with or without photosensitivity. Confirmation of an acute attack of porphyria requires the demonstration of increased porphyrin precursors in the urine. Most commonly, increased excretion of the monopyrrole, porphobilinogen, is accompanied by increased excretion of urinary 5-aminolaevulinate. However, porphobilinogen excretion is not increased in the rare aminolaevulinate dehydratase deficiency or in the pseudoporphyria of lead poisoning.

Acute attacks of porphyria appear to be more common in women as a result of changes in sex steroids, and many women who have periodic attacks do so in the 1 or 2 days before the onset of menstrual bleeding; as the menopause approaches, the pattern may worsen, but with the onset of oligomenorrhoea or amenorrhoea, severe attacks of porphyria usually cease. Sometimes, acute attacks lasting a day or two may have their onset in the midmenstrual period around the time of ovulation. Many mild attacks of porphyria resolve spontaneously within a few days, either as a result of withdrawal of the precipitating factor or because of natural hormonal rhythms. Prolonged attacks are usually the consequence of multiple factors and delays in the institution of definitive therapy. The ensuing neurological injury, accompanied in severe attacks by bulbar and respiratory paralysis, may lead to prolonged or permanent disability. Experience shows that in many such cases inappropriate drugs have been given to counter the early manifestations of the condition, e.g. analgesics, psychotropic drugs, and anticonvulsants. Thus the initiating medical interventions ultimately prove to be critical determinants of outcome where the diagnosis is not suspected or, if known, has been perilously ignored.

Individual drugs unsafe in acute porphyria
Alcohol Erythromycin Nifedipine
Aluminium-containg antacids Ethamsylate Nitrofurantoin
Aminoglutethimide Ethionamide Orphenadrine
Amiodarone Ethosuximide Oxybutynin
Azopropazone Etomidate Oxycodone
Baclofen Fenfluramine Oxymetazoline
Bromocriptine Flucloxacillin Oxytetracycline
Busulphan Flupenthixol Pentazocine
Captopril Griseofulvin Phenoxybenzamine
Carbamazepine Halothane Phenylbutazone
Carisoprodol Hydralazine Phenytoin
Chloral hydrate Hyoscine Piroxicam
Chlorambucil Isometheptene mucate Prilocaine
Chloramphenicol Isoniazid Pyrazinamide
Chloroform Ketoconazole Ranitidine
Clonidine Lignocaine Rifabutin
Cocaine Lisinoprila Rifampicin
Colistin Loxapine Simvastatin
Cyclophosphamide Mebeverine Sulphinpyrazone
Cycloserine Mefenamic acid Sulpiride
Cyclosporin Meprobamate Tamoxifen
Danazol Methotrexate Theophylline
Dapsone Methyldopa Thioridazine
Dexfenfluramine Metoclopramide Tinidazole
Dextropropoxyphene Metyrapone Triclofos
Diclofenac Miconazole Trimethoprim
Doxycycline Mifepristone Valproate
Enconazole Minoxidil Verapamil
Enflurane Nalidixic acid Zuclopenthixol
From the British National Formulary (2001).

Published by the British Medical Association and Royal Pharmaceutical Society of Great Britain.

a In previous editions. This author has associated the agent with induction of porphyria.

The following drugs are thought to be safe in acute porphyrias:

Antihistamines: cetirizine, chlorpheniramine, cyclizine.

Diuretics: acetazolamide, amiloride, bumetanide, cyclopenthiazide, triamterene.

Ergot derivatives: oxytocin is probably safe.

Sulphonylureas: glipizide.

Analgesics: morphine, diamorphine, codeine, dihydrocodeine, fentanyl, and pethidine are safe.

Tranquillizers: chlorpromazine, haloperidol.

Local anaesthetics: bupivacaine, lignocaine can be used with caution.

Antimicrobials: rifamycins have been used without ill effect in some patient