Genetic Constitution

Inherited factors that influence response to drugs are discussed in general under Pharmacogenetics (p. 122). It is convenient here to describe the porphyrias, a specific group of disorders for which careful prescribing is vital.

The porphyrias comprise a number of rare, genetically determined single enzyme defects in haem biosynthesis. Acute porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are characterised by severe attacks of neurovisceral dysfunction precipitated principally by a zvide variety of drugs (and also by alcohol, fasting, and infection); nonacute porphyrias (porphyria cutanea tarda, erythropoietic protoporphyria and congenital erythropoietic porphyria) present with cutaneous photosensitivity for which alcohol (and

8 Fogel B S 1983 New England Journal of Medicine 308:1600.

prescribed oestrogens in women) is the principle provoking agent.

In healthy people, forming haemoglobin for their erythrocytes and haem-dependent enzymes, the rate of haem synthesis is controlled by negative feedback according to the amount of haem present. When more haem is needed there is increased production of the rate-controlling enzyme delta-aminolaevulirtic acid (ALA) synthase which provides the basis of the formation of porphyrin precursors of haem. But in people with porphyria one or other of the enzymes that convert the various porphyrins to haem is deficient and so porphyrins accumulate. A vicious cycle occurs: less haem —> more ALA synthase —> more porphyrin precursors, the metabolism of which is blocked, and a clinical attack occurs.

It is of interest that those who inherited acute intermittent porphyria and variegate porphyria suffered no biological disadvantage from the natural environment and bred as well as the normal population until the introduction of barbiturates and sulphonamides. They are now at serious disadvantage, for many other drugs can precipitate fatal acute attacks.

The exact precipitating mechanisms are uncertain. Increase in the haem-containing hepatic oxidising enzymes of the cytochrome P450 group causes an increased demand for haem. Therefore drugs that induce these enzymes would be expected to precipitate acute attacks of porphyria and they do so; tobacco smoking may act by this mechanism. Apparently unexplained attacks of porphyria should be an indication for close enquiry into all possible chemical intake. Guaiphenesin, for example, is hazardous; it is included in a multitude of multi-ingredient cough medicines (often nonprescription). Patients must be educated to understand their condition, to possess a list of safe and unsafe drugs, and to protect themselves from themselves and from others, including prescribing doctors.

The greatest care in prescribing for these patients is required if serious illness is to be avoided. Patients (1 in 10 000 UK population) are so highly vulnerable that lists of drugs known or believed to be unsafe are available, e.g. in the British National Formulary. Additionally, we provide a table of drugs considered safe for use in the acute porphyrias at the time of publication (Table 8.2). The list is revised regularly, mostly with additions made as information becomes available. Updated information can be obtained.9

Use of a drug about which there is uncertainty may be justified. Dr M. Badminton writes: 'Essential treatment should never be withheld, especially for a condition that is serious or life-threatening. The clinician should assess the severity of the condition and the activity of the porphyria. If no recognised safe option is available, a reasonable course is to:

1. Measure urine porphyrin and porphobilinogen before starting treatment.

2. Repeat the measurement at regular intervals or if the patient has symptoms in keeping with an acute attack. If there is an increase in the precursor levels, stop the treatment and consider giving haem arginate for acute attack (see below).

3. Contact an expert centre for advice.'

In the treatment of the acute attack it is rational to use any safe means of depressing the formation of ALA-synthase. Haem arginate (human haematin) infusion, by replenishing haem and so removing the stimulus to ALA-synthase, is effective if given early, and may prevent chronic neuropathy. Additionally, attention to nutrition, particularly the supply of carbohydrate, relief of pain (with an opioid), and of hypertension and tachycardia (with a (3-adreno-ceptor blocker) are important. Hyponatraemia is a frequent complication, and plasma electrolytes should be monitored.

In the treatment of the acute attack it would seem rational to use any safe means of depressing the formation of ALA-synthase. Indeed, haem arginate (human haematin) infusion, by replenishing haem and so removing the stimulus to ALA-synthase, appears to be effective if given early, and may prevent chronic neuropathy. Additionally, attention to nutrition, particularly the supply of carbohydrate, relief of pain (with opioid), and of hypertension and tachycardia (with propranolol) are important.

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