Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Abstract

The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic "bottleneck" in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.

The Acute Porphyric Attack: A Difficult Diagnosis for a Potential Lethal Event in Emergency Medicine

“…The restoration of a normal porphyrin metabolism in an AIP symptomatic patient (who thereafter became attack-free) after liver transplantation, confirms the key role of the liver as a source of non-porphyrin precursors in acute porphyrias [87,88]. Exogenous and endogenous factors able to induce the expression and/or the activity of ALA-S1 (as in the case of drugs or pathological conditions reducing the free heme pool) are well-known potential triggering factors of APAs [1][2][3]70].…”

“…Also the frequency and severity of APAs have a great variability: some patients experience frequent, severe and sometimes life-threatening attacks, even in the absence of exogenous precipitating factors [6]. Nevertheless, in most cases, an APA is precipitated by one or more "triggering factors", such as drugs, changes in hormone balance (as during menses or hormonal therapies), local or general anesthesia, sedative use (especially barbiturates), misuse of alcohol or illicit substances (amphetamines, cocaine and other derivatives), prolonged fasting or diet restrictions, intense mental or physical stress, or acute infections [1,2,6,70]. In women, recurrent attacks often coincide with the luteal phase of the menstrual cycle [71].…”

“…Except in the case of mild attacks, most patients require hospitalization and a continuous monitoring of neurologic status, blood pressure, heart rate, fluid and electrolyte balance, muscle, tendon and respiratory function. Symptoms (ex: systemic arterial hypertension, vomiting, seizures) should be treated avoiding porphyrinogenic drugs [7,25,70,92]. Opiates should be considered as mandatory in pain management during APA, being careful to prevent the opioid dependence in case of prolonged use [3,25].…”

“…The role of drugs in precipitating porphyric attacks, due to their possible effect on heme metabolism, is well-established; any drug treatment for a patient with porphyria should be prescribed according to an accurate reference to a drug list [3,20,70,125]. This is particularly important in surgery, many anesthetics being well-known powerful precipitant factor of acute attack [1,13,70,126,127]. Complete lists of potentially safe and unsafe drugs are continuously upgraded, and they are available on the net, at http://www.drugs-porphyria.org/ and http://www.porphyria-europe.com [89,128].…”

Prospect and progress of gene therapy in acute intermittent porphyria

“…Hormonal, metabolic, and environmental factors, such as exposure to certain drugs or reduced food intake, can contribute to the development of a symptomatic disease [10,11], as they can increase the requirement of heme and consequently induce the activation of delta-aminolevulinic acid synthase-1 (ALAS1). The induction of the rate-limiting enzyme in the heme biosynthesis pathway then leads to the production of aminolevulinic acid (ALA) and porphobilinogen (PBG), which, due to the reduced capacity of PBGD, accumulate and subsequently trigger the onset of symptoms.…”