Drugs and acute porphyrias: reasons for a hazardous relationship.

C L I N I C A L F E AT U R E S

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

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DOI: 10.3810/pgm.2014.11.2839

Giulia Roveri, MD Fabio Nascimbeni, MD Emilio Rocchi, MD Paolo Ventura, MD Centre for Porphyrias and Diseases from Disturbances of Amino Acid Metabolism, Division of Internal Medicine II, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy

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. Keywords: biochemical mechanism; enzymatic deficiency; heme biosynthesis; porphyrias

Introduction

Correspondence: Paolo Ventura, MD, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Policlinico Hospital of Modena, Largo del Pozzo 71, 41124 Modena, Italy. Tel: 39-059-4225542 Fax: 39-059-4224363 E-mail: [email protected]

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Porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis.1–4 They can be considered as storage diseases, because the partial enzymatic defect gives rise to an accumulation of different metabolic intermediates, whose toxicity is responsible for the peculiar clinical pictures of these diseases. In the acute porphyrias, the serious (and potentially fatal) clinical neurovisceral symptoms (acute porphyric attacks [APAs]) are mainly ascribed to the accumulation of neurotoxic nonporphyrin precursors (mainly deltaaminolevulinic acid [ALA] and porphobilinogen [PBG]; Figure 1). Many different factors, both endogenous and exogenous, are known to influence the metabolism of heme, favoring the accumulation of these precursors, thus contributing to trigger APAs in patients who are carriers of genetic mutations responsible for acute porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and the very rare delta-aminolevulinic acid dehydratase porphyria).5,6 To date, many different drugs are known to be capable of precipitating an APA, so that acute porphyrias are also considered as pharmacogenetic or toxicogenetic diseases.5,7,8 This paper article

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Drugs and Acute Porphyrias


Figure 1. Schematic representation of heme metabolism.

reviews the different biochemical mechanisms underlying the capacity of some drugs to precipitate an APA (drug porphyrogenicity) in carriers of genetic mutations that are responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.

Material and Methods

PubMed, Medline, and Embase were searched for studies and review articles, and key references within articles, related to the mechanisms of drug induction of APA in acute porphyrias. We used the search terms drug and drugs combined with each of the following: porphyrias, cytochromes, ALAsynthase, heme-oxygenase, heme, haem, acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and ALA-d deficiency porphyria. No formal evaluation of the

level of evidence was conducted in developing this narrative review.

Metabolism of Heme and Its Regulation

Heme, the most important porphyrin in mammals, results from the incorporation of ferrous iron into the tetrapyrrole ring of protoporphyrin IX. Due to the peculiar biological properties of the tetrapyrrolic structure, heme constitutes the active site of many enzymes that participate in different and essential biological reactions, such as cellular respiration, the metabolism of steroid hormones and of many xenobiotics (including lipophilic drugs), the resistance to oxidative stress, and the biosynthesis of different important intracellular messengers (eg, cyclic guanosine monophosphate). Furthermore, as it is the prosthetic group of hemoglobin,


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heme ensures gas transport (oxygen, carbon dioxide) by erythrocytes.9–11


Heme Biosynthesis

The complex biosynthesis of heme is achieved by a series of biochemical reactions catalyzed by 8 dedicated enzymes, which are compartmentalized within the cell: the first and the last 3 reactions of the metabolic sequence occur inside the mitochondria, whereas the intermediate reactions take place within the soluble fraction of cytoplasm (Figure 1).7,9,10,12 The bulk of the biosynthesis of heme occurs in erythroid cells (within the bone marrow) and corresponds to the amount necessary for hemoglobin formation. However, all cells containing mitochondria can synthesize heme, and about 15% of the daily production occurs in the liver, to produce heme proteins, especially as different groups of cytochromes.7,9,10,12 The biosynthesis of heme is a very effective process; indeed, under normal conditions, < 2% of precursors (as both porphyrins and nonporphyrin precursors) are produced in excess during the process. Therefore, the finding of high concentrations of intermediates of the heme biosynthetic process in biological samples (plasma, urine, and stool) should suggest some kind of disturbance in the heme metabolism, mostly due to a different grade of block in the metabolic pathway.3,7,13

Table 1. Compounds and Conditions Known to Induce the Expression of HO-1 Compounds or conditions

Examples

Heme compounds

Hemin,69 hemoglobin70; co-protoporphyrin71

Therapeutic agents

Aspirin72; paclitaxel73; rapamycin74; statins75 (not atorvastatin76); no releasing molecules77; sildenafil78; isoproterenol79; probucol80; carvedilol,81 griseofulvin55

Hormones

Epinephrine82; thyroid hormones83; angiotensin II84; insulin85; glucagon86; cytokines15,87 (transforming growth factor-β88); atrial natriuretic peptide89

Endogenous mediators

Nitric oxide90; prostaglandins (J291); lipoxins92; eicosanoids93; cyclic guanosine monophosphate94

Natural antioxidants compounds contained in food and plants

Curcumin95; flavonoids96; garlicderived organosulfur compounds97; isothiocyanates98; resveratrol99; anthocyanins100; rosolic acid101; caffeic acid phenethyl ester102; gingko biloba103

Biologic and other stress conditions

Ultraviolet A104; heat shock105; shear stress106; endotoxins107; bacterial antigenic substances (BCG and Corynebacterium parvum108); hypoxia109; hyperoxia110; hydrogen peroxide104; fasting and hypoglycemia111

Chemicals

Heavy metals112 and heavy metal salts (cadmium chloride104); pesticides (sodium arsenite113); halogenated hydrocarbons82; organic solvents and reagents (carbon disulfide, bromobenzene, carbon tetrachloride).82

Tumor promoters

Phorbol esters114,115

Heme Catabolism

Heme oxygenase (HO) is the main enzyme responsible for heme catabolism. It catalyzes the stereospecific degradation of heme to biliverdin, with the concurrent release of iron and carbon monoxide (Figure 1).14 In mammals, biliverdin is then transformed to bilirubin by the action of the cytosolic enzyme biliverdin reductase; bilirubin is subsequently conjugated with glucuronic acid (by uridine diphosphoglucuronosyl transferases [UGTs]) and then excreted into the bile. Many different cell types, such as those of the liver, kidney, brain, and gut, have demonstrated an ability to catalyze heme transformation to biliverdin in culture.14,15 In humans, there are 2 HO isoenzymes (HO-1 and HO-2). Each is a product of 2 distinct genes and has 2 different types of regulation16–19; HO-2 seems to be constitutively expressed, whereas HO-1 seems to be inducible by a large number of structurally different pharmacological and nonpharmacological compounds, as well as by a variety of conditions, such as heat shock or different conditions of cellular stress. It is well known that HO-1 activity is significantly increased in most tissues after exposure to its natural substrate, heme, as well as after exposure to various metals or synthetic 110

metalloporphyrins, xenobiotics, or different endocrine factors (Table 1).14,20 Conversely, the exact function of HO-2 in tissues is not completely understood yet, though its critical role in cell development and signal transduction (especially in nervous tissue) is emerging. Great variability in the tissue distribution of both isoforms of HO has been observed; in particular, the basal expression of constitutive HO-2 protein varies significantly in different tissues.14

Regulation of Heme Tissue Levels: Differences in Erythroid and Nonerythroid Tissues

Closely linked processes of synthesis and degradation maintain heme tissue levels. Figure 2 demonstrates the regulation of the heme metabolism. The rate-limiting enzyme of the whole biosynthetic process of heme is believed to be




Figure 2. Schematic representation of the regulation of heme metabolism.

Abbreviation: ROS, reactive oxygen species.

5-aminolevulinate synthase (ALA-S; and, in part, PBG deaminase); this enzyme exists in two isoforms: erythroid (ALA-S2) and nonerythroid (ALA-S1, or ubiquitous isoform).7,21,22 Heme is a potent inhibitor of both the expression and the activity of ALA-S1, the rate-limiting enzyme in the heme synthetic pathway. Many different drugs and chemical compounds, through interaction with the nuclear receptors constitutively active receptor (CAR)/pregnane xenobiotics receptor (PXR), may stimulate ALA-S1 expression; even drugs blocking activity of cytochrome P-450 (CYP) 3A4/2C9 may act as stimulators of ALA-S1. Heme is also a potent inducer of HO-1 activity and expression, and of many different drugs and chemical compounds or physiological/ physiopathological conditions (see Table 1). The dual nature of ALA-S reflects different regulatory mechanisms; in the liver, all the enzymes involved in heme synthesis are extremely effective and subjected to a rapid turnover (the mitochondrial ALA-S1 half-life is estimated to be 30 minutes to 1 hour) and synthesis, making it possible for the hepatocytes to respond properly to changes in metabolic needs.13,23 The continuous and immediate availability of heme is ensured by the immediate (in a few hours) induction of the expression of the ubiquitary isoform of the 5-aminolevulinate synthase (ALA-S1), in response to a reduction of the intracellular free heme pool, a condition that may follow both an increase in cellular requirement of heme proteins

and an increase of heme catabolism. In contrast, high levels of cellular heme represses the expression of ALA-S1 (and stimulates heme degradation through the induction of HO), thus reducing the free heme pool. Heme also inhibits the transport of ALA-S1 from the cytosol (its site of synthesis) into the mitochondria (its site of action).21,24 Conversely, in erythroid progenitor cells, the biosynthesis of heme is regulated in order to guarantee a continuous production of the large amounts of heme needed for the synthesis of hemoglobin. For this reason, in the bone marrow, the regulation of heme biosynthesis is mainly linked to the availability of iron, probably as an effect of an iron-binding element located on the 5’-untranslated region of the ALA-S2 gene.7,9,12,21,24–26 In erythroid cells, an excess of heme appears to stimulate cell proliferation and differentiation and to increase both messenger RNA (mRNA) levels and enzyme activity of ALA-S2. Heme excess seems also to be able to enhance the mRNA synthesis of globin.24–26 Even in the bone marrow, an excess of heme may stimulate HO (HO-1) expression, thus inducing an increase in the levels of free iron, which, in turn, results in the further formation of ALA-S2 mRNA.27

The Porphyrias

The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the cycle of


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Table 2. Classification of Porphyrias Type of porphyriaa

Enzymatic defect

Main site of enzymatic defect

Photosensitivity

Acute attacks

ALA-dPb

ALA dehydratase

Liver

−

++/+++

AIP

Porphobilinogen deaminase

Liver

−

++/+++

PCT

Uroporphyrinogen decarboxilase

Liver

++

−

Hereditary coproporphyria (HCP)

Coproporphyrinogen oxidase

Liver

+/++

+/++

VP

Protoporphyrinogen oxidase

Liver

+/++

+/++

Congenital erythropoietic porphyria (CEP)

Uroporphyrinogen III synthase

Bone marrow

++++

−

Erythropoietic protoporphyria (EPP)

Ferrochelatase

Bone marrow

+++

−

a

Entries in bold are acute porphyrias. Very rare. Abbreviations: AIP, acute intermittent porphyria; ALA-dP, ALA-dehydratase deficiency porphyria; EPP, erythropoietic protoporphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria.


b

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 metabolic intermediates accounting for direct or indirect toxic effects.1–3,6,28 The porphyrias are generally classified as erythropoietic or hepatic depending on the organ in which the metabolic defect is prevalent and thus on the site of major production or accumulation of porphyrins or their precursors. These rare diseases are also classified as acute or nonacute, based on their main clinical features, even though the clinical manifestations sometimes overlap in some forms.1,3,6,29 The main clinical landmarks of acute porphyrias are recurrent acute crisis (APAs) characterized by neurovisceral crisis with abdominal pain, mental symptoms, and potentially life-threatening acute neuropathy.1,6,28 The nonacute porphyrias are characterized mainly by cutaneous manifestations related to photosensitivity (Table 2).1,2,4,7,13,29–36 It is noteworthy that all acute porphyrias are hepatic porphyrias, thus suggesting the key role of the liver in the pathogenesis of these rare diseases.6,30

Drugs and Acute Porphyrias: A Hazardous Relationship

Many different factors, both endogenous and exogenous, may influence the synthesis (and the catabolism) of heme and of its precursors, thus contributing to the severity of the clinical expression of different kinds of acute (hepatic) porphyrias. Indeed, the porphyrias should be considered as multifactorial diseases, in which genetic and environmental factors interact in determining the outcome of the disease.4 112

Drugs frequently play a pivotal role among the environmental triggering factors of acute porphyrias.3,28,35,37 In the presence of an inherited enzymatic deficiency of heme metabolism potentially responsible for an acute porphyria (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or delta-aminolevulinic acid dehydratase porphyria; Table 2), many environmental factors can trigger the serious (and potentially fatal) clinical manifestations of the disease.34 It is well known that drugs are one of the most important precipitating factors of acute porphyric attacks, so that the acute porphyrias are also considered to be pharmacogenetic or toxicogenetic diseases.8,34,35,38 The capacity of a drug to induce an APA (ie, drug porphyrogenicity) depends mostly on its ability to directly activate the synthesis of ALA-S1 or to block its negative regulatory feedback control by reducing the hepatic free heme pool (Figure 2).7

Mechanisms of Drug Porphyrogenicity

Induction of ALA-S1 Via Induction of Cytochrome Expression Many lipophilic drugs, based on their capacity of induction or consumption/inhibition of cytochrome P-450 (CYP) enzymes, may be classified as inducers or inhibitors of CYP enzymes.34 Concerning the porphyrogenicity of the cytochrome-inducer drugs, the capability to induce the synthesis of CYP is responsible for the concomitant activation of the transcription of ALA-S1; the expression of apoCYP (protein precursors of cytochromes) is in fact strictly coordinated at the transcriptional level with that of ALA-S1, which is needed to supply heme for saturation of the CYP to be formed.34,39,40




Nuclear receptors (ie, DNA-binding proteins activated by xenobiotics) are involved in the hepatic transcription of ALA-S1 induced by drugs; these nuclear receptors differ in ligand affinity as well as in the response elements of their main target—the CYP genes.39 Almost all drug-induced transcriptions of CYP are mediated by CAR and PXR; only a few commonly prescribed drugs, such as the statins, bind the peroxisome proliferator activated family of receptors, which activate the transcription of a less abundant CYP subfamily. The nuclear receptors, when activated, bind to a second nuclear receptor, the 9-cis retinoid acid xenobiotic receptor; the resulting heterodimer attaches to recognition sites within enhancer sequences on their apoCYP and ALA-S1 target genes and activates their combined transcription. Therefore, a drug may be considered a potential candidate to be porphyrogenic when it is a ligand of CAR or PXR. A prerequisite for porphyrogenic action of a drug is that it induces a volume of apoCYP that is large enough to cause extensive activation of ALA-S1 expression for the synthesis of heme, as well as to determine a high liver consumption of heme sufficient to turn off the physiologic inhibitory control of ALA-S1.39 Beyond the amount of drug necessary for triggering the process, another main determinant of the porphyrogenicity of a drug is the affinity between the substance and the nuclear receptor. The subclass of CYP that is induced is also important; indeed, in the human liver, CYP3A4 and CYP2C9 are largely represented, constituting > 50% of the hepatic microsomal CYP content. The quantitative transcriptional response to an inducer will thus depend on which apoCYP subclass is induced by the drug; the induction of CYP3A4 and CYP2C9 activates ALA-S1 to a greater extent than does the induction of other CYPs. Drugs with these capabilities include antiepileptic drugs; the calcium channel blocker isradipine; the antibiotics sulfadiazine, sulfamethoxazole, and rifampicin; the fungicide ketoconazole; and the reproductive steroids progesterone, medroxyprogesterone, and norethisterone—all substances that have been described as capable of precipitating APA in carriers of acute porphyrias.8,41–44 Several substances are potent inducers of multiple microsomal liver enzymes and thus they are extremely porphyrogenic. The most studied drugs belonging to this category are the many antiepileptic drugs, such as phenobarbital, phenytoin, carbamazepine, and primidone. Their extraordinary porphyrogenicity derives from the extensive stimulation of ALA-S1 transcription activated by the synchronous induction of several CYP subclasses.40,41,43,44

Induction of ALA-S1 Via Inactivation/Inhibition of Cytochromes The CYPs also may be responsible for the transformation of several drugs into transient reactive intermediates that in turn irreversibly inhibit the CYPs through several mechanisms, such as the formation of adducts with amino acids at the active site of the enzyme, or with nitrogen atoms of the iron protoporphyrin or with ferrous iron of heme. The irreversible inhibition of CYP permanently removes the enzyme from the working pool; the elimination of the heme component of the enzymes reduces the hepatocyte regulatory heme pool and leads to a compensatory stimulation of heme synthesis. Examples of CYP3A4 inhibitors known to be harmful in acute porphyrias are amiodarone, chloramphenicol, dihydralazine, diltiazem, erythromycin, mifepristone, raloxifene, ritonavir, roxithromycin, tamoxifen, and verapamil.8,13,39,41,42,44–48 Other compounds (such as halothane, carbon tetrachloride, and peroxides) irreversibly inactivate CYPs through derangement of their heme prosthetic group without adduct formation.34 Many drugs known to act as CYP3A4 inhibitors (eg, diclofenac, fluoxetine) may result in acute porphyrias because concentrations of a significant cytochrome inactivation are much higher than those reached in clinical use or for the inhibitory effect in vivo and are significantly lower than those observed in experimental studies.49

Induction of ALA-S1 Via Metabolic Signaling Some nuclear signaling, such as peroxisome proliferatoractivated receptor-gamma coactivator 1α (PGC-1α), which is involved in a different manner in the endogenous regulation of many metabolic pathways, can take part in the global inductive process of the ALA-S1 activation, which explains why the ALA-S1 transcription is also controlled by some endocrine-metabolic circuits (starvation, gonadal activity, activity of the hypothalamic-hypophysis-adrenal axis, hormone signaling, etc), whose interference may have porphyrogenic effects.34,40,50–54

Induction of ALA-S1 Via the Induction of Heme-Oxygenase Expression Agents or conditions that upregulate heme oxygenase, the main enzyme of heme catabolism, may be considered as porphyrogenic; they cause an increase in heme catabolism, thus reducing free heme pool concentrations and activating ALA-S1 transcription. Well-known inducers of HO-1 are stress, fasting, endotoxins, heavy metals, and organic solvents.7,14,20 It has been demonstrated that some drugs are able


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to induce an increase in HO-1 activity (eg, chronic enflurane or isoflurane administration and dietary griseofulvin) or in HO mRNA expression (chronic enflurane and isoflurane anesthesia and veronal treatment) in animal models of acute porphyria (Table 1).20,55,56


Drugs and Acute Porphyrias: A Real Issue in Drug Prescribing

The multitude of potentially implicated mechanisms and the great variety of unrelated drug chemical structures make it very difficult to predict with certainty which agent can have porphyrogenic properties. For this reason, the identification of harmful substances for patients with porphyria is still incomplete.13,35 The classification of drugs as safe or unsafe in cases of acute porphyria is based mostly on anecdotal reports of the effects observed in patients with acute porphyrias, on clinical reports of induction of an APA by other agents, or on the measurement of porphyrins or porphyrin precursors (ALA and PBG) in urine and feces after drug consumption. Drugs may also be tested in vitro (on cellular cultures) in order to assess their ability to induce ALA-S1 activity or to determine their effects on the synthesis of porphyrins.39 Alternatively, drug action on heme metabolism can be investigated in vivo on animal models of acute porphyrias.13,37 Unfortunately, anecdotal evidence is often conflicting, and it is not always possible to demonstrate the authenticity and reliability of this evidence. Cell cultures and animal models tend to overestimate drug porphyrogenicity, and they do not always correctly predict the effects on patients with acute porphyrias.13,34,35 A mechanistic prediction based on the drug’s chemical structure would preclude the need for experimental data and would avoid the problems entailed in clinical reports and in extrapolations from animal tissues to human experience, making it possible for a prediction to be made even before a drug enters into clinical practice. Unfortunately, early attempts to correlate drug porphyrogenicity with chemical structure gave disappointing results, demonstrating that this problem is more complex than expected. It now seems clear that it is not only the drug’s structure that may predict its porphyrogenicity but also the drug’s other metabolic aspects, such as its distribution within the body.57 Currently, drugs considered as safe or unsafe for patients with acute porphyrias are often classified in lists available in the literature or on the Internet, together with other information provided by specialized centers or patients’ associations around the world.48,58–60 These lists are made by combining clinical reports and experimental studies, but there are many 114

concerns about their validity, due not only to the frequent lack of data about many drugs, but also to the varying data in the different lists, as well to the poor quality and the scarce amount of data used to create these recommendations, which result often in ambiguity among the different sources. In the last decade, the international communities of porphyria specialists have made a great effort to pool their expertise in order to improve patient care. As a result, the specialists’ different experiences in dealing with the use of drugs in acute porphyrias have been pooled, in order to design systematic databases of safe and unsafe drugs. The Norwegian Porphyria Centre (NAPOS),44 in collaboration with the European Porphyria Network (Epnet) and many other porphyria specialists, has created a database that references most of the available information about the safety of drugs in acute porphyrias (to date, it contains data on > 1000 drugs).41,42,48,61,62 Differently from the other available lists of drugs, this database is built on a well-characterized assessment of the potential of drugs to provoke an APA, and provides guidance on drug prescription based on a careful evaluation of international clinical experience, published case reports, previously published drug lists, and theoretical considerations.34,44 The drugs are classified into 5 categories, reflecting the different risk of provoking an APA. The categories range from nonporphyrogenic drugs (which can be used safely) to high-risk porphyrogenic drugs (which should be prescribed only in cases of urgent indications and under careful clinical monitoring). The NAPOS database guidance on drug prescription also takes into account the patient’s clinical characteristics, in order to predict the individual susceptibility to drug-induced APA. Another major advantage of this database is that it is kept current, as the information about both established drugs and recent drugs is continually revised.44 Even if some degree of uncertainty remains, the use of this systematic database, in our experience, helps physicians to prescribe drugs and to reduce the risk of drug-induced attacks. Though specific epidemiological data are lacking, the decreased prevalence of symptomatic acute porphyrias observed in recent years in Europe (confirmed also by the experience of Italian porphyria specialist centers [data unpublished]) may also be ascribed to this systematized approach to drug use.5,63 As an example, Table 3 lists drugs that are frequently used in clinical practice, classified on the basis of their potential to cause acute porphyrias. The classification is updated according to the NAPOS database.44




Table 3. Drugs Most Frequently Used in Clinical Practicea Drug Class

Safe

Probably Safe

Anesthetics

Atropine Propofol

Sevoflurane Lidocaine and ropivacaine

Use With Caution

Analgesics and antiinflammatory

Aspirin and paracetamol Codeine and morphine Tramadol Celecoxib Ibuprofen

Diclofenac

Prednisone Methylprednisolone Hydrocortisone

Antibiotics

Aminoglycosides Azithromycin β-lactams and carbapenems Ciprofloxacin, levofloxacin, norfloxacin, and moxifloxacin Glycopeptides Metronidazole -Fosfomycin

Clarithromycin

Lincosamides

Diuretics

Furosemide Hydrochlorothiazide

Potassium Canrenoate

Cardiologic drugs

β-blockers Felodipine, amlodipine Candesartan, valsartan, irbesartan, losartan, and telmisartan Isosorbide and nitroprusside Glyceryl trinitrate

Captopril, enalapril, fosinopril, lisinopril, and ramipril

Drugs used in hyperlipidemia

Bezafibrate, gemfibrozil, fenofibrate Colestyramine Ezetimibe Simvastatin, rosuvastatin, pravastatin

Fluvastatin

Anticoagulants and antiaggregants

Heparin and low molecular weight heparin Warfarin Fondaparinux

Clopidogrel Dabigatran and rivaroxaban

Ulcer and dyspepsia

Cimetidine, ranitidine Omeprazole, pantoprazole

Lansoprazole, esomeprazole

Antiemetics and vertigo

Setrons Levopromazine, Chlorpromazine Scopolamine Metoclopramide Betahistine

Sedatives and hypnotics

Lorazepam, triazolam, midazolam, alprazolam, and diazepam Zopiclone

Zolpidem

Flunitrazepam, nitrazepam

Phenobarbital

Chlordiazepoxide

Antidepressants and antipsychotics

Fluoxetine Venlafaxin Trazodone

Citalopram, escitalopram Mirtazapine Mianserin Amitriptyline

Fluvoxamine, paroxetine, and sertraline Nefazodone

Risperidone

Haloperidol Promazine

Antiepileptics

Clonazepam Gabapentin Lamotrigine Levetiracetam Vigabatrin

Ethosuximide Felbamate Topiramate

Valproic acid Carbamazepine Phenytoin Phenobarbital Primidone

Tiagabine

Diltiazem and verapamil Hydralazine Isradipine Disopyramide Mexiletine Propafenone

Avoid

Unknown

Ketamine Thiopental

Tubocurarine Etomidate Etodolac Pyrazolone Phenylbutazone

Chloramphenicol Erythromycin Nitrofurantoin Rifampicin Thrimethoprim/ sulfametoxazole

Colistin Streptomycin Tetracyclines

Spironolactone

Indapamide Metolazone

Methyldopa

Procainamide

Ticlopidine

Domperidone Dimenhydrinate Cinnarizine

(Continued)


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Table 3. (Continued) Drug Class

Safe

Probably Safe

Use With Caution

Avoid

Unknown

Drugs for diabetes

Acarbose Insulin Metformin Glimepiride

Glipizide Nateglinide Glibenclamide

Rosiglitazone

Tolbutamide

Gliquidone Repaglinide Gliclazide Chlorpropamide

Miscellaneous

Butylscopolamine Theophylline Levo-thyroxine Azathioprine

Flumazenil Naloxone and naltrexone

Androgens Oral contraceptives Ketoconazole Mercaptopurine

Alcohol (ethanol)

Miconazole Radiologic contrast media

Go to http://www.drugs-porphyria.org for a more complete and thorough consultation.44 Modified and updated from Disler et al116 and Thunell et al.34


a

The pathophysiology of APA is certainly complex and multifactorial, because, in addition to ALA-S1 induction, other mechanisms predispose to the development of acute attacks. Indeed, only 10% to 20% of carriers of acute porphyrias develop clinically overt disease.1–3,6,64 Currently, there are no reliable data to explain why some carriers appear to be resistant to disease development (latent carriers), whereas others are vulnerable to trigger factors that have a variable severity from individual to individual and, for a single carrier, from time to time.2,3,7,65 It seems possible to estimate the susceptibility to druginduced APA in each individual by taking into account some well-defined predisposing factors: (1) age (prepubertal children have a lower risk); 2) sex (females have a higher risk than males); (3) disease history (carriers in remission or those who have never experienced acute attacks seem to have a lower risk, whereas patients with a history of recurrent APAs are at higher risk); (4) recent or current exposure to others ALA-S1 inducers; and (5) genetic background, which refers not only to the alterations in genes coding for enzymes in the heme biosynthetic pathway responsible for acute porphyria, but also to other genetic factors that could be involved in facilitating the clinical expression of the primary gene defect.2,34,44 Genetic polymorphisms in responses to triggering factors38 and constitutional differences in the structure or function of multiple genes that interact to influence the control of ALA-S1 transcription may be relevant issues.66 For example, the differences in hepatic polymorphisms of CYPs could explain why acute attacks can be triggered by a certain drug in some individuals, whereas others are resistant to exposure to the same unsafe drug; only a single study has explored this hypothesis in patients with acute porphyrias.67 Nevertheless, the problem remains very complex, because it is not only liver cytochromes that are involved in determining the susceptibility to porphyrogenic agents, but also those present in other tissues (mitochondrial and microsomal 116

cytochrome P-450, reduced nicotinamide adenine dinucleotide phosphate cytochrome P-450 reductase), especially in the brain (acute porphyrias are primarily neurologic disorders).68 For these reasons, it has not been possible to definitively predict the individual risk in porphyria carriers. As a rule, only safe drugs should be prescribed to a patient affected by acute porphyria. When a potentially unsafe drug is necessary for a carrier of a gene defect configuring an acute porphyria, the benefit deriving from drug utilization should outweigh the risk of triggering an APA. The possibility of identifying the patient’s level of risk (from “not susceptible” to “highly susceptible” to drug-induced APA) based on clinical data, as suggested by the NAPOS database, may be very helpful in decision making.44 Many clinical conditions (eg, cardiac arrhythmias, serious infections resistant to antibiotics considered safe, tuberculosis, HIV infection, epilepsy, psychiatric disturbances, etc; Table 4) should raise concern in practitioners treating patients with acute porphyria. Nevertheless, when the use of well-known porphyrogenic drugs is necessary, because there are no alternatives or in presence of severe life-threatening diseases, the drug should be administered and the patient should undergo a close clinical and biochemical (repeated measurements of urinary ALA and PBG) monitoring. Indeed, we should never refuse to use a potentially porphyrogenic drug if it is essential for optimal treatment, with the prospect of promptly intervening (infusion of hematin with/ without carbohydrate) if there are signs of development of an APA.5,6,13,34,35 Similar recommendations are made in cases of inadvertent use of a porphyrogenic drug, such as by human error or by the failure to determine the porphyric status of the patient in a timely manner.13

Nonacute Porphyrias

In nonacute (chronic) porphyrias, the evidence for the relationship between drugs and clinical exacerbations is




Table 4. Medical Specialties More Often Facing the Issue of Prescribing Potentially Unsafe Drugs in Patients With Acute Porphyrias Medical specialty

Conditions

Drugs

Neurology

Epilepsy Migraine Cerebrovascular diseases

Antiepileptic agents Drugs for pain Platelet anti-aggregant drugs

Anesthesia/surgery

General anesthesia Therapy of pain

Anesthetics NSAIDs Corticosteroids

Eheumatology

Autoimmune diseases

Corticosteroids

Infectious diseases

Pneumonias, sepsis, septic shock Fungal infections HIV TBC

Antibiotics Antifungal drugs HAART (ritonavir) Rifampicin

Cardiology

Arrhythmias hypertension, congestive heart failure, Coronary heart disease

Antiarrhythmic drugs Antihypertensive drugs Diuretics (antialdosterone drugs) Platelet anti-aggregant drugs

Psychiatry

Psychosis, depression, alcohol abuse

Atypical major sedatives Antidepressive drugs Alcohol

Endocrinology/gynecology

Contraception, osteoporosis, diabetes

Estroprogestinic drugs Oral antidiabetics agents

Internal medicine and emergency unit

All the above conditions Starvation states

far weaker than in acute porphyrias, and it is not clear why phenotypic manifestations are not influenced by porphyrogenic drugs. It is believed that there are no unsafe drugs for patients with congenital erythropoietic porphyria and erythropoietic protoporphyria, whereas an association between some drugs seems to exist, in particular estrogen-containing compounds, and the worsening of cutaneous manifestations in porphyria cutanea tarda.13 A particular caution is needed in prescribing antimalarial drugs for patients with PCT. Even if chloroquine or its analogues are used at low doses for the treatment of cutaneous manifestations of this disease, their use at high doses (ie, those used for malaria treatment) can cause a rapid and massive mobilization of porphyrins from the liver and possibly the consequent development of acute hepatitis.62

Conclusion

Acute porphyrias are rare but potentially lethal diseases, especially if misdiagnosed or inappropriately treated. The use of unsafe drugs in patients affected by acute porphyrias represents a well-defined trigger of the serious (and potentially fatal) clinical manifestations of these diseases (APAs). The biochemical reasons why so many drugs are potentially dangerous in these diseases have important implications in the clinical management of these complex patients (both in

the treatment of the disturbance per se and in prescribing drugs). Practitioners should by refer to systematic operative databases or to expert centers when treating these patients.

Conflict of Interest Statement

Giulia Roveri, MD, Fabio Nascimbeni, MD, and Emilio Rocchi, MD, have no conflicts of interest to declare. Paolo Ventura, MD, is a member of the advisory board for and has received funding for consultation, research, and lecturing from Orphan Europe Italy.

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