Mazindol. Phenylpropanolamine. Diethylpropion. Other drugs. Thalidomide. Cyclophosphamide. Bevacizumab. Dasatinib. Pergolide. Phenformin. Leflunomide.
Chapter 8 Humbert M, Souza R, Simonneau G (eds): Pulmonary Vascular Disorders. Prog Respir Res. Basel, Karger, 2012, vol 41, pp 76–84
Drug- and Toxin-Induced Pulmonary Arterial Hypertension Laura Pricea ⭈ Kim Bouillonb ⭈ S. John Worta ⭈ Marc Humbertc a
Royal Brompton Hospital, Department of Critical Care, National Heart and Lung Institute, and bUniversity College London, Department of Epidemiology and Public Health, London, UK; cUniversité Paris-Sud 11, Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine- Béclère, Assistance Publique, Hôpitaux de Paris, Clamart, France
Abstract Pulmonary arterial hypertension (PAH) is a progressive disease leading to remodeling of small pulmonary arteries. The exact pathogenesis of PAH is uncertain; however, several risk factors are likely to contribute. These include inflammatory ‘hits’, such as a viral infection, and inherited disorders in vascular cell growth, such as a mutation in the bone morphogenetic protein receptor type 2 gene. It has also become apparent, first through early associations and later with larger epidemiological studies, that the use of certain drugs and toxins are important in triggering PAH, especially in susceptible individuals. One of the earliest observations of drug-related PAH followed use of the stimulant appetite suppressant aminorex fumarate. Similar associations have also been reported, especially in other stimulant anorectics such as the serotonin reuptake inhibitor dexfenfluramine, as well as a range of other agents, including illegal substances. Agents are described to cause ‘isolated PAH’, or PAH as part of a multisystem process, such as that which followed toxic oil syndrome in the 1980s. Furthermore, some substances specifically lead to pulmonary veno- occlusive disease. All these agents have been recently categorized according to the strength of their association with PAH. Clinicians should be aware of the associations of exposure of these drugs with PAH. Copyright © 2012 S. Karger AG, Basel
Pulmonary arterial hypertension (PAH) is a progressive disease leading to remodeling of the small pulmonary arteries, resulting in an increase in pulmonary vascular resistance and premature death from right heart failure [1]. PAH and pulmonary veno-occlusive disease (PVOD), are classified in Groups 1 and 1’, respectively, of the updated clinical classification of pulmonary hypertension (see
table 2 in Montani and Simonneau [this vol., p. 2]) [2], and the conditions within these groups have similarities in terms of clinical manifestations, hemodynamic measures, pathological changes, and treatment. Their common histopathological features include pulmonary artery medial hypertrophy, intimal thickening, adventitial fibrosis, and plexiform lesions (in PVOD, the vascular changes predominate in small postcapillary pulmonary venules; fig. 1). Although the pathogenesis of these conditions is not fully understood, it is thought that several risk factors trigger the onset of the disease and/or worsen its progression, and these may include drugs and toxins (tables 1 and 2) [2]. Cases that are clearly precipitated by a drug or toxin are termed ‘drug- and toxin-induced PAH’. The identification of drugs and toxins as risk factors for PAH poses a great challenge to both the physician and the epidemiologist: their role in pathogenesis may be suggested from the drug and social history, and the setting up of cohort or case-control studies from large patient databases is important to assess the probability of causality. Drugs and toxins associated with PAH are listed in table 1 [2]. Agents have been described as contributing to pulmonary vascular disease as an isolated process or as part of a multisystem disorder. This chapter will review the principle drugs and toxins that have been implicated in PAH and PVOD. It should also be noted that some agents are likely to contribute to the pathophysiology of persistent pulmonary hypertension of the newborn, but a detailed description of this is beyond the scope of this article.
a
b
c
d
Fig. 1. Presentations of idiopathic PAH and PVOD. a High-resolution contrast CT showing enlargement of the central pulmonary artery and mosaic attenuation perfusion abnormality in idiopathic PAH. b Pathological examination of lung tissue in idiopathic PAH shows marked medial hypertrophy (arrow) and plexiform lesions (*). c High-resolution chest CT shows nodular centrilobular ground-glass opacities and septal lines in PVOD. d Pathological examination of lung tissue in PVOD shows narrowing of small pulmonary veins (* = the lumens of the pulmonary veins). Images supplied by Drs. David Montani, Peter Dorfmüller, Sophie Maitre, Dominique Musset, Gerald Simonneau, and Marc Humbert (Universite Paris-Sud 11, Hopital Antoine Beclere, Clamart, France).
Proposed Pathological Mechanisms in Drug- and Toxin-Induced Pulmonary Arterial Hypertension
There are little data on cellular mechanisms for most proposed drugs and toxins contributing to PAH. An exception may be that of the activation of serotoninergic signaling associated with stimulant appetite suppressants and other agents: serotonin [5- hydroxytryptamine (5-HT)] is a direct pulmonary vasoconstrictor and an active mitogen for smooth muscle cells, and plasma levels are elevated in PAH where abnormal handling by platelets is likely [3]. The active metabolite of dexfenfluramine is a 5-HT 2B receptor
Drug- and Toxin-Induced PAH
agonist, and it has been shown that PAH development requires activation of 5-HT 2B receptors [4]. Although these agents do inhibit serotonin reuptake, it is not always the case that plasma serotonin levels are increased following their use [5]. They are also thought to interact with serotonin transporters in the lung: aminorex and fenfluramine act as serotonin transporter substrates, thereby increasing extracellular serotonin [6]. Fenfluramines [7] and pergolide [8] have also been shown to cause inhibition of voltagegated K[+] channels in pulmonary arterial smooth muscle cells, leading to vasoconstriction. The contribution of sympathomimetic agents (including stimulant anorectics and
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Table 1. Drugs and toxins related to pulmonary hypertension Drugs and toxins associated with PAH Appetite suppressants Aminorex Fenfluramine Dexfenfluramines Benfluorex Propylhexedrine Phendimetrazine Mazindol Phenylpropanolamine Diethylpropion Other drugs Thalidomide Cyclophosphamide Bevacizumab Dasatinib Pergolide Phenformin Leflunomide Interferon-α2 Alglucerase Substance abuse 4-methyl-aminorex Methamphetamine Cocaine Toluene Herbal preparations Hypericum perforatum (Saint John’s wort) Pyrrolizidine alkaloids Drugs associated with PVOD Mitomycin-C BCNU Cyclophosphamide Bleomycin MOPP/COPP Substances associated with systemic diseases Toxic rapeseed oil L-tryptophan
drugs of abuse) to PAH pathophysiology is unclear, with proposed mechanisms including pulmonary vasoconstriction, fenfluramine-like effects, toxic endothelial injury, vasculitis, and dysregulation of mediators of vascular tone. It is also likely that the contribution of drugs and toxins represents a single step in the multifaceted pathological process
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Table 2. Risk of pulmonary arterial hypertension associated with a selection of drugs and toxins Definite
Likely
Possible
Toxic rapeseed oil Aminorex Fenfluramine Dexfenfluramine
Amphetamines Methamphetamines L-tryptophan
St John’s Wort Cocaine Phenylpropanolamine Chemotherapeutic agents Selective serotonin reuptake inhibitors
that leads to PAH in susceptible individuals, such as those with a predisposing genetic tendency such as a mutation in bone morphogenetic protein receptor type 2 (see chapter by Girerd et al. [pp. 65–75]).
Drugs Associated with Isolated Pulmonary Arterial Hypertension
Appetite Suppressants Aminorex Fumarate Aminorex fumarate structurally resembles adrenaline and ephedrine (fig. 2), and is a potent appetite suppressant and central stimulant. Its use in the 1960s led to an outbreak of rapidly progressive PAH (then termed primary pulmonary hypertension), with a median exposure-to-onset time, when known, of 8 months (ranging from 3 weeks to over 1 year), as first described in a Swiss medical clinic [9]. A collaborative study identified 582 cases of PAH, of which 61% had used aminorex [10], and it was withdrawn from Switzerland in 1968. The incidence of PAH in patients who had used aminorex was shown to be about 0.2% overall [11] and related to the amount of drug taken. Furthermore, if discontinued early enough, a regression of PAH could be seen [12]. Fenfluramines The fenfluramines (DL-fenfluramine and its analogue dexfenfluramine; fig. 2) are serotonin reuptake inhibitors and were widely used obesity medications. Early reports associated their use with PAH, with time from exposure to onset of symptoms varying from 3 months to 8 years [13–15]. In 1993, a French 5-year retrospective review of 73 PAH patients found that 20% had been exposed to fenfluramines [16]. A multicenter case-control study conducted in 1992, the International Primary Pulmonary Hypertension Study (IPPHS), found a strong association
Price · Bouillon · Wort · Humbert
