Be alert for the possibility of drug-induced pulmonary arterial hypertension

Clinician awareness of which drugs may be associated with the development of pulmonary arterial hypertension (PAH) may improve the early diagnosis and reversal of PAH, without necessitating treatment discontinuation, according to results from a review recently published in the journal Heart Failure Reviews.

“With increasing recognition of PAH in clinical practice, we wanted to provide the readers with a comprehensive overview of a potentially avoidable and reversible cause of PAH,” said lead reviewer Lohit Garg, MD, cardiology fellow, Department of Cardiovascular Medicine, Lehigh Valley Health Network, Allentown, PA.

Currently, pulmonary hypertension (PH) comprises five clinical groups, with drug-induced PAH classified under Group 1. PH patients diagnosed with PAH are hemodynamically characterized by the presence of pre-capillary PH, which is defined by a pulmonary artery wedge pressure (PAWP) of ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 3 Wood units in the absence of other causes of pre-capillary PH.

Current classifications specify that PAH can be associated with exposure to certain drugs or toxins, including anorectic agents, amphetamines, or SSRIs.

To identify additional drugs that may be associated with an increased risk for the development of PAH, Dr. Garg and colleagues reviewed all the English literature available on PubMed, Google Scholar, and FDA sites from 1960 through 2016, the following drugs to have definite associations with PAH:

• aminorex;
• fenfluramine;
• dexfenfluramine;
• toxic rapeseed oil;
• selective serotonin reuptake inhibitors (SSRIs); and
• benfluorex, a fenfluramine derivative.

Agents that may have likely associations with PAH include:

• amphetamines/methamphetamines;
• dasatinib; and
• L-tryptophan.

“The primary mechanism seems to be related to alteration in serotonergic pathways and is potentially reversible if identified early and the causative drug is discontinued. The association is strong for few drugs, more than others, especially methamphetamines, anorexic agents, and SSRIs. There are other drugs that have the variable effect and the clinicians need to be aware of the association,” said Dr. Garg.

Dr. Garg and colleagues concluded that PAH remains a rare complication of several drugs, which suggests individual susceptibility is possible. He called for further studies to identify those patients at risk of drug-induced PAH.

“Drug-induced PAH portends a diagnostic and management dilemma for clinicians involved in the care of such patients. While future studies may address the clinical needs, physicians should address exposure to all potential drugs (recreational and prescription) during the workup of PAH. Awareness regarding the drug use and PAH development may result in early diagnosis and potentially reversing the effect with discontinuation of the drug,” concluded Dr. Garg.