What are the other Names for this Condition? (Also known as/Synonyms)

• Drug or Toxin-Induced Pulmonary Arterial Hypertension
• Medication-Induced Pulmonary Arterial Hypertension
• Toxin-Induced Pulmonary Arterial Hypertension

What is Drug and Toxin-Induced Pulmonary Arterial Hypertension? (Definition/Background Information)

• Pulmonary arterial hypertension (PAH) is a specific type of hypertension that is caused by increased blood pressure within the pulmonary (lung) arteries. When PAH is thought to be caused by the use of a specific drug or medication or develops secondary to toxin exposure, it is considered Drug and Toxin-Induced Pulmonary Arterial Hypertension
• In general, pulmonary hypertension (PH) is a disorder characterized by very high blood pressure (above normal) in the lungs due to a variety of causes. It should not be confused with systemic hypertension, otherwise known as ‘high blood pressure’
• The World Health Organization (WHO) has clinically classified pulmonary hypertension according to certain groups. Drug and Toxin-Induced Pulmonary Arterial Hypertension forms part of WHO group 1 (sub group 1.3)
• The signs and symptoms of Drug and Toxin-Induced Pulmonary Arterial Hypertension may include shortness of breath, chest pain, fatigue, and dizziness. A diagnosis of the condition may involve procedures such as right-heart catheterization and acute vasodilator challenge
• The treatment measures of Drug and Toxin-Induced Pulmonary Arterial Hypertension involves the use of medications, such as calcium channel blockers, and bringing about certain lifestyle modifications, among others. In some, avoiding exposure to the toxins, or stopping the offending medication, or proposing alternate medications may help resolve the condition
• The prognosis of Idiopathic Pulmonary Arterial Hypertension may be improved if diagnosed promptly and treated appropriately. However, the overall prognosis depends on several factors and may vary on a case-to-case basis

Who gets Drug and Toxin-Induced Pulmonary Arterial Hypertension? (Age and Sex Distribution)

• Drug and Toxin-Induced Pulmonary Arterial Hypertension can occur at any age
• Both males and females are affected, and no gender predominance is noted
• The condition may be observed in individuals of all races and ethnic groups

What are the Risk Factors for Drug and Toxin-Induced Pulmonary Arterial Hypertension? (Predisposing Factors)

The risk factors for Drug and Toxin-Induced Pulmonary Arterial Hypertension include:

• Drugs that have been clearly established as risk factors include:
  • Appetite suppressants (such as aminorex, fenfluramine, dexfenfluramine, and methamphetamines)
  • Toxic rapeseed oil
  • Benfluorex
  • Dasatinib
• Drugs that are possible risk factors include:
  • Amphetamines
  • Diethylpropion
  • L-tryptophan
  • Methamphetamines and cocaine
  • Phenylpropanolamine
  • Leflunomide
  • Phentermine
  • Mazindol
  • Interferon-alpha/beta
  • St. John’s wort
  • Alkylating agents
  • Bosutinib
  • Indirubin
• In women who underwent prior treatment with imatinib, this appears to increase the risk of Dasatinib-associated pulmonary arterial hypertension

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Drug and Toxin-Induced Pulmonary Arterial Hypertension? (Etiology)

The mechanism of development of Drug and Toxin-Induced Pulmonary Arterial Hypertension is unknown. It is thought to be related to the aberrant expression and regulation of particular growth factors such as serotonin or platelet derived growth factor (PDGF), as a result of medication use or exposure to certain toxins.

• Serotonin has been shown to affect the growth of the smooth muscle cells in pulmonary arteries and vessels. Many of the drugs (mentioned previously), particularly belonging to the methamphetamine family, affect the so-called serotonin transporters
• It is believed that by affecting serotonin transporters, especially in smooth muscle cells in the walls of pulmonary arteries and vessels, this is in part the mechanism of action of Drug-Induced Pulmonary Arterial Hypertension
• In patients who take Dasatinib, a chemotherapy agent for chronic myelogenous leukemia (CML), PDGFs are antagonized. This is thought to play a role in developing Dasatinib-associated pulmonary arterial hypertension

What are the Signs and Symptoms of Drug and Toxin-Induced Pulmonary Arterial Hypertension?

The signs and symptoms of Drug and Toxin-Induced Pulmonary Arterial Hypertension depend on a set of several factors that include the age and overall health status of the individual.

The common signs and symptoms exhibited by individuals with Drug/Toxin-Induced Pulmonary Arterial Hypertension are similar to most individuals with pulmonary hypertension. These include:

• Progressive shortness of breath, especially while exercising, is the most common symptom
• Fatigue (frequent tiredness)
• Chest pain
• Dizziness or fainting
• Swelling of the ankles/legs
• Palpitations
• Bluish lips and skin, observed during the later stages
• Irregular heartbeat (arrhythmias)
• Fluid in the abdomen (ascites)

How is Drug and Toxin-Induced Pulmonary Arterial Hypertension Diagnosed?

To diagnose Drug and Toxin-Induced Pulmonary Arterial Hypertension (IPAH), a diagnosis of pulmonary hypertension (PH) must first be established. This involves certain preliminary diagnostic procedures. Depending on the results of these tests, confirmation will be made with a right-heart catheterization.

After a diagnosis is made, the healthcare provider may inquire about past and present use of medications, recreational and illicit drug use, and exposure to various toxins. This can help in diagnosing and differentiating Drug or Toxin-Induced Pulmonary Arterial Hypertension from other types of pulmonary hypertension.

The preliminary procedures may include:

• A complete physical examination of the patient 
• A thorough checking of the patient’s medical history and a detailed checking of the family history of the patient
• Blood tests:
  • Blood tests help rule out other diseases, such as HIV infection, liver disease, rheumatoid or connective tissue disease, and thyroid disease
  • They also help in checking the blood oxygen levels
  • The measurement of brain natriuretic peptide (BNP) can be used to assess the strain on one’s heart
• Chest X-ray: Chest X-rays can reveal structural signs of pulmonary hypertension by identifying changes in the pulmonary arteries or enlargement of the right side of the heart
• Electrocardiogram (ECG): An electrocardiogram checks the electrical impulses of the heart. There are certain identifiable patterns on an ECG that may indicate pulmonary hypertension. However, ECG is not specific enough to diagnose the condition by itself, so a combination of tests may be recommended by the healthcare provider
• Echocardiogram: In this procedure, a sonogram of the heart is taken and used to measure overall functioning as well as measure the pressure within the chambers of the right heart. An echocardiogram is also often times used to monitor a patient’s condition after diagnosis and during treatment
• Pulmonary function tests: These tests help measure the quality of breathing and check the functioning of the lungs (such as how much air is breathed in and out, as well as the quality of oxygen exchange)
• Exercise tolerance test (six-minute walk test): This helps to measure the patient’s ability to exercise
• Nuclear scan (ventilation/perfusion scan or V/Q scan): This tool helps identify any new or chronic blood clots in the vessels of the lungs that could be causing pulmonary hypertension

The gold standard for pulmonary hypertension diagnosis and management is right-heart catheterization and acute vasodilator challenge.

• Right-heart catheterization:
  • If pulmonary hypertension is suspected based off preliminary tests and procedures, a right-heart catheterization test is ordered to help confirm the diagnosis
  • This test can accurately quantify right-heart pressures (measure the pressure within the chambers of the right heart), especially the pressure inside the pulmonary arteries
  • During this procedure, a very small catheter is inserted into a large vein (either within the patient’s groin or neck) and passed into the patient’s heart and vasculature to measure the internal blood pressures 
• Vasodilator study (acute vasodilator challenge):
  • While this test is not used to necessarily “diagnose” pulmonary hypertension, it is used to evaluate the patient for possible therapeutic management
  • Like right-heart catheterization, a catheter is placed within the pulmonary artery to test for vasodilation (or relaxation) in response to a class of medications called calcium channel blockers (CCBs)
  • The response and dosing of CCBs can be evaluated with this procedure

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Drug and Toxin-Induced Pulmonary Arterial Hypertension?

Following are the possible complications that may arise due to Drug and Toxin-Induced Pulmonary Arterial Hypertension:

• Right-sided heart failure with hepatic congestion (due to deposition of stones in the liver)
• Pedal edema: Swelling of the leg or ankle
• Pleural effusions: Building-up of excess fluid around the lungs
• Worsening dyspnea (shortness of breath) upon exertion

How is Drug and Toxin-Induced Pulmonary Arterial Hypertension Treated?

For those with definite or possible risk factors for Drug and Toxin-Induced Pulmonary Arterial Hypertension, removal of the offending agent (if possible) is essential. For example, discontinuation of interferon or Dasatinib therapies have been demonstrated to lead to reversal of the associated pulmonary hypertension. The pros and cons of removing potentially life-saving treatment should be factored in by an experienced healthcare professional.

Drug and Toxin-Induced Pulmonary Arterial Hypertension is a rare condition that is best treated at a medical center with appropriate expertise. Several medical treatments are highlighted below:

• Conventional medical therapies:
  • Calcium channel blockers (CCBs): These are a group of medications that help vasodilate (or relax) the arteries. However, CCBs are only appropriate for patients demonstrating a favorable response to the vasodilator study
  • Inotropic agents: These are medications that assist in the pumping of the heart 
  • Diuretics, salt limitation, and weight monitoring may be recommended, to limit excess strain on the heart
  • Supplemental oxygen may help an individual meet the ‘oxygen needs’ for normal daily activities
  • Blood thinners: These medications help prevent blood clots, especially in the lung blood vessels
• Oral, inhaled, subcutaneous, or intravenous treatment options:
  • Endothelin receptor antagonists (ERAs) help in preventing pulmonary blood vessels from narrowing which helps keep the pressures towards normal levels
  • Phosphodiesterase inhibitors (PDE 5 Inhibitors), prostacyclin analogues, and soluble guanylate cyclase (sGC) stimulators, all aid in allowing vessels of the lungs to vasodilate (or relax)
• Additional treatment options may include:
  • Lifestyle modifications, such as nutrition, exercise, avoiding tobacco, and limiting alcohol consumption, are beneficial
  • Judicious exercising may be effective in limiting deconditioning (by building stamina), improving the quality of life, and exercising capacities. Isometric exercises, such as heavy weightlifting, should be avoided
  • Lung transplantation may be required with advanced forms of the disorder

How can Drug and Toxin-Induced Pulmonary Arterial Hypertension be Prevented?

Drug and Toxin-Induced Pulmonary Arterial Hypertension may not be always prevented from taking place. Being aware of the potential side effects will aid in early diagnosis and prevent long-term complications. Discontinuing the medication (or the use of alternative medications), or avoidance of exposure to the causative toxin, will most likely help resolve the condition in many.

• Avoidance of recreational drugs, various toxic agents, and inappropriate weight loss drugs is important
• Some medications that cause pulmonary hypertension may be necessary for controlling a particular condition affecting the individual. In such cases, the healthcare provider may modify the medication or propose an alternative therapy. If this is not possible, the side-effects that develop should be monitored, and the pros and cons of continuing the therapy should be weighed in

What is the Prognosis of Drug and Toxin-Induced Pulmonary Arterial Hypertension? (Outcomes/Resolutions)

The prognosis of Drug and Toxin-Induced Pulmonary Arterial Hypertension differs from one individual to another, depending on the severity of the condition/pulmonary hypertension. An earlier and focused treatment can help improve outcomes. The prognosis also depends on the overall health status of the individual and whether he/she responds to treatment measures.

• For those with established pulmonary hypertension, the use of selective serotonin reuptake inhibitors (SSRIs) has been associated with a poor prognosis
• Pulmonary hypertension is a negative prognostic sign in many medical conditions, meaning that the presence of pulmonary hypertension makes the overall health outcomes worse (such as COPD or heart failure)
• Individuals with advanced heart disease, a suboptimal 6-minute walk test (exercise tolerance test to measure one’s ability to exercise without significant signs and symptoms), and with conditions, such as advanced liver disease and connective tissue disease, have poor prognosis

Additional and Relevant Useful Information for Drug and Toxin-Induced Pulmonary Arterial Hypertension:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/pulmonary-hypertension-ph/