Treprostinil

Mechanism of Action

Treprostinil is a chemically stable prostacyclin analog. Its principal pharmacologic action is direct vasodilation, which causes reduction of pulmonary and systemic arterial pressure, reducing right and left ventricular afterload; therefore improves the cardiac output. It also has an antiplatelet effect.[4]

Administration

Treprostinil is available in three formulations: intravenous or continuous subcutaneous, oral, and inhaled. Each formulation is beneficial to patients with PAH. Different routes have different adverse effects, and the knowledge of these effects will facilitate transitioning between these formulations. For example, patients receiving the infusion form experienced infusion site pain, patients receiving the oral form experienced abdominal discomfort, which this activity will discuss in more detail in the “Adverse Effects” section. The subcutaneous (SQ) route is preferred as the drug will rapidly and completely absorb and is administered via an infusion pump. If the patient is not tolerant of the SQ infusion route, they can change to IV infusion. In this case, the solution must be diluted and administered through an indwelling central catheter, which can increase the risk of sepsis and bacteremia. Patients receiving inhaled treprostinil should be able to care for the system and the accessories. They should also have backup devices to avoid interruption of the treatment.

Treprostinil should not be mixed with any other medications. The oral form can be administered with food and should not be crushed or chewed. The absorption of the oral treprostinil increases when administered following a high-fat, high-calorie meal. Dosing requires adjustment in hepatic impairment due to decreased hepatic clearance and increased systemic exposure.

The metabolism of this medication is hepatic via CYP2C8 to form several inactive metabolites, which then get excreted through urine and feces.

It has not undergone testing in other types of PH.[5][2]

SQ absorption is almost immediate, whereas orally, the time to peak is 4 to 6 hours. The half-life is 4 hours. 

Adverse Effects

Local adverse effects are the most common side effects related to either the SQ or inhaled routes of administration:

• Skin manifestations such as infusion site reaction (83%), pain (85%), rash, and infection (seen with the SQ form)
• Respiratory manifestations such as cough, sore throat, and throat irritation (seen with inhaled form)

Systemic adverse effect:

• Central nervous system: Headache, syncope, paresthesia, jaw pain
• Cardiovascular: Flushing, hypotension, edema
• Gastrointestinal symptoms including nausea, abdominal discomfort, and diarrhea (mostly seen with oral form)

Long term adverse effects[6][7][2][3]:

• Epistaxis, hemoptysis, nasal discomfort, wheezing, and pneumonia

Contraindications

There are no contraindications to administering the SQ, IV, or inhaled route of medication. However, the dosage requires adjustment in mild, moderate, and severe hepatic dysfunction. Contraindications to the oral form of treprostinil include severe hepatic dysfunction (Child-Pugh class C).[8]

Monitoring

Treprostinil dosing must be carefully titrated slowly in an individualized manner, monitoring for symptom improvement with minimal adverse reactions at the current dosage.

Since treprostinil metabolism is via the liver, in patients with hepatic impairment, infusion and oral form of this medication can be initiated at a lower dose and titrated slowly.[7].

Researchers have not studied the safety of the inhaled form in patients with underlying pulmonary disease.

Toxicity

Researchers did encounter treprostinil overdose during the trials, which presented with signs and symptoms of vasodilatation such as flushing, hypotension, and headache. It can also result from pump dysfunction, accidental bolus administration, or prescribing the wrong dose. These symptoms are self-limited and will be resolved by temporarily discontinuing the medication or reducing the dosage.[6][9]

Enhancing Healthcare Team Outcomes

In patients with PAH (WHO group 1), treprostinil has been shown to improve the quality of life and the exercise capacity of patients who receive treatment. The effects of this drug have been the subject of study in multiple randomized controlled trials (RCT).

• TRUST trial showed that intravenous treprostinil improves the exercise capacity and dyspnea in treatment-naive patients with pulmonary artery hypertension.[10]
• TRIUMPH trial showed that inhaled treprostinil improved the quality of life and 6MWD in patients who were symptomatic on bosentan and sildenafil.[3]

However, patients with PAH will benefit from an interprofessional team approach to determine the optimal management. Patients with pulmonary hypertension, when treated with treprostinil, need close monitoring as adverse effects are common. Nursing will be at the front lines in this aspect since they have the first contact with the patient at each visit. They must report any suspected therapy failure or adverse effects to the prescribing physician immediately. Also, not all patients have the same response to the drug. Patients need to receive education from the pharmacist that medication compliance is critical for optimal response. Pharmacists must also perform medication reconciliation and verify dosing parameters. Only through interprofessional collaboration, as outlined above, can the patient achieve the best available results from treprostinil therapy. [Level 5]

However, the outcomes for most patients with pulmonary hypertension are guarded; to date, medications do improve the quality of life but offer no cure. The life expectancy of these patients is also markedly reduced.