Pulmonary Arterial Hypertension Treatment with Sildenafil and Tadalafil

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• PAH Treatment Medications
• Mechanism of Action
• First-Line Therapy
• Dosing Information
• Side Effects
• Full Transcript

PAH Treatment Medications

Dr. Aaron Waxman, MD, a leading expert in pulmonary hypertension, discusses key medications for pulmonary arterial hypertension. He explains that phosphodiesterase 5 inhibitors, including sildenafil (Viagra) and tadalafil (Cialis), are central to PAH therapy. Dr. Waxman also mentions riociguat (Adempas), a soluble guanylate cyclase stimulator that works in the same pathway. These drugs are all potent vasodilators that target the underlying vascular issues in PAH.

Mechanism of Action

Dr. Aaron Waxman, MD, details how these pulmonary arterial hypertension medications work. He explains that they operate within the nitric oxide pathway, which is the body's most potent vasodilator. Nitric oxide works through cyclic GMP. Phosphodiesterase 5 inhibitors like sildenafil and tadalafil prevent the breakdown of cyclic GMP, allowing it to remain active longer. In contrast, riociguat directly stimulates soluble guanylate cyclase, increasing the production of cyclic GMP. This action is crucial because patients with PAH often have inadequate nitric oxide production.

First-Line Therapy

Dr. Anton Titov, MD, asks about the placement of these drugs in the PAH treatment algorithm. Dr. Aaron Waxman, MD, confirms that sildenafil and tadalafil are considered first-line therapy for pulmonary arterial hypertension. He states they are generally very well tolerated and easy for patients to use. Riociguat is also effective but is a little more complicated to initiate due to a required titration process. Dr. Aaron Waxman, MD, emphasizes that these medications are not combined with each other but are used as individual agents.

Dosing Information

The dosing for pulmonary arterial hypertension differs from that used for erectile dysfunction. Dr. Aaron Waxman, MD, explains that the approved dose for sildenafil in PAH is 20 milligrams three times daily, based on clinical trials. However, he notes that physicians often titrate the dose for individual patients. For tadalafil, the dose used in PAH treatment is 40 milligrams taken once every day. This frequent, higher dosing is specific to managing the chronic nature of pulmonary arterial hypertension.

Side Effects

Dr. Anton Titov, MD, inquires about the safety profile of these PAH treatments. Dr. Aaron Waxman, MD, explains that significant cardiovascular side effects are rare. This is because phosphodiesterase 5 is predominantly localized to lung vessels and the penis. Some patients might experience a slight drop in blood pressure. The most common side effect is headache, which Dr. Waxman describes as more of a nuisance than a severe problem. These headaches are usually readily managed with over-the-counter pain relievers like acetaminophen or NSAIDs.

Full Transcript

Dr. Anton Titov, MD: You mentioned phosphodiesterase type 5 inhibitors. They are also used for erectile dysfunction. Common medications are Viagra (sildenafil) and Cialis (tadalafil). There are other medications in that class. These medications are also used to treat pulmonary arterial hypertension.

Dr. Anton Titov, MD: How are phosphodiesterase type 5 inhibitors used for pulmonary arterial hypertension therapy? Are they effective?

Dr. Aaron Waxman, MD: There is probably a different dosing schedule. Phosphodiesterase 5 inhibitors are in the nitric oxide pathway. Nitric oxide is our most potent vasodilator. It works through cyclic GMP. All the phosphodiesterase 5 inhibitors do is keep that cyclic GMP around longer by preventing its breakdown.

Dr. Aaron Waxman, MD: Within the same pharmaceutical pathway, we also have a medication called riociguat (Adempas). It is a soluble guanylate cyclase stimulator. It increases the amount of available cyclic GMP. Riociguat works in parallel with nitric oxide. It also works independently of nitric oxide in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension generally have inadequate nitric oxide production. All of these medications are vasodilators. There is probably some added benefit of vasodilation in pulmonary arterial hypertension, although we don't fully understand yet how.

There is cellular remodeling in pulmonary arterial hypertension. It is both myocardial remodeling and vascular remodeling. But there is no way to know which patients are going to get the most benefit from each individual medication.

I would say from an efficacy standpoint they are all pretty equivalent in pulmonary arterial hypertension. We don't combine these medications. But as individual medications, sildenafil, tadalafil, and riociguat are all pretty equivalent.

Dr. Anton Titov, MD: Are they used early in therapy for pulmonary arterial hypertension, or are they used when the first line of therapy fails?

Dr. Aaron Waxman, MD: No, they probably are now first-line therapy. Certainly sildenafil and tadalafil are considered first-line therapy because they are generally very well tolerated. They are easy to use and have been around for a long time in pulmonary arterial hypertension.

Riociguat is a little more complicated to use because there is titration involved. It has a broader FDA approval targeting indication for use, including chronic thromboembolic disease. But otherwise, it is probably equally effective in pulmonary arterial hypertension.

Dr. Anton Titov, MD: What is a typical dose of tadalafil and sildenafil in pulmonary arterial hypertension? Is it a smaller dose compared with doses used for erectile dysfunction indications?

Dr. Aaron Waxman, MD: We did the clinical trials in pulmonary arterial hypertension. We studied sildenafil at 20 milligrams, 40 milligrams, and 80 milligrams three times per day. The usual dose of sildenafil for erectile dysfunction is 25, 50, 75, or 100 mg "when you need it."

Certainly during the clinical trial, we were using Viagra at those doses. It was before Viagra was approved for pulmonary arterial hypertension. There is room for dose adjustment. The only dose of sildenafil that was approved was 20 milligrams three times a day.

From an insurance standpoint, we might have a little difficulty changing the dose, but we often do titrate the dose. We used tadalafil (Cialis) at 40 milligrams once a day for treatment of pulmonary arterial hypertension.

Dr. Anton Titov, MD: Every day? This is a frequent and fairly large dosing for pulmonary arterial hypertension treatment. What were the cardiovascular side effects of tadalafil and sildenafil? What other side effects have you seen in treatment of pulmonary arterial hypertension?

Dr. Aaron Waxman, MD: It is interesting. The reason we went to phosphodiesterase inhibitor medications is this: phosphodiesterase 5 is predominantly localized to the vessels of the lung and the vessels of the penis. We don't see a huge incidence of cardiovascular side effects.

There are some patients whose blood pressure may be a little low with these medications. But most patients with pulmonary arterial hypertension tolerate sildenafil and tadalafil quite well.

The most important side effect that we see is headache. But it is not a bad headache; it can be a nuisance. Headache from sildenafil or tadalafil is usually readily responsive to Tylenol and aspirin or other non-steroidal anti-inflammatory medications.