macitentan and tadalafil

Action and Spectrum

Actions and Spectrum: 

macitentan is an endothelin receptor antagonist. It blocks both endothelin receptor type A (ETA) and endothelin receptor type B (ETB). Endothelin is a substance that causes blood vessels to constrict, leading to increased blood pressure. In conditions like pulmonary arterial hypertension (PAH), there is an overproduction of endothelin, which contributes to the narrowing of the pulmonary arteries and increased lung resistance. By blocking the effects of endothelin on its receptors, macitentan promotes vasodilation and reduces the pressure in the pulmonary arteries, thus improving blood flow and decreasing the workload on the heart. 

tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor. PDE5 is an enzyme that breaks down cyclic guanosine monophosphate (cGMP), a signaling molecule that promotes the relaxation of smooth muscles in the arteries. In pulmonary arterial hypertension (PAH), there is a deficiency of cGMP, leading to increased vascular tone and constriction. By inhibiting PDE5, tadalafil prevents the breakdown of cGMP, leading to increased levels of cGMP and enhanced relaxation of smooth muscles in the pulmonary arteries. This results in vasodilation and improved blood flow, reducing pulmonary arterial pressure. 

Spectrum of activity: 

macitentan is specifically indicated for treating adults’ pulmonary arterial hypertension (PAH). It improves exercise capacity and delays disease progression in patients with PAH. 

tadalafil is indicated for treating pulmonary arterial hypertension (PAH) in adults. It improves exercise capacity and delays disease progression in patients with PAH. Tadalafil is also used to treat erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) in men. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Headache (14%) 

nasopharyngitis (≤20%) 

Anemia (13%) 

Bronchitis (12%) 

pharyngitis (≤20%) 

1-10% 

Increased serum transaminases 

Influenza 

Urinary tract infection 

Post marketing reports 

Flushing 

Hepatic injury 

Hypersensitivity reaction 

Edema 

Symptomatic hypotension 

Angioedema 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: macitentan should not be used in individuals with known hypersensitivity or allergy to the active substance or other medication components. 
• Severe Hepatic Impairment: macitentan is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as limited information is available on its safety and efficacy in this population. 
• Hypersensitivity: tadalafil should not be used in individuals with known hypersensitivity or allergy to tadalafil or other medication components. 
• Nitrates and Riociguat: tadalafil is contraindicated with nitrates or riociguat, as concomitant use may significantly drop blood pressure. 
• Severe Renal Impairment: tadalafil is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) due to limited data on its safety and efficacy in this population. 
• Severe Hepatic Impairment: tadalafil is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) due to limited data on its safety and efficacy in this population. 
• Hereditary Eye Disorders: tadalafil is contraindicated in patients with hereditary degenerative retinal disorders such as retinitis pigmentosa. 

Caution: 

• Hepatic Impairment: macitentan may be associated with liver function abnormalities. Caution should be exercised when using macitentan in patients with mild to moderate hepatic impairment (Child-Pugh Class A or B).  
• Anemia: macitentan can cause a decrease in hemoglobin levels (anemia). Regular monitoring of hemoglobin levels is recommended, and if significant anemia occurs, appropriate management should be initiated. 
• Fluid Retention: Fluid retention can occur with macitentan treatment, particularly in patients with underlying heart failure.  
• Cardiovascular Issues: tadalafil can cause a decrease in blood pressure. Caution is advised in patients with a history of cardiovascular disorders, including heart attack, stroke, life-threatening arrhythmias, unstable angina, or uncontrolled high blood pressure. 
• Vision and Hearing Loss: tadalafil has been associated with rare cases of sudden vision or hearing loss. Patients experiencing sudden vision or hearing impairment while using tadalafil should seek immediate medical attention. 
• Priapism: tadalafil can cause a prolonged erection (priapism), which can be painful and may lead to permanent damage to the penis.

Pregnancy / Lactation

Pregnancy consideration: It is contraindicated during pregnancy due to the risk of fetal harm. It may cause congenital disabilities and fetal death. 

Lactation: Excretion of the drug in human breast milk is known 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

macitentan is an endothelin receptor antagonist that blocks both endothelin receptor type A (ETA) and endothelin receptor type B (ETB). By inhibiting these receptors, macitentan reduces the constriction of blood vessels, leading to vasodilation and improved blood flow in the pulmonary arteries. 

tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor that increases cyclic guanosine monophosphate (cGMP) levels in smooth muscle cells. Increased cGMP promotes relaxation of the blood vessels, including those in the lungs, leading to vasodilation and improved blood flow in the pulmonary arteries. 

Pharmacodynamics:  

The combination of macitentan and tadalafil could lead to additive vasodilatory effects and cause a significant drop in blood pressure, which can be dangerous and life-threatening. 

Pharmacokinetics: 

Absorption 

Both macitentan and tadalafil are orally administered medications, and they are absorbed through the gastrointestinal tract. Macitentan is taken once daily, while tadalafil can be taken once daily or as needed, depending on the indication (PAH vs. erectile dysfunction). 

Distribution 

After absorption, both medications are distributed through the bloodstream to their target sites of action. 

Metabolism 

macitentan is primarily metabolized in the liver by an enzyme called CYP3A4, while tadalafil is metabolized mainly by CYP3A4 and, to a lesser extent, by other enzymes. 

Elimination and Excretion 

Both macitentan and tadalafil and their metabolites are eliminated from the body primarily through the feces (biliary excretion) and, to a lesser extent, in the urine. 

Adminstartion

Administration: 

Oral administration 

Take the medication along with the food 

Patient Information Leaflet

Patient information leaflet 

Generic Name: macitentan and tadalafil 

Why do we use macitentan and tadalafil? 

macitentan and tadalafil are both medications used to treat PAH individually, and they have different mechanisms of action. macitentan is an endothelin receptor antagonist that helps dilate blood vessels in the lungs, while tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor promoting vasodilation.