2. INTRODUCTION
Macitentan (Opsumit) is a novel dual endothelin receptor antagonist (ERA)
with sustained receptor binding properties developed by Actelion
Pharmaceuticals Ltd.
In October 2013, oral macitentan 10 mg once daily received its first global
approval in the US for the treatment of pulmonary arterial hypertension (PAH)
Under regulatory review in several other countries for the same indication.
Clinical development underway for other indications, including Eisenmenger
syndrome, ischaemic digital ulcers secondary to systemic sclerosis, and
glioblastoma
3. WHAT IS PH?
Characterized by sustained elevation of pulmonary vascular resistance, leading
to right ventricular failure and death.
Mean pulmonary arterial pressure greater than 25 mm Hg at rest or greater
than 30 mm Hg during exercise
Increased pulmonary vascular resistance is the main pathogenic mechanism.
Typically due to vasoconstriction, remodeling, and thrombosis of the small
pulmonary arteries and arterioles.
4. ET-1 & PAH
Endothelin (ET)-1 is upregulated in patients with PAH and influences
pathological changes, including vasoconstriction, proliferation and fibrosis in
the lung via two ET receptor subtypes, ETA (located mainly in smooth muscle
cells) and ETB (located in endothelial and smooth muscle cells)
5. MACITENTAN: PHARMACOLOGY
Mechanism of Action: Endothelin receptor antagonist (ERA); prevents
binding of endothelin (ET)-1 to both ET-A and ET-B receptors with high affinity
to ET receptors in pulmonary arterial smooth muscle cells
Metabolism: In liver; mainly by CYP3A4, minor amount by CYP2C19
Warnings: should not be used in pregnant women due to harmful effects on
the developing foetus
6. USES & DOSAGE
In PAH: 10 MG Once daily
Route: Oral
Orphan Designations:
Fixed dose combination of macitentan and tadalafil for treatment of
pulmonary arterial hypertension
Chronic thromboembolic pulmonary hypertension (CTEPH)
9. INTRODUCTION
Chemically, riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-
pyrimidinyl(methyl) carbamate.
The molecular formula and molecular weight of riociguat are C20H19FN8O2 and 422.42 g/mol, respectively.
New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators.
10. MECHANISM OF ACTION
Stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for
nitric oxide (NO)
NO binds to sGC and catalyzes synthesis of cGMP, which in turn activates protein kinase G regulation of
cytosolic calcium ion concentration; this cascade changes actin-myosin contractility resulting in vasodilation
PAH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of the
NO-sGC-cGMP pathway
Elicits a dual mode of action; it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and
also directly stimulates sGC via a different binding site, independently of NO
11. Bioavailability: 94%
Peak plasma time: 1.5 hr
Food does not affect bioavailability
Metabolism in liver- CYP1A1, CYP3A, CYP2C8 and CYP2J2
Dosage – 0.5mg to 2.5mg TID
Protein bound: 95%; primarily to albumin and alpha-1-acidic glycoprotein
Half-life: 12 hr ((patients with PAH); 7 hr (healthy individuals)
Systemic clearance: 1.8 L/hr (patients with PAH); 3.4 L/hr (healthy individuals)
Excretion: 40% urine; 53% feces
12. ADVERSE EFFECT
Headache
Hypotension
Indigestion
Diarrhea
Dizziness
Anemia (low number of red blood cells)
Gastro-esophageal reflux disease
Constipation
13. SELECTION OF PATIENTS
Patients with symptomatic PAH (idiopathic, familial, or associated with connective-tissue disease, congenital heart
disease, portal hypertension with liver cirrhosis, or anorexigen or amphetamine use) are included if they have-
1. pulmonary vascular resistance greater than 300 dynes/sec/ cm–5
2. a mean pulmonary-artery pressure of at least 25 mm Hg, and
3. a 6-minute walk distance of 150 to 450 m.
14. CONCLUSION
According to a study conducted –
Riociguat significantly improved the 6-minute walk distance, as well as pulmonary vascular resistance and
several other secondary efficacy end points, in patients with symptomatic pulmonary arterial hypertension who
were receiving no other treatment for the disease or who were receiving endothelin- receptor antagonists or
prostanoids.
