This document discusses pulmonary arterial hypertension (PAH), including its definition, classification, pathogenesis, clinical manifestations, natural history, diagnosis, and management. PAH is defined as a sustained elevation of pulmonary arterial pressure over 25 mm Hg at rest or 30 mm Hg with exercise, caused by various genetic and environmental factors. It is classified into 5 groups by the WHO based on underlying mechanisms. Common symptoms include dyspnea and fatigue. Treatment includes anticoagulants, vasodilators like prostacyclins, endothelin receptor blockers, PDE-5 inhibitors, and in severe cases, lung transplantation.

1. BY
Dr. VASUDEVA CHETTY.P

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 Pulmonary arterial hypertension is defined as a
sustained elevation of pulmonary arterial pressure to
more than 25 mm Hg at rest or to more than 30 mm
Hg with exercise, with a mean pulmonary-capillary
wedge pressure and left ventricular end-diastolic
pressure of less than 15 mm Hg.
Definition

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 Pulmonary hypertension is usually classified as primary
(idiopathic) or secondary.
 It is now clear, however, that there are conditions within
the category of secondary pulmonary hypertension that
resemble primary pulmonary hypertension in their
histo-pathological features and their response to
treatment.
 For this reason, the World Health Organization (WHO)
classified pulmonary hypertension into five groups on
the basis of mechanisms, rather than associated
conditions.

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 Imbalance of vascular effectors
 Associated environmental factors:hypoxia,
anorexigens[fenfluramine,dexfenfluramine],CNS
stimulants[methamphetamine,cocaine]
 Other associated conditions: scleroderma, (HIV),
human herpesvirus (HHV), portal hypertension,
thrombocytosis, hemoglobinopathies, and hereditary
hemorrhagic telangiectasia.
 Associated genetic abnormalities:
Pathogenesis

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There is increased expression of TF in the vasculature of patients with severe PAH.
TF activation leads to rapid initiation of coagulation when a vessel is damaged and is
involved in the migration and proliferation of PASMCs . TF can induce angiogenesis
by clotting-dependent mechanisms via thrombin generation and fibrin deposition.

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Clinical manifestations

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 The natural history of IPAH was well described by the
National Institutes of Health (NIH) registry, which enrolled
194 patients at 32 clinical centers from 1981 to 1985, before the
availability of any disease-specific therapy.
 The median survival was 2.8 years, with 1-, 3-, and 5-year
survival rates of 68%, 48%, and 34%, respectively.
 Associated conditions influence outcomes: Patients with CTD
and HIV-associated PAH tend to have a worse prognosis,
whereas those with congenital heart disease–associated PAH
tend to have a better prognosis.
Natural history of IPAH

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Prognostic factors

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Diagnostic algorithm for evaluation of PAH

18.  Medical management include:
 Digoxin ,Diuretics
 Supplemental oxygen
 Anticoagulants
 Vasodilator therapies:
--CCBs
--Prostacyclins
--Endothelin receptor blockers
--PDE-5 inhibitors
 Riociguat
 Fasudil
 Others.
 Surgical management include:
--Atrial septostomy
--heart-lung and Lung transplantation.
Management

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23.  Oral anticoagulant therapy is widely recommended
for patients with PAH, supported by the numerous
studies implicating thrombin as contributing to
disease progression.
 The current recommendation is to use warfarin in
relatively low doses, as has been recommended for
the prophylaxis of venous thromboembolism, with
the international normalized ratio (INR) maintained
at 2.0 to 3.0 times that of controls.
Anticoagulants

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Vasodilator therapies

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 Current practice guidelines recommend that calcium
channel blockers be used in vasoreactive patients, which is
not an U.S. Food and Drug Administration (FDA)-approved
use.
 It has been reported that up to 20% of patients with IPAH
are vasoreactive and will respond to high doses of calcium
channel blockers, with a dramatic reduction in pulmonary
artery pressure and pulmonary vascular resistance;
 High doses (e.g., amlodipine, 20 to 30 mg/day; nifedipine,
180 to 240 mg/day; diltiazem, 720 to 960 mg/day) must be
used to realize full benefit.

26.  Continuous intravenous infusion of epoprostenol
(synthetic prostacyclin) has been shown in randomized
clinical trials to improve symptoms related to IPAH,
exercise tolerance, hemodynamics, and short-term
survival.
 The short half-life (6 minutes) of epoprostenol is believed
to contribute to the hemodynamic collapse that has
occurred when the infusion is abruptly interrupted. Side
effects related to epoprostenol include flushing, headache,
diarrhea, and a unique type of jaw discomfort that occurs
with eating.
 The optimal dose of epoprostenol has never been
determined, but doses between 25 and 40 ng/kg/min are
typical .
Prostacyclins

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 Treprostinil is a stable prostacyclin analogue that has
pharmacologic actions similar to those of
epoprostenol, but differs in that it is chemically
stable at room temperature and has a longer half-life
(4 hours).
 Treprostinil has also been approved for intravenous
administration. The optimal dose of treprostinil has
never been determined, but doses of 75 to 150
ng/kg/min are typical.
 Iloprost, an analogue of prostacyclin, has been
approved for use via inhalation. Because of the short
half-life of iloprost, however, it requires frequent (up
to 12/day) inhalations. Iloprost is given by 2.5- or
5.0-μg ampules via a dedicated nebulizer that limits
the dose of drug that can be delivered.

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 Inhibition of the phosphodiesterase type 5 (PDE5)
enzyme produces pulmonary vasodilation by promoting
an enhanced and sustained level of cGMP, an identical
effect to that of inhaled NO.
 Sildenafil is a PDE5 inhibitor that has been shown to be a
selective pulmonary vasodilator with similar efficacy to
that of inhaled NO in lowering pulmonary artery
pressure. Sildenafil has a preferential effect on the
pulmonary circulation because of the high expression of
the PDE5 isoform in the lung.
 The recommended dosage is 20 mg three times daily, but
dosages as high as 80 mg three times daily have been
used safely, and in some patients may be more effective.
Side effects are generally mild and mainly related to
vasodilation (headache, flushing, and nasal congestion).
 Tadalafil is a long-acting selective PDE5 inhibitor that has
been recently approved for PAH. The effective dose was
40 mg once daily.
PDE-5 inhibitors

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 Bosentan, a nonselective ET receptor blocker, has produced an
improvement in 6-minute walk distance after 16 weeks as
compared with placebo in several clinical trials. It also has been
shown to lengthen a composite endpoint of time to clinical
worsening. The approved dosage of bosentan is 125 mg twice
daily.
 Ambrisentan is an ET-A-selective endothelin receptor blocker
that can be given once daily at a 5-mg dose, which can be
increased to 10 mg if the drug is well tolerated.
 Sitaxsentan is an ETA-selective endothelin receptor blocker that
can be given once daily at a 100 mg dose. Sitaxsentan is
currently approved only in the European Union, Canada, and
Australia.
 These drugs have similar side effects, which include peripheral
edema. They also have a potential of causing liver toxicity
requiring monthly monitoring of liver enzyme levels, and have
interactions with warfarin that require careful monitoring of the
INR
Endothelin receptor blockers

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 Imatinib inhibits the tyrosine kinase activity of the Bcr-Abl
oncoprotein, the stem cell factor c-kit, and the platelet-derived
growth factor receptor (PDGF-R) kinases. PDGF seems to play
an important role in the pathobiology of pulmonary vascular
remodeling. In vitro, imatinib inhibits PDGF-induced
proliferation and migration of cultured pulmonary artery
smooth muscle cells from patients with idiopathic PAH,
through blockage of PDGF-R phosphorylation.
 Soluble guanylate cyclase stimulator (riociguat)
 Riociguat is a first-in-class oral drug that directly stimulates
soluble guanylate cyclase, both independently of endogenous
NO and in synergy with NO.
 A single-dose hemodynamic study in 15 patients with PAH,
CTEPH, or PH associated with mild to moderate interstitial
lung disease reported that 1 or 2.5 mg of riociguat significantly
improved cardiopulmonary hemodynamics, including mPAP
and PVR, in a dose-dependent manner and to a greater extent
than inhaled NO.

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 Rho-Kinase Inhibitor:Fasudil is a potent and
selective inhibitor of Rho-kinase, with its inhibitory
effect on Rhokinase being 100- and 1,000-fold more
potent than on protein kinase C and myosin light
chain kinase, respectively.
 Long-term oral treatment with fasudil markedly
ameliorated PH and pulmonary vascular lesions in a
MCT-induced model in rats and a hypoxia-induced
model in mice. Intravenous administration of fasudil
also effectively reduces PVR in patients with PAH.

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