Pulmonary Hypertension

Pulmonary hypertension is defined as increased mean pulmonary

artery pressure (PAP) to > 25 mmHg at rest as assessed during right
heart catheterization. (ULN: 14 + 3)
 Updated Clinical Classification
of Pulmonary Hypertension

3
4 2

1
1) Pulmonary arterial hypertension (PAH).
2) PH due to left sided heart disease.
3) PH due to lung disease and/or hypoxia.
4) Thromboembolic PH.
5) Multifactorial PH. (as in sarcoidosis)
 Cor Pulmonale
(Diseased Heart due to diseased Lung)

RV LV Lung Disease RV LV
Causing PH

Cor Pulmonale: Right ventricular hypertrophy, with or without

failure, due to pulmonary hypertension resulting from diseases
affecting the structure and/or the function of the lung, and not
resulting from left sided cardiac disease. It has 2 types:
Hypoxic Cor 3
Pulmonale:
3
4

1 Vascular Cor
Pulmonale:
1 4
(1) Pulmonary Arterial Hypertension (PAH)
• Idiopathic (IPAH). Drugs Causing PH
• Drug and toxin associated. Low Probability Drugs

• Associated with congenital heart disease. • SSRIs: as Fluxotine

• Associated with schistosomiasis. • Pergolide: dopaminergic

agent used for treatment
• Pulmonary veno-occlusive disease. of parkinsonism.

High Probability Drugs • Oral contraceptives

• Anorexigenic agents as Fenfluramine – withdrawn group

They are potent SSRIs → ↑ serotonin which acts as a growth factor
for pulmonary artery smooth muscle cells.
• Amphetamines as Methylpropanolamine – rarely used group
(used to increase alretness and decrease appetitie).
They have pharmacologic similarities with fenfluramine.
• Dastinib: - used for treatment of chronic myeloid leukaemia.
Congenital Heart Diseases Causing PH

ASD with Left to Right shunt VSD with Right to Left shunt
(Eisenmenger`s syndrome)
Granulomatous reaction around Schistosoma ova in lung tissue
(2) PH due to left sided Heart Disease
• Left ventricular dysfunction (systolic and/or diastolic).
• Mitral valve disease (stenosis and/or regurgitation)
PH can be found in virtually all patients with severe
symptomatic mitral valve disease.

(3) PH due to Lung Disease and/or Hypoxia

• Obstructive lung diseases, mainly COPD.
• Restrictive lung diseases, as IPF.
• Central hypoventilation and sleep disordered breathing
• Chronic exposure to high altitude.
Factors Increasing Pulmonary Vascular Resistance
in Chronic Respiratory Diseases
Anatomic
• Attenuation (compression, destruction) of pulmonary vascular
bed (emphysema).
• Interstitial fibrosis.
• Thromboembolic lesions.
Functional
• Alveolar hypoxia:
o Acute Hypoxia → pulmonary VC
o Chronic hypoxia → remodeling of pulmonary vascular bed
(intimal thickening and smooth m. proliferation)
• Hyperviscosity (polycythaemia).
• Hypervolaemia (polycythaemia, metabolic alkalosis induced by
respiratory acidosis).
• PH is a poor prognostic factor in such cases as COPD, IPF.
• There is no specific treatment for PH in these cases.
• Long term oxygen therapy (LTOT) and other measures to relieve
hypoxia ↓ hypoxic pulmonary VC → ↓ pulmonary arterial
pressure, but it rarely returns to normal.
• Vasodilators (calcium channel blockers and PAH-targeted drugs)
are NOT recommended because they may accentuate V/Q
mismatch → more hypoxia.

(A) (B)
(4) Thromboembolic PH
• Acute: massive or submassive pulmonary embolism.
The most important
pathophysiologic process
is non- resolution of acute
embolic masses which
undergo fibrosis leading to
mechanical obstruction of pulmonary arteries.
• Chronic: chronic or recurrent thromboembolism
(pulmonary showers).
Up to 50% of patients have no past history of DVT or
acute pulmonary embolism.
Most Common Causes of PH
• COPD.
• Sleep apnoea syndrome.
• Left sided heart diseases. (hypertensive, coronary, …)
• Schistosomiasis: declining in Egypt and worldwide.
 Diagnosis of PH
• Symptoms: low fixed cardiac output →
• Effort syncope.
• Effort blurring of vision.
• Effort angina.
• Easy fatigue.
• Signs: dilated right ventricle and pulmonary artery.

• ECG:
• Tall peaked P-wave (P-pulmonale)
• In advanced cases: arrhythmias as atrial flutter, atrial fibrillation.
The latter causes rapid irregular heart rate → further decrease of
COP
• Chest X-Ray:

RVH (arrows, note filling of the retrosternal space by an enlarged

right ventricle in the lateral view)
and enlarged central pulmonary arteries (arrowheads).
 Pulmonary vasculature Aneurysmal dilatation of
showing central dilatation pulmonary artery
and peripheral oligaemia
• Echocardiography:
• Should always be performed when PH is suspected.
• may be technically difficult due to chest hyperinflation.

• Right Heart Catheterization: Gold standard,

but uncommonly used.
It is done in cases of PAH to:
• Confirm diagnosis.
• Assess severity.

• Do Vasoreactivity Testing
- Inhaled NO is the vasodilator agent most commonly used.
- Alternatives include IV epoprostenol, IV adenosine, inhaled iloprost.
- Positive response is defined by ↓ mean PAP > 10 mmHg to reach an
absolute value of < 40 mmHg.
- Only about 10% of IPAH patients meet these criteria. Those +ve
acute vasoreactivity test responders are the patients most likely to
have a sustained response to long term treatment with calcium
channel blockers (CCBs).
 Treatment of PH
(with particular emphasis on IPAH)

General Measures and Non PAH-Targeted Drugs

PAH-Targeted Drugs

General CCBs
Measures
• Long term oxygen therapy (LTOT).
• Anaemia treatment.
• Infection prevention.
• Venous thromboembolism prevention.
• Diuretics
Long Term Oxygen Therapy
• Not needed by most patients of IPAH who may have only mild
hypoxaemia, unless they travel to high altitude (> 1500 – 2000 m),
when they need supplemental O2.
• Most patients with PH due to lung disease have significant
hypoxaemia because of V/Q mismatch (and other factors). Oxygen
therapy would be beneficial to reduce both hypoxaemia and PH
(through reducing hypoxic pulmonary VC).
It should maintain PaO2 > 60 mmHg.

Anaemia Treatment
Any degree of anaemia, even if mild, should be corrected because
PAH patients are highly sensitive to reduction in Hb level (low fixed
COP).

Infection Prevention
Influenza and pneumococcal vaccines are recommended in IPAH
because these patients have increased susceptibility to develop
pneumonia.
Venous Thromboembolism Prevention
• Increased risk of VTE in IPAH is due to
o Abnormalities in coagulation and fibrinolytic pathways.
o Presence of mural thrombi in central pulmonary arteries.
o Associated risk factors as heart failure, immobility.
o Risk of venous catheter thrombosis in patients treated with long term
IV prostaglandins. (Anticoagulation of these patients is mandatory, in
absence of contraindications).
• Oral anticoagulants are used to target INR 1.5 – 2.5 (2 – 3 in patients with
chronic thromboembolic PH)
Diuretics
• Generalized oedema results from Rt sided heart failure.
• Patient is advised to reduce salt and water intake.
• Diuretics have a clear symptomatic benefit.
• IV administration of diuretics may be temporarily preferred to overcome
reduced oral bioavailability due to intestinal mucosal oedema.
• Loop diuretics are generally used, eg, Frusemide 20 mg twice daily.
It may be increased in resistant cases up to 500 mg/day.
Calcium Channel Blockers
• Utility should 1st be demonstrated by acute vasoreactivity testing.
• Ideally patients who have not undergone testing or had a negative
test should not be started on CCBs because of lack of efficacy and
potebtial severe side effects (hypotension, syncope, right ventricular
failure).

• Agents are started at low doses and then gradually increased to

relatively high doses, eg,
- Nifedipine (Adalat LA) 30 mg X 2 → 60 mg X 2
- Diltiazem (Altiazem) 60 mg X 3 → 120 mg X 3
- Amlodipine (Norvasc) 2.5 mg X 1 → 10 mg X 1
• Limiting factors for dose increase are:
o Systemic hypotension.
o Pedal oedema (esp. with amlodipine).

• Patients who are not candidate for, or not responding to CCBs

should be treated with PAH- targeted drugs.
 Pulmonary Hypertension
1) Pulmonary arterial hypertension (PAH).
Types:
* Idiopathic PAH (IPAH).
2) PH due to left sided heart disease.
3) PH due to lung disease and/or hypoxia.
4) Thromboembolic PH.
5) Multifactorial PH. (as in sarcoidosis)

Treatment: • Long term oxygen therapy (LTOT).

• Anaemia treatment.
• Infection prevention.
• Venous thromboembolism prevention.
• Diuretics
• CCBs.
• PAH targeted drugs.
 Pharmacologic Targeting of Endothelial Dysfunction

Vascular Endothelium: cellular

monolayer lining the blood vessels.
Endothelial Function: to maintain
normal rheological properties of blood:

to keep blood flowing smoothly and halt the processes of

atherosclerosis, thrombosis and inflammation.
This depends on the balance between 2 groups of
endothelium- derived mediators:
 Prostacyclin Endothelins
(Prostaglandin I2) Angiotensin II
NO (EDRF) Thromboxanes

Vasodialtor Vasoconstrictor
Anticoagulant Coagulant
Antiproliferative Proliferative
Anti-inflammatory Inflammatory
In PAH

↓ PGI2
↑ Endothelins
↓ NO
Endothelins
• They comprise 3 structurally similar 21 amino acid peptides.
• Endothelin 1 (ET-1) is the most abundant isoform.
• It is the most potent vasoconstrictor in human
cardiovascular system, with a remarkably long- lasting action.
• The 1ry source of ET-1 is vascular endothelial cells, but it is
produced also by many other cell types.
• Hypoxia induces expression of ET-1 genes. This may
partially explain the pulmonary hypoxic vasoconstrictor
response.
• ET-1 acts primarily on the underlying smooth muscle cells
causing vasoconstriction and smooth m. cell proliferation.
• It acts also on fibroblasts, causing proliferation and fibrosis.
Endothelin Receptors
• Two types: ETA and ETB.
• They are located on:
o Vascular endothelial cells: ETB only
o Vascular smooth m. cells: ETA predominate over ETB
• ETA receptors on vascular smooth m. cells mediate direct, strong ETB
ETA
and long- lasting vasoconstriction.
• ETB receptors on endothelial cells counterbalance ETA
the effect of ETA stimulation:
ETB
o Release of NO and prostacyclin which mediate
vasodilatation and inhibit ET-1 release.
ETA
o Clearance of circulating ET-1.
• ETB receptors on vascular smooth m. cells are thought ETA
ETB

to mediate vasoconstriction also.

• The lung plays a predominant role in the endothelin
system:
o It contains some of the highest concentrations of ET-1
in any organ.
o ETB receptors on the lungs play an important role in
clearance of circulating ET-1.
• ET-1 plays mainly a paracrine/autocrine rather than a
systemic role as evidenced by its very short plasma half life
(1 minute) and very low plasma concentration that is below
the threshold thought to be necessary to significantly
activate ET-1 receptors.
• The free concentration of the ligand does not necessarily
reflect the biologic activity of the system.
• Activation of the endothelin system was demonstrated in
both plasma and lung tissue of PAH patients.
Prostaglandin I2 (Prostacyclin)
• It is synthesized primarily by vascular endothelial cells.
• Its natural ligand is the prostacyclin IP receptor, which is
expressed in many organs, including pulmonary arteries.
• Stimulation of IP receptors leads to:
o Vasodialataion (potent, involving all vascular beds).
o Inhibition of vascular smooth m. proliferation.
o Inhibition of platelet aggregation (most potent endogenous
inhibitor of platelet aggregation).
o Bronchodilatation.
o Inhibition of gastric acid secretion and motility.

• In PAH, pulmonary concentrations of Prostacyclin are

reduced, probably due to ↓ prostacyclin synthase
expression.
Nitric Oxide
• NO is synthesized in
endothelial cells from
the amino acid L-
arginine under effect of
the enzyme endothelial
NO synthase (eNOS).
• In smooth m. cells,
NO activates the
enzyme guanyl cyclase
(GC) which catalyzes the conversion of guanine
triphosphate (GTP) to cyclic guanine monophosphate
(cGMP). The latter acts as the 2nd messenger of the NO
pathway.
Phosphodiesterase 5 (PDE5) inactivates cGMP,
converting it to GMP.
 How to Pharmacologically Target These 3 Systems?

Endothelin Prostacyclin NO
System System System
• ↓ ET-1 production • Prostacyclin • NO
analogues
• Block ET-1 • NO donors
(Prostanoids)
receptors
• PDE5Is
• IP receptor agonists

The only practical options:

• Endothelin receptor • Prostacyclin • PDE5Is

antagonists (ERAs) analogues
(Prostanoids)
• IP receptor agonists
Inhaled Nitric Oxide may be used as an add on therapy to
currently approved PAH drugs, but application in the
outpatient setting is limited by the need for cumbersome
equipment and frequent administration due to very short
half life.
NO releasing Agents as Nitrates failed to produce
beneficial long- term effect because negligible pulmonary
VD was counterbalanced by significant peripheral VD and
reflex tachycardia, both of which are poorly tolerated by
patients with severe PAH.
 WHO Functional Classification of PAH
• The clinical severity of PAH is classified into 4 classes
according to the system that was originally developed for
heart failure by the New York Hear Association (NYHA).
• Functional class determines the recommended lines of
treatment, and is a powerful predictor of outcome.
• FC I: No limitation of activity. No symptoms even during exertion.
Usually defined in asymptomatic at risk patients (eg, due to +ve family
history) or patients improving with treatment.
• FC II: Slight limitation of activity. Ordinary activities cause some
symptoms.
• FC III: Moderate limitation of activity. Less than ordinary activities
cause marked symptoms.
• FC IV: Severe limitation of activity. Severe symptoms even at rest.
Features of heart failure as generalized oedema.
 Treatment Directions by Functional Class
• FC I (at risk):
• Monitoring for the development of symptoms that would signal
disease progression.
• Treatment of contributing causes of PH as COPD, sleep apnoea.
• FC II:
• Acute Vasoreactivity +ve: CCBs.
• Acute Vasoreactivity –ve or failure or contraindication for CCBs:
Initiate monotherapy with either ERA or PDE5I.
• FC III:
• Start with ERA and/or PDE5I.
• If no adequate response: Add a prostanoid.
(or start with a prostanoid in severe cases).
• FC IV: IV epoprostenol is the recommended 1st line of treatment.
2nd line: ERA and/or PDE5I.
Initial combination therapy may be considered.
 Prostanoids and IP Receptor Agonists
• IV epoprostenol was the 1st drug to be approved for PAH.
• It continues to be the gold standard of therapy for severe
PAH (FC III or IV).
• Its effects are more consistent, rapid, titrable and robust
than other PAH approved medications (including other
prostanoids).
• It is the only treatment shown to confer a survival benefit
in IPAH in a randomized study.
• Despite these facts, IV epoprostenol and prostanoids in
general are markedly underutilized.
• Because of ease of administration, oral agents are
generally preferred as initial therapy unless the condition
is severe.
 IV Epopoprostenol (Flolan)
• It is the sodium salt of prostacyclin.
• Available as powder in vials of 0.5 or 1.5 mg with 50 mL
solvent.
• Produces significant, predictable and dose- related ↓ in
pulmonary vascular resistance associated with a dose
related ↑ in COP.
• Treatment is usually initiated in hospital, particularly in
severely ill patients in order to:
o Ensure stabilization and improvement of the clinical
status.
o Educate both patient and family about safe
administration.
• The earliest formulations had very low thermal stability → need for a
frozen gel or ice pack to keep the drug at 2 – 8 OC.
The pack is changed every 12 hh.
• A more thermostable formulation has subsequently been developed.
• Reconstituted soln. must be protected from light and used within 8h
(room temp) or 48hh (2- 8 OC). It should not be frozen.
• Half life is short (3 – 5 min), so it should be given as a continuous IV
infusion using a battery operated infusion pump and a permanent
tunneled catheter.
• During episodes of catheter malfunction, it may be temporarily
administered as an ordinary IV infusion through a small vein.

• Contraindications: congestive heart failure due to

severe left ventricular systolic dysfunction (↑
mortality).
• Interactions: ↑ Digoxin concentration
→ risk of digoxin toxicity.
• The ambulatory infusion pump
should be:
o Small and lightweight.
o Able to adjust infusion rate in
2mcg/kg/min increments.
o Have alarms for occlusion,
end of infusion and low battery.
• Dose: initiated at 2 – 4 mcg/kg/min to be increased
2 mcg/kg/min every 15 minutes as needed. Dose escalation
may be limited by adverse effects (flushing, headache,
hypotension, nausea, vomiting, diarrhoea, musculoskeletal
pains). Optimal dose ranges 20 – 40 mcg/kg/min.
• Less common SE: chest pain, abdominal pain, anxiety,
dizziness, palpitations, bleeding complications.
• Following dosage adjustment, heart rate and BP (supine
and standing) should be monitored closely for several
hours.
• Serious adverse events related to the delivery system:
o Infection.
o Thromboembolism (prophylactic anticoagulation required).
o Pump malfunction.
o Catheter obstruction.

• Interruption of delivery of whatever cause → rebound

worsening of PH → symptomatic deterioration, even death.
• IV epoprostenol requires high degree of patient training,
motivation and support. It should be provided only by
centers with experience and staffing required to provide 24
hh support for complicated patients.
 Inhaled Iloprost

• A chemically stable prostacyclin analogue.

• t ½ : 20 – 30 mins.
• Dose: 2.5 - 5 mcg/inhalation, repeated 6 – 12 times daily
(median 30 mcg daily).
• May be used for acute vasoreactivity testing.
• SE:
o Cough.
o Chest pain.
o Pharyngolaryngeal pain.
o Dry mouth.
 Oral Selexipag

• A novel orally available long acting selective IP

receptor agonist.
• Chemically, it is unrelated to prostacyclin or its
analogues.
• t ½ : 6 – 12 hh. So given twice daily.
 Endothelin Receptor Antagonists (ERAs)

Dual Blockers Selective ETA Blockers

Block both ETA and ETB Receptors:
Ambrisentan
- Bosentan
- Macitentan
It is not known whether selective ETA blockade confers a greater
clinical benefit than dual receptor blockade.
 Bosentan
• Dose: 62.5 mg twice daily for 4 weeks, then
125 mg twice daily.
(but continued same dose if body weight < 40 kgm).
• Kinetics: mainly excreted through the biliary route.
Effect of renal impairment is small and does not require
dose adjustment.
• Side Effects:
Eleveted Liver Enzymes (Boxed Warning)
• Reported in 11% of cases.
• Elevations are dose- dependent, occur both early and
late in treatment, usually progress slowly and are
typically asymptomatic.
• They usually revert to normal after treatment cessation or
interruption. They may revert to normal while continuing treatment.
• Transaminases should be measured before initiation of treatment and
then monthly. Action depends on level of elevation:
3 - 5X ULN : Confirm by another test
If confirmed: ↓ dose to 62.5 mg twice daily or interrupt treatment.
Monitor every 2 weeks. If level returns to pretreatment value, continue.
5 – 8X ULN: Confirm by another test.
If confirmed: stop treatment.
Monitor every 2 weeks. If level returns to pre-treatment value, consider
re-introduction.
> 8X ULN: Stop and do not re-introduce (may use an alternative ERA).
• Continuation refers to continuing the same dose while re-introduction
means returning to the lower starting dose of 62.5 mg twice daily.
• Transaminases should be checked 3 days after re-introduction and
then every 2 weeks.
• The drug should be stopped at any time if transaminase
elevation is accompanied by
o Clinical features of hepatic dysfunction: nausea,
vomiting, fever, abdominal pain, jaundice, lethargy.
o ↑ Bilirubin > 2X ULN.
Pregnancy Category X = may cause Serious Birth Defects
(Boxed Warning)
• A negative pregnancy test should be documented
before the drug is dispensed to a female in the child
bearing age.
• Two reliable non- hormonal contraceptive methods
should be used during treatment.
• Follow up pregnancy tests are done monthly. The
physician should be notified once pregnancy is
suspected.
Other Side Effects
• Fluid retention → oedema
(may exaggerate that caused by PAH).
• Oligospermia: due to suppression of spermatogenesis:
common but usually transient.
• ↓ Hemoglobin: by an average of 0.9 gm/dL,
- Detected within the 1st few weeks of treatment, followed
by stabilization.
- Hb level is recommended to be checked after 1, 3
months of treatment, then every 3 months.
• Angioedema: 8 – 20 h after starting treatment.
It responds to treatment without discontinuing the drug.
Drug Interactions:
• Cyclosporin A: Bosentan ↓ plasma level of Cx A by 50%
whereas the latter markedly ↑ plasma level of Bosentan
due inhibition of transport protein mediated uptake of
Bosentan by hepatocytes.
• Hormonal Contraceptives: decreased level, so they are
unreliable in patients treated with Bosentan
• Statins: decreased level. The lipid profile should be
monitored. Statin dose may need to be increased.
• Glyburide (in Diavance): Increased risk of liver enzyme
elevation. So, an alternative hypoglycemic agent is to be
used.
• PDE5Is: decreased level, but clinical significance not
defined. Specific interaction studies are needed.
Contraindications:
• Pregnancy.
• Elevated transaminases > 3X ULN at baseline
(monitoring liver injury difficult) or other evidence of
moderate to severe liver impairment.
• With Cyclosporin A.
 Other ERAs

• Less likely to cause elevated liver enzymes, so may be

used as alternative to Bosentan.
• Monthly monitoring of liver enzymes is not required.
• Macitentan is 10 fold more potent than Bosentan.
It has greater tissue penetration and longer duration of
action.
 Phosphodiesterase 5 Inhibitors (PDE5Is)
• Phosphodiesterases are a superfamily of enzymes that inactivate:
- cAMP → AMP
- cGMP → GMP
• Phosphodiesterase 5 is abundantly expressed in lung tissue and
appears to be upregulated in PAH.
• Mild and moderate renal or hepatic failure does not significantly
affect the metabolism of PDE5Is
• Side Effects: generally well tolerated, transient and dose dependent:
- Hypotension: risky if coadministered with NO donors as nitrates.
So, this combination is contraindicated
- VD → Headache, flushing, nasal congestion.
- Digestive disorders (nausea, dyspepsia).
- Impaired color vision: mainly with sildenafil due to inhibition of the
retinal PDE6.
• 3 preparations are commonly used for treatment of
erectile dysfunction: Sildenafail, Tadalafil, Vardenafil.
• The 1st 2 have been approved for treatment of PAH.
• Sildenafil: (t ½ 4 hh) has the advantages of low cost and
excellent tolerability.
It is started a dose of 20 mg thrice daily.
• Tadalafil: (t ½ 17.5 hh) more convenient because given
once daily.