Sildenafil in Pulmonary Hypertension

Dr.Sid Kaithakkoden MDMBBS,DCH,DNB,MD,MRCPCH,FCPS

alavisaid@aol.com

Pharmacology• Sildenafil is a selective Phosphodiesterase-5

inhibitor that has been reported to be a potent pulmonary vasodilator

• Sildenafil selectively inhibits phosphodiesterase 5 (PDE5 is abundant in pulmonary and penile tissue) which leads to stabilization of cyclic guanosine monophosphate (cGMP)

• cGMP is a second messenger of nitric oxide (NO)

• Stabilization of cGMP results in increasing nitric oxide (NO) at the tissue level leading to pulmonary vessel vasodilatation

• Nitric oxide has been considered the closest thing to an ideal vasodilator

• Sildenafil is a more potent acute pulmonary vasodilator than inhaled nitric oxide, however, Sildenafil is not pulmonary vascular specific

• Sildenafil administered orally has been shown to have beneficial effects in patients with PAH even during treatment with inhaled NO

• Sildenafil also prevents rebound pulmonary vasoconstriction on withdrawal of inhaled NO

Figure 1 Lung histology. (A) Arrow showing pulmonary vasculopathy with intimal proliferation and marked medial thickening. (B) Arrow showing impaired alveolarisation.

Rashid, A et al. Arch Dis Child 2005;90:92-98

Figure 1 Algorithm of the treatment of paediatric pulmonary arterial hypertension.

•Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near normal levels (<40 mg Hg)•Experience no change or an increase in their cardiac index•Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance•Normal right atrial pressure and cardiac output

PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1077-1083 (doi:10.1542/peds.2005-0523)

Oral Sildenafi l in Infants With Persistent Pulmonary Hypertension of

the Newborn: A Pilot Randomized Blinded Study

Hernando Baquero, MD, Amed Soliz, MD, Freddy Neira, MD, Maria E. Venegas, MD and Augusto Sola,

MD Division of Neonatology, Universidad del Norte, Barranquilla, Colombia

Division of Neonatology, Miami Children's Hospital, Miami, Florida

Division of Neonatology, Emory University, Atlanta, Georgia

• OBJECTIVE. – to evaluate the feasibility of using oral Sildenafil and its

effect on oxygenation in PPHN.

• DESIGN.– randomized, masked study in infants >35.5 weeks'

gestation and <3 days old with severe PPHN and oxygenation index (OI) >25 admitted to the NICU (Hospital Niño Jesús, Barranquilla, Colombia)

– The first dose (1 mg/kg) or placebo was given by orogastric tube <30 minutes after randomization and every 6 hours

– Preductal saturation and blood pressure were monitored continuously

– OI was calculated every 6 hours– The main outcome variable was the effect of oral

Sildenafil on oxygenation– Sildenafil or placebo was discontinued when OI was <20

or if there was no significant change in OI after 36 hours.

• RESULTS– Six infants with an OI of >25 received placebo, and 7

received oral Sildenafil at a median age of 25 hours. All infants were severely ill, on fraction of inspired oxygen 1.0, and with similar ventilatory parameters.

– In the treatment group, OI improved in all infants within 6 to 30 hours, all showed a steady improvement in pulse oxygen saturation over time, and none had noticeable effect on blood pressure; 6 of 7 survived

– In the placebo group, 1 of 6 infants survived.

• CONCLUSIONS. – Oral Sildenafil improved OI in infants with severe PPHN,

which suggests that oral Sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial.

Cochrane review• Kanthapillai P, Lasserson TJ, Walters EH.

Sildenafil for pulmonary hypertension. Art. No.: CD003562. DOI: 10.1002/14651858.CD003562.pub2. Date of last subtantive update: August 01. 2004

• Objectives– To determine the clinical efficacy of Sildenafil,

administered via any route to people with pulmonary hypertension in primary or secondary forms.

• Search strategy– MEDLINE, EMBASE and CENTRAL were searched with

pre-defined search terms. Searches were unto October 2005.

• Selection criteria– Randomised controlled trials were considered for

inclusion in the review.

• Main results– Four studies recruiting 77 participants met the inclusion

criteria of the review– Two studies assessed the acute effects of Sildenafil– Two small crossover study assessed the effects of long

term administration– The 'acute effect' studies indicated that Sildenafil has a

pulmonary vasodilatory effect– The two crossover studies showed improvement in

symptoms– One study showed improvement in fatigue domains from

a validated health status questionnaire– Both crossover studies reported that the drug was well

tolerated.