Flolan is used to treat primary pulmonary hypertension which is characterised by high blood pressure in the blood vessel that carries blood from the heart to the lungs, and increased resistance in the blood vessels of the lung. The cause of primary pulmonary hypertension is not known.

Flolan belongs to a group of medicines called prostaglandins. Flolan works by widening the blood vessels in the lungs and so lowering the blood pressure in your lungs (known as a vasodilator action).

Fen-phen

From Wikipedia, the free encyclopedia
Fen-phen was an anti-obesity medication (an anorectic) which consisted of two drugs: fenfluramine and phentermine. Fenfluramine, and later a related drug, dexfenfluramine, was marketed by American Home Products, now known as Wyeth.

After reports of valvular heart disease and pulmonary hypertension primarily in women who had been undergoing treatment with fen-phen, the Food and Drug Administration (FDA) requested its withdrawal from the market in September 1997.

The action was based on findings from doctors who had evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicated that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. This is a much higher than expected percentage of abnormal test results.

In July 1997, researchers at the Mayo Clinic and Mayo Foundation reported 24 cases of rare valvular disease in women who took the "fen-phen" combination therapy. FDA alerted medical doctors that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s MedWatch program or to the respective pharmaceutical manufacturers.

Subsequently, FDA received 66 additional reports of heart valve disease associated mainly with "fen-phen." There were also reports of cases seen in patients taking only fenfluramine or dexfenfluramine. FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and patient package inserts. As of 1997, the FDA continued to receive reports of cardiac valvular disease in persons who have taken these drugs. This valvular disease typically involves the aortic and mitral valves.

As of 2004, fen-phen is no longer widely available. In April 2005, American Lawyer magazine ran a cover story on the fen-phen mass tort crisis and reported that more than 50,000 product liability lawsuits had been filed by alleged fen-phen victims. Estimates of total liability run as high as $14 billion.

Systematic (IUPAC) name
5-[7-hydroxy-8- (3-hydroxyoct-1-enyl) -4-oxabicyclo[3.3.0]oct-3-ylidene] pentanoic acid
Identifiers
CAS number 35121-78-9
ATC code B01AC09
PubChem 114805
DrugBank APRD00949
Chemical data
Formula C20H32O5
Mol. mass 352.465 g/mol
SMILES search in eMolecules, PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat. ?
Legal status
Routes ?

Prostacyclin is a member of the family of lipid molecules known as eicosanoids. A synthetic form of prostacyclin, used as a medicine, is referred to as epoprostenol. It is produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane).

The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3.(Fischer, 1985) The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ?-6 arachidonic acid. PGI3 is derived from the ?-3 EPA.
Contents

* 1 Mode of action
* 2 Pharmacology
* 3 References
* 4 See also

Mode of action

Prostacyclin acts chiefly to prevent platelet formation and clumping involved in blood clotting. It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane, another eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two hormones in relation to vascular damage.

Pharmacology

Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:

* as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
* in pulmonary hypertension.

Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to PGH2, the immediate precursor of prostacyclin.

References

* Dorlands Medical Dictionary. epoprostenol. Retrieved on February 10, 2006.
* Fischer S, Weber PC (Sep 1985). Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry.. Retrieved on February 10, 2006. PubMed abstract

Pulmonary hypertension
Classification & external resources ICD-10 I27.0, I27.2
ICD-9 416
DiseasesDB 10998
eMedicine radio/583
MeSH D006976

In medicine, pulmonary hypertension (PH) is an increase in blood pressure in the pulmonary artery or lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion. Depending on the cause, pulmonary hypertension can be a severe disease with a markedly decreased exercise tolerance and right-sided heart failure. It was first identified by Dr Ernst von Romberg in 1891.[1] It can be one of five different types, arterial, venous, hypoxic, thromboembolic, or miscellaneous.

Although the terms primary pulmonary hypertension (meaning of unknown cause) and secondary pulmonary hypertension (meaning due to another medical condition) still persist in materials disseminated to patients and the general public, these terms have largely been abandoned in the medical literature. This change has occurred because the older dichotomous classification did not reflect pathophysiology or outcome. It led to erroneous therapeutic decisions, i.e. treat "primary" pulmonary hypertension only. This in turn led to therapeutic nihilism for many patients labeled "secondary" pulmonary hypertension, and could have contributed to their deaths. The term "primary pulmonary hypertension" has now been replaced with "idiopathic pulmonary arterial hypertension". The terms "primary" and "secondary" pulmonary hypertension should not be used any longer. Further details are in the Classification section below.
Contents

* 1 Signs and symptoms
* 2 Causes
* 3 Pathogenesis
* 4 Diagnosis
* 5 Classification
o 5.1 Current classification
o 5.2 Previous terminology
* 6 Epidemiology
* 7 Treatment
o 7.1 Vasoactive substances
o 7.2 Surgical
* 8 Prognosis
* 9 References
* 10 External links

Signs and symptoms

A history usually reveals gradual onset of shortness of breath, fatigue, non-productive cough, angina pectoris, fainting or syncope, peripheral edema (swelling of the limbs, especially around the ankles and feet), and rarely hemoptysis (coughing up blood). Pulmonary arterial hypertension (PAH) typically does not present with orthopnea or paroxysmal nocturnal dyspnea, while pulmonary venous hypertension typically does.

In order to establish the cause, the physician will generally conduct a thorough medical history. A detailed family history is taken to determine whether the disease might be familial. A history of exposure to cocaine, methamphetamine, alcohol leading to cirrhosis, and smoking leading to emphysema are considered significant. Physical examination is performed to look for typical signs of pulmonary hypertension including a loud P2 (pulmonic valve closure sound), (para)sternal heave, jugular venous distension, pedal edema, ascites, hepatojugular reflux, clubbing etc.

Causes

The most common cause of pulmonary hypertension is left heart failure leading to pulmonary venous hypertension. This may be due to systolic or diastolic malfunction of the left ventricle or due to valvular dysfunction such as mitral regurgitation or mitral stenosis. It usually manifests as pulmonary edema.

Common causes of pulmonary arterial hypertension (PAH) include HIV, scleroderma and other autoimmune disorders, cirrhosis and portal hypertension, sickle cell disease,[2] congenital heart disease, thyroid diseases,[3] and others. Use of weight loss pills such as Fen-Phen, Aminorex, fenfluramine (Pondimin), and phentermine led to the development of PAH in the past.[4] Other causes include sarcoidosis, histiocytosis X, and fibrosing mediastinitis. Pulmonary embolism also leads to pulmonary hypertension, acutely as well as chronically. When none of these causes can be found, the disease is termed idiopathic pulmonary arterial hypertension (IPAH).

Lung diseases that lower oxygen in the blood (hypoxia) are well known causes of pulmonary hypertension, including COPD, interstitial lung disease, Pickwickian syndrome or obesity-hypoventilation syndrome, and possibly sleep apnea. Human herpesvirus 8, also associated with Kaposi's sarcoma, has been demonstrated in patients with PAH, suggesting that this virus may play a role in its development.[5] Recent studies have been unable to find an association between human herpesvirus 8 and idiopathic pulmonary arterial hypertension.

When a family history exists, the disease is termed familial pulmonary arterial hypertension (FPAH). IPAH and FPAH are now considered to be genetic disorders linked to mutations in the BMPR2 gene, which encodes a receptor for bone morphogenetic proteins,[6] as well as the 5-HT(2B) gene, which codes for a serotonin receptor.[7]

Pathogenesis

Whatever the initial cause, pulmonary hypertension involves the tightening of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, much as it is harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become both stiffer and thicker, further increasing the blood pressure within the lungs and impairing blood flow. In addition, the increased workload of the heart causes thickening and enlargement of the right ventricle, making the heart less able to pump blood through the lungs, causing right heart failure. As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore it becomes harder and harder for the left side of the heart to pump to supply sufficient oxygen to the rest of the body, especially during physical activity.

Diagnosis

Because pulmonary hypertension can be of 5 major types, a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thomboembolic, or miscellaneous varieties.

A physical examination is performed to look for typical signs of pulmonary hypertension. These include altered heart sounds, such as a widely split S2 or second heart sound, a loud P2 or pulmonic valve closure sound (part of the second heart sound), (para)sternal heave, possible S3 or third heart sound, and pulmonary regurgitation. Other signs include jugular venous distension (enlargement of the jugular veins), peripheral edema (swelling of the ankles and feet), ascites (abdominal swelling due to the accumulation of fluid), hepatojugular reflux, and clubbing.

Further procedures are required to confirm the presence of pulmonary hypertension and exclude other possible diagnoses. These generally include pulmonary function tests, blood tests, electrocardiography (ECG), arterial blood gas measurements, X-rays of the chest (followed by high-resolution CT scanning if interstitial lung disease is suspected), and ventilation-perfusion or V/Q scanning to exclude chronic thromboembolic pulmonary hypertension. Biopsy of the lung is usually not indicated unless the pulmonary hypertension is thought to be due to an underlying interstitial lung disease. But lung biopsies are fraught with risks of bleeding due to the high intrapulmonary blood pressure. Clinical improvement is often measured by a "six-minute walk test", i.e. the distance a patient can walk in six minutes. Stability and improvement in this measurement correlate with better survival.

Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure sampling with a Swan-Ganz catheter provides the most definite measurement. PAOP and PVR can not be measured directly with echocardiography. Therefore diagnosis of PAH requires a cardiac catheterization. A Swan-Ganz catheter can also measure the cardiac output, which is far more important in measuring disease severity than the pulmonary arterial pressure.

Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12–16 mm Hg (1600–2100 Pa). Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mm Hg (3300 Pa). If mean pulmonary artery pressure rises above 30 mm Hg (4000 Pa) with exercise, that is also considered pulmonary hypertension.

Diagnosis of PAH requires the presence of pulmonary hypertension with two other conditions. Pulmonary artery occlusion pressure (PAOP or PCWP) must be less than 15 mm Hg (2000 Pa) and pulmonary vascular resistance (PVR) must be greater than 3 Wood units (240 dyn•s•cm-5 or 2.4 mN•s•cm-5).

Classification
Current classification

In 2003, the 3rd World Symposium on Pulmonary Arterial Hypertension was convened in Venice to modify the classification based on the new understanding of disease mechanisms. The revised system developed by this group provides the current framework for understanding pulmonary hypertension.

The system includes several improvements over the former 1998 Evian Classification system. Risk factor descriptions were updated, and the classification of congenital systemic-to pulmonary shunts was revised. A new classification of genetic factors in PH was recommended, but not implemented because available data were judged to be inadequate.

The Venice 2003 Revised Classification system can be summarized as follows:[8]

* WHO Group I - Pulmonary arterial hypertension (PAH)
* WHO Group II - Pulmonary hypertension associated with left heart disease
* WHO Group III - Pulmonary hypertension associated with lung diseases and/or hypoxemia
* WHO Group IV - Pulmonary hypertension due to chronic thrombotic and/or embolic disease
* WHO Group V - Miscellaneous

Previous terminology

The terms primary and secondary pulmonary hypertension (PPH and SPH) were formerly used to classify the disease. This led to the assumption that only the primary disease should be treated, and the secondary variety should be ignored in favor of treating only the underlying illness. In fact all forms of pulmonary arterial hypertension are treatable. Unfortunately, this classification system still persists in the minds of many physicians, and probably leads to many patients with being denied treatment. This nihilistic approach to pulmonary arterial hypertension may also contribute to underdiagnosis. It is estimated that there are about 100,000 patients with PAH in the US, but only 15-20,000 have been diagnosed. Many others have been misdiagnosed as COPD, asthma, or congestive heart failure.

The term primary pulmonary hypertension (PPH) has now been replaced with idiopathic pulmonary arterial hypertension (IPAH) in much of the medical literature. However, some physicians continue to use the older classification inappropriately.

Epidemiology

IPAH is a rare disease with an incidence of about 2-3 per million per year and a prevalence of about 15 per million. Women are almost three times as likely to present with IPAH than men.

Other forms of PAH are far more common. In scleroderma the incidence has been estimated to be 6 to 60% of all patients, in rheumatoid arthritis up to 21%, in systemic lupus erythematosus 4 to 14%, in portal hypertension between 2 to 5%, in HIV about 0.5%, and in sickle cell disease ranging from 20 to 40%.

Diet pills such as Fen-Phen produced an annual incidence of 25-50 per million per year.

Treatment

Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary venous hypertension is synonymous with congestive heart failure, the treatment is to optimize left ventricular function by the use of diuretics, beta blockers, ACE inhibitors, etc., or to repair/replace the mitral valve or aortic valve.

In PAH, lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner.

High dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality.

Vasoactive substances

Three major pathways are involved in abnormal proliferation and contraction of the smooth-muscle cells of the pulmonary artery in patients with pulmonary arterial hypertension. These pathways correspond to important therapeutic targets in this condition and play a role in determining which of three classes of drugs — endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin derivatives — will be used.

Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin, marketed as Flolan®) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. Iloprost (Ilomedin®) is also used in Europe intravenously and has a longer half life. Iloprost (marketed as Ventavis®) is the only inhaled form of prostacyclin approved for use in the US and Europe. This form of administration has the advantage of selective deposition in the lungs with less systemic side effects.

The dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer®) was approved in 2001. Two selective endothelin receptor antagonists (ETA only) are in the final stages of approval: sitaxsentan and ambrisentan. Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved for the treatment of PAH in 2005. It is marketed for PAH as Revatio®. Tadalafil (currently marketed as Cialis® for erectile dysfunction) is currently is Phase III trials. Vasoactive intestinal peptide by inhalation should enter clinical trials for PAH in 2007. PRX-08066 is a serotonin antagonist currently being developed for hypoxic pulmonary hypertension.

Surgical

Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxia). It is best performed in experienced centers. Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a survival of about 5 years.

Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a large and very difficult procedure that is currently performed in a few select centers. Case series show remarkable success in most patients.

Treatment for hypoxic and miscellaneous varieties of pulmonary hypertension have not been established. However, studies of several agents are currently enrolling patients. Many physicians will treat these diseases with the same medications as for PAH, until better options become available.

Prognosis

The NIH IPAH registry from the 1980's showed an untreated median survival of 2-3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale). Although this figure is widely quoted, it is probably irrelevant today. Outcomes have changed dramatically over the last two decades. This may be because of newer drug therapy, better overall care, and earlier diagnosis (lead time bias). A recent outcome study of those patients who had started treatment with bosentan (Tracleer®) showed that 86% patients were alive at 3 years. With multiple agents now available, combination therapy is increasingly used. Impact of these agents on survival is not known, since many of them have been developed only recently. It would not be unreasonable to expect median survival to extend past 10 years in the near future.