–> Download here the complete AMIP manual!


In the last 15 years, IP therapy has undergone rapid evolution especially for the progress made in the forms of pulmonary arterial hypertension. Different therapies are available depending on the type of IP. In secondary forms to other pathologies you try to solve the disease that caused the IP, without using specific medications. In the forms of the IAP (the classification group) a conventional therapy and a specific therapy are implemented instead. Currently, specific drugs belong to three different classes:

  • ERA (endothelin receptor antagonists): Bosentan (Tracleer) and Ambrisentan (Volibris);
  • Phosphodiesterase-5 inhibitors: Sildenafil (Revatio) and Tadalafil (approximately);
  • Prostanoids: Epoprostenol (Flolan), Treprostinil (Remodulen), and Iloprost (Ventavis).

Such medications may be used in monotherapy or as association therapy between different classes. The treatments currently existing allow to help almost all the sick and allow the doctor to choose the most suitable treatment for each patient. In fact the therapy varies according to the type of IP, its severity and the characteristics of the individual patient. The progress made in recent years in the treatment of the IAP is the result of continuous scientific research that affects the pathology. Clinical trials are still underway to assess the efficacy of new drugs, belonging to different classes than those previously mentioned.


Secondary IP forms: Treatment of the disease that caused the IP (II, III, IV and V classification Group)

In secondary IP forms the treatment should be aimed at eliminating the causes that caused the disease. If the pathology that caused the IP is not cured, it will continue to feed it. In addition, when the IP persists for a long time, curing the disease that triggered it may no longer be sufficient to regress the state, so you will need to start a separate treatment. We can say that the IP, once started, feeds on itself.


Pulmonary arterial hypertension (I Group)

The main objectives of the therapy are to treat heart failure, to prevent the thrombotic phenomena that can occur within the restricted pulmonary vessels and to reduce the action of those factors that cause the vasoconstriction and the progressive Occlusion of the vessels of the pulmonary circle. The therapy is therefore distinguished in conventional (basic) and specific.


Conventional therapy

It is essentially aimed at treating the signs of congestive heart failure. It uses:

  • Oxygen: As the disease progresses, the amount of oxygen in the blood can be reduced to such an extent that it is necessary to use a device that dispense it nasally. Some patients need to make it a continuous use, others may need additional oxygen only when they walk or during their daily activity. According to the degree of progression of the disease it is therefore advisable to avoid those conditions that could expose the subject to low percentages of oxygen in the inhaled air, such as high altitudes and air travel. The oxygen can be found in different forms: it can be brought home contained inside cylinders, in which it is stored at a temperature of-150 ° C; It can be found in large tanks from which it is possible to fill other small and portable, or you can rent a concentrator of oxygen, which sucks it from the air. The concentrator requires frequent cleaning, essential to avoid suction of germs or dust, and cannot be used to fill portable cylinders. Another option for oxygen delivery is given by a portable system that consists of a much smaller and lighter container than a normal cylinder, which supplies oxygen. In each of these systems, oxygen is inhaled with a facial mask or through a cannula (nasal pitchfork). Caution: Oxygen is highly flammable, so caution should be taken when you are near flames or heat sources. It is necessary to keep the cylinder and the connecting pipe at a safe distance from every flame or lit cigarette.
  • Diuretics: can be used at high doses. Cardiac failure caused by the IP causes fluid retention. Sometimes it is possible to contain such retention by reducing salt in the diet. Other times it is necessary to start taking a diuretic to help the kidneys to eliminate excess liquids. Two commonly used diuretics are Furosemide (Lasix) and spironolactone (Aldactone), the latter predominantly with an action of potassium saver, important for the electrical stability of the heart. In fact the use of diuretics can lead to an excessive elimination of this electrolyte, so it is advisable to periodically check its values and help the body to maintain its normal levels, for example by eating foods that are rich: bananas, Peaches, legumes and avoiding some foods like licorice, which can make them lower values. The use of diuretics may also cause an excessive loss of other electrolytes such as magnesium, responsible for cardiac arrhythmias and muscle weakness. Foods rich in magnesium include: bran, lentils, whole grains, walnuts, almonds, peanuts and green vegetables.
  • Anticoagulants: They are indicated in the prevention of the formation of trumpets within the confined vessels, which can make the IP worse. These drugs hinder blood clotting. Studies have shown that patients with IP that take anticoagulants are more likely to survive than those who do not use them. It is usually prescribed Warfarin (Coumadin) or Acenocumarolo (Sintrom). It is important not to go above or below the optimum level of anticoagulation. Unfortunately, many foods, medications and other substances condition the action of anticoagulants. To maintain proper dosage, it is necessary to periodically check the INR (International Normalised ratio) or prothrombin time, which measures the time taken by the blood to coagulate. Most patients must carry out this check once a month, by means of a blood collection, the frequency of which depends on the stability of the INR value to be maintained in the range between 2.0 and 2.5. Each patient assumes their own personal dose of anticoagulant; Taking a larger amount of this drug does not mean being more sick; Several factors make sure that different individuals need a different amount of medication to achieve the same level of anticoagulation. If an operation or even a simple dental surgery is scheduled during the intake of the anticoagulant therapy, it is usually necessary to suspend the administration of anticoagulants about 3-4 days before the intervention, because to eliminate The action of such drugs takes a few days. During the suspension time the drug is replaced with heparin, through subcutaneous injections. Anticoagulant therapy can have important side effects because it increases the tendency to bleed. Those who take such medications must pay special attention and avoid cuts, wounds or traumas of any kind. Substances that interact with anticoagulants. To prevent dangerous bleeding, aspirin (acetylsalicylic acid) or medicines that contain it should not be used unless prescribed by your doctor. Aspirin can cause blood loss especially within the gastro-intestinal tract. In general, anti-inflammatory drugs and painkillers should be avoided. In case of a cold or fever may be used, such as analgesic or febrile, acetaminophen. In any case, given that many drugs can interact with anticoagulants, you should always warn your doctor that you are using it. Ways in which the diet interacts with anticoagulants. Vitamin K, which plays an important role in the synthesis of coagulation factors, makes the anticoagulant less effective. It is found in large quantities especially in vegetables with a wide leaf, but also in olive oil and soy. Vegetables can still be eaten without any problems. You just have to avoid changing the amount of vegetables present in your diet in a sudden way. For against vitamin E It increases the effect of the anticoagulant. So you need to be careful every time you change your diet or take on new medications. It is good rule to always consult a specialist if you want to undertake a slimming diet or before using new medicines.
  • Digoxin (Lanoxin): When the right ventricle has weakened this substance may help it to contract better and in some cases its use can be assessed. Some substances such as Diltiazem (Dilzene, Tildiem) Increase the effect of digoxin. In some cases, this substance may accumulate in the body and cause symptoms such as nausea, loss of appetite, diarrhea, headaches, confusion, depression, eye disorders and cardiac arrhythmias.
  • CA-antagonists: nifedipine (Adalat), Diltiazem (Tildiem, Dilzene), Verapamil (Isoptin) and amlodipine (NORVASC) CA-antagonists are very effective drugs in the treatment of a subset of patients with IAP responsive to the acute test of vasoreattività. This test is performed during the right cardiac caism, causing the patient to inhale a short-acting vasodilator, most often nitric oxide. Approximately 10% of patients are responsive to this test and may benefit from the administration of these high-dose medications. In other patients, the small arteries of the lungs can be so rigid that they are no longer able to expand even with the help of the antagonistic Ca, so the use of the drug can be very dangerous. In fact, in these patients the administration of these drugs could cause a dilation of the only systemic vessels and therefore a severe reduction of the pressure measured on the arm, which can lead to severe cardiac damage.

How these drugs work interact with the mode of cellular contraction. In fact, smooth muscle cells in the arteries need calcium to contract, so these medicines prevent the cells from using calcium, keeping the arteries dilated and thus lowering the systemic pressure (the one measured at ARM) and the lung one.

Which antagonists are using the most commonly used substance is nifedipine (adalat); Amlodipine (NORVASC) and Diltiazem (Tildiem, Dilzene) are other examples of calcium that can be used.

Side effects calcium antagonists dilate all the body's blood vessels, not just those that need it (for patients with IP it is important that you dilatinate the pulmonary vessels). So side effects include swelling to the feet, ankles and calves. However, these signs may also be an index of worsening IP, so the patient may have difficulty in understanding the cause. In General, if the drug has reduced the wheezing to the patient, the swelling of the feet and legs is probably just a side effect that can be controlled with diuretics. If the feet swell and the breathlessness has not improved, you have to warn the doctor. Sometimes the calcium antagonists make too much lower the general systemic pressure (the one that is measured with the arm) causing the head turns. Other times you can still have headache or thickening of the gums. In All these cases it is important to inform your doctor.

Dosage you try to reach the highest possible dosage of medicine, to have the greatest clinical benefit, compatibly with the appearance of the side effects. Precautions to be taken if you use calcium antagonists:

  • Do not chew and do not divide the tablets so as not to destroy the matrix (internal structure that serves to release the active substance at a constant speed within 24 hours);
  • Never stop suddenly their intake, the suspension must take place under the strict supervision of a doctor because it can also lead to serious cardiac consequences;
  • Avoid drinking large amounts of grapefruit juice, because they can enhance the action of the blocker.


Specific therapy

The use of specific medications for pulmonary arterial hypertension is based on the modification of the factors responsible for the development of the typical lesions of the disease. The objectives of the therapy are:

  • To correct the reduced production of Prostacyclin, a vasodilator and antiproliferative substance (epoprostenol, Treprostinil, Iloprost);
  • Hinder the effect of a vasoconstrictor-acting protein, endothelin, most present in patients with IAP (endothelin receptor antagonists: Bosentan, Ambrisentan);
  • Enhancing the effect of nitric oxide (NO), a potent vasodilator in the body (phosphodiesterase 5 inhibitors: Sildenafil, Tadalafil).


PROSTACICLINE: Epoprostenol (Flolan), Treprostenil (Remodulen), Iloprost (Ventavis).

1. Epoprostenol (Flolan)

The Epoprostenol ("Flolan" is the trade name) is a molecule synthesized in the laboratory, but acts as a substance produced naturally in our organism (prostacyclin) by cells that coat the blood vessels (endothelial cells). It was the first drug available for the IAP therapy (introduced in Italy in 1999). In September 1995, the agency of the American drug (Food and drug Administration, FDA) approved its marketing following a series of studies that demonstrated its efficacy in improving cardiac function, stress tolerance and Survival, in patients with pulmonary arterial hypertension in III and IV functional class. It has been shown that this therapy should not be started too late, as patients who start at a more advanced stage of the disease have a lesser benefit than those who start earlier.

How the Epoprostenol works

The action of Epoprostenol is expressed in several ways: dilates the blood vessels, prevents platelets from aggregating, improves cardiac function, slows the growth of muscle cells that line the small pulmonary vessels. Its action can also improve over time (this is the reason why patients who do not respond to the acute vasodilation test can still start therapy with Flolan). Its final effect is the reduction of the pressure in the pulmonary artery and in the right atrium and the improvement of cardiac function and oxygen saturation in the blood. Symptoms decrease and in some cases disappear. These changes occur already after a few weeks from the beginning of therapy but sometimes even after months. In Some patients the Flolan seems to even regress the course of the disease.

Preparing the drug

The preparation of the drug requires attention in every single step. In fact, the Flolan is available in the form of cold dried powder that must be dissolved in a solvent (glycine) before it can be administered. Once prepared, the drug must be loaded into a special tank which will be connected to the pump that is going to infuse it continuously (twenty-four hours a day). These operations must be done daily, usually by the patient or a member of his or her family.

Drug Administration

The duration of action of the Flolan is very short (only a few minutes) and this explains why it can not be taken in the form of pills, but it needs an intravenous infusion. Its administration involves the use of portable infusion pumps (the size of a Walkman). The pump continuously infuses the drug through a silicone catheter, inserted into the operating room with local anesthesia, which after a course under the skin of about 8 10 cm (is tunneled) is inserted into the subclavian vein. The subcutaneous course is necessary to give stability to the catheter and reduce the risk of infection. The infusion pump is worn in a part of the body (it can be attached to the belt or placed in a pouch, in a handbag or in a backpack). The dosage of the drug is increased periodically to achieve the optimum dose, which will achieve maximum clinical efficacy. This dose is personalized, it also takes into account the body weight of the subject, and requires periodic increases, because patients develop a certain resistance to the medicine (tolerance).

Side effects

Side effects are frequent, but in most cases they are bearable and usually decrease as the body gets used to the drug (they tend to increase each time you increase the dose and then stabilize again). The most frequent are due to the vasodilation that the drug causes in the body and are: flushes, headache, pain in the jaws and legs, nausea and diarrhea. To decrease the pain in the jaw (which is reduced by chewing) it is advisable to start the meal by slowly eating a craker or a piece of bread. Acetaminophen can reduce the headache caused by Flolan, while diarrhea can be reduced with Lopemid or Imodium. The Flolan makes people more sensitive to light, so those who use it must avoid exposing themselves too much in the sun. Once initiated, the therapy with epoprostenol should never be abruptly interrupted, since even a short interruption can cause a rapid recurrence of symptoms and in some cases death. Therefore it is necessary to keep a safety pump at hand, already programmed with its own infusion speed, and new batteries in case of breakdowns to the Drug Administration system.

Risk of infection

The most frequent complication in therapy with Flolan is the infection linked to the presence of the catheter (venous access). The infection occurs in about 20% of patients each year (hence in almost all patients over 5 years). It is important to distinguish a local infection from a systemic one. The signs of a localized infection of the skin are: redness, pain, secretions, swelling. The signs of a generalized infection (affecting the whole body) are: fever, tremor and shivering, worsening of the usual symptoms (breathlessness, fatigue). This last condition is the most dangerous for our organism, so it is necessary to readily recognize it to start a therapy early. The frequency of infection can be reduced by regularly changing the sterile bandage and disinfecting the dermal catheter insertion area every 3 days. It is essential, before preparing the Flolan, or to change the connecting catheter, or dressing, to thoroughly wash your hands and perform all operations in a "clean" environment. If you have cooled down or if you have a cough, it is useful to wear a mask before tinkering with the various devices of the drug and pump.

When to go to the nearest emergency room:

  • When the catheter is obstructed and the Flolan does not circulate, even if the infusion device appears to be working well (increased drug residue in the reservoir);
  • When the catheter is injured or damaged (before leaving for the first aid, it is useful to staple the catheter to a point between the thorax and the damaged area);
  • When the catheter is pulled out of its housing (in this case it is useful to apply pressure to the catheter's dermal insertion point with a sterile swab);
  • When the patient has high fever, trembles, has chills of cold (these may be signs of a generalized infection)

Suggestions to patients using FLOLAN:

  • Always carry with you a spare pump, batteries, tubes and the necessary for the medications.
  • After the Flolan has been mixed with the liquid solution, it can freeze in case of great cold, so protect your pump and tubing.
  • In summer, to prevent your ice reserves from melting while you travel, ask your doctor if the drugs can go with dry ice in a heat bag. The drug must be stored in a cool environment at a temperature below 25 °c.
  • If you are near a NMR device (nuclear magnetic resonance imaging), keep the pump away from the magnetic field so that its program is not erased.
  • Buy a calendar or an agenda to jot down the days when you need to change the dose of the drug or check your prothrombin/INR time, and take note of the problems and side effects of the medications you take (so you can report them to your doctor).
  • To decrease the pain in the jaw try to rub your cheeks when you chew the first mouthful. 
  • To relieve leg cramps, try dipping them in hot water, or cover them with a programmed electric blanket at minimum temperature.
  • Do not go through the metal detector that you can find located at airports or banks. After having known people of all ages, from young children to the elderly, who have a good quality of life thanks to the epoprostenol, it can be said that the benefits of this treatment are far superior to its side effects. Many of the people who use the Flolan go to school, travel and continue to do their job.

 2. Remodulen (Treprostinil)

The Remodulen is an analogue of prostacyclin, like the epoprostenol, but with respect to the latter has both a greater chemical stability, which allows to maintain it at room temperature already dissolved in a solution (remains stable for five years), both A longer half-life (about 4 hours) that guarantees the possibility of subcutaneous administration, considered less risky and more manageable than the intravenous one. As the Flolan also remoduln dilates the blood vessels of the lungs, retards the process of cell proliferation and the progression of damage to the wall of the vessels. Its action increases the oxygen saturation of the blood, increases the tolerance to exercise, improves cardiac function, prolongs survival and improves the quality of life of the person who assumes it.

Medication preparation and administration

The Remodulen is administered subcutaneously (i.e. under the skin) and not intravenous as the Flolan. Its delivery is done through a small micro infusion pump, as large as a mobile phone, connected to a thin catheter with subcutaneous insertion. The drug is contained in tiny syringes placed inside the pump (active round the clock); The syringe, which becomes the internal tank of the pump, is connected to the infusion catheter which is inserted into the subcutaneous tissue of the abdomen (where adipose tissue is most represented). Patients learn to insert the catheter into the skin, at a point called "Infusion Point". The drug inside the SIRINGASERBATOIO should be replaced every 3 days, while the subcutaneous catheter may be changed less frequently (usually after a few weeks). The Remodulen does not require special mixes or preparations, the liquid is marketed in glass vials already ready for use. No refrigeration is required. The care and management of both the infusion point and the pump require an excellent level of cleanliness, as for the Flolan. Hygiene is used to reduce the risk of localized infection at the subcutaneous infusion point of the catheter. The treatment can be started in hospital, to allow doctors and nurses who deal with IP to teach the patient all the "tricks" for the management of therapy. The dose of the drug is progressively increased to obtain a suitable clinical benefit, as well as for Flolan. In some countries the drug may also be administered in intravenous form.

  • Always keep your fingernails clean and cut very short. Daily clean them with the toothbrush.
  • Take a nice shower before changing the catheter monthly.
  • Disinfect your hands before preparing the medicine every three days and before changing the catheter once a month. Disinfect them further in the various steps.
  • When preparing the medicine or changing the catheter: Use a previously disinfected tray that will serve to support the new catheter, medicine and Sparaaghi.
  • Disinfect the Remodulen container and shoot it needles every time you use it.
  • Thoroughly disinfect the part where the catheter will be inserted. Use sterile gauze and disinfect as if they were rays of the sun.
  • Disinfect your hands after throwing the old catheter and disinfect the part where it was inserted, betadine and oxygenated water and cover it with a patch.

Tips: The week that you changed the catheter monthly is preferable to wear comfy clothes or empire style or slacks with the slow elastic. It is important to be comfortable because the abdomen tends to swell in the early days. If you do not want to show the pump you can hide it by sewing a small bag inside the trousers or skirt if they are provided with elastic waist. There are those who put the pump in the garter or in the bra. Many people use a handkerchief over the catheter to avoid more irritation the week that the catheter has changed. The sensitivity decreases because the skin is not in contact with the various fabrics. Caution that it does not protrude the catheter wire because it could easily become caught in anything. It will avoid the substitution of the same and the consequent pain. If the catheter is filled with blood, a capillary may have ruptured. Replace immediately with a new catheter on the opposite side of the abdomen.

Side effects

The main drawback of reformin is the pain in the site of Infu Sione, which for some patients can also be very intense. These disorders are usually limited to the first week after the catheter insertion site is changed and can be handled with painkillers. The amount of pain varies from person to person and from time to time in the same patient. However over time the pain, in those who warn him and continue the treatment, often seems to fade or attenuate. The discomfort is not due to the presence of the small subcutaneous catheter that injects the substance, but may depend on the irritation caused by the drug to the nerve terminals. Moreover, the Treprostinil may have the same side effects as the Flolan, although usually in a milder form, such as: jaw pain, migraine, facial redness, nausea, diarrhea and vomiting. Some individuals may also develop forms of sensitivity to sunlight. Currently some clinical studies are evaluating its efficacy in a tablet formulation.

3. ILOPROST (Ventavis)

It is a stable analogue of prostacyclin with a half-life of about 50 minutes. This substance, as well as Flolan and Remodulen, dilates the blood vessels and contributes to slowing down the progression of the disease by preventing vasoconstriction and obstruction of the vessels, increases the saturation of oxygen and the cardiac output, improves the Exercise tolerance. In the treatment of IP this drug was initially used intravenously; It is currently used inhaled in an attempt to concentrate the action of the drug in the pulmonary circle, where it increases blood flow to the lungs.

Drug Administration

The Iloprost is inhaled in the lungs using a nebulizer, a device that nebulizes the drug into light vapor made up of small particles. Inhalation lasts about 10 minutes per dose and the effects last an average of one to two hours. The nebulizer must be kept well, clean and maintained in good condition. The care and management of a long-term therapy requires shrewdness and maintenance of the nebulizer device, while the moment of inhalation requires a good understanding and collaboration on the part of the patient, who will have to regulate his breathing with The delivery of the drug by the device. Many daily administrations are required (8-9 times) as the effect of the drug only lasts for a limited time. This can be very annoying for some people, but it is crucial not to skip doses, because the beneficial effects of therapy would be reduced or even completely lost.

Side effects

The side effects of Ventavis may include annoying or bronchospasm cough, while the side effects typical of other prostacicline analogues (Flolan and reformin) are much less frequent (jaw pain, nausea, vomiting, diarrhea, Migraine, redness to the face, sensitivity to light). A limitation of this treatment mode is the need to perform inhalations many times a day and often the need to associate another drug to maintain an effective clinical response over time.



Endothelin receptor antagonists

Endothelin is a substance produced by the layer of cells that covers the blood vessels and is normally found within the body. It is a powerful vasoconstrictor that plays an important role for the blood flow, since it restricts the wall of the vessels, increasing the pressure inside them. It exerts its action through the interaction with two receptors ETA and ETB. ETA receptors promote a vasoconstrictor and cellular multiplication effect, while ETB receptors have a different effect depending on endothelial cells (vasodilation) or smooth muscle cells (vasoconstriction). In the IP patients an increase of its quantity in the bloodstream has been documented: This is due both to an increase in its production and to a reduction of its elimination. During the last years numerous studies have demonstrated the role of endothelin in the development of pulmonary arterial hypertension as an important mediator of the multiplication of smooth endothelial and muscular cells. A correlation between the blood concentration of this protein, the severity of the disease and its progression has also been observed. In conclusion, although it is not yet clear whether the increase in endothelin is the cause or consequence of the disease, some data confirm the hypothesis of its central role in the development of pulmonary arterial hypertension.

1. BOSENTAN (Tracleer)

The Bosentan is an antagonist of the ETA and ETB receptors of the endothelin, and is active orally. By counteracting the action of endothelin, this drug can lead to an improvement in cardiac function and a reduction in blood pressure in the lungs, thus improving the stress tolerance and clinical condition of the patient. On the basis of these observations, in the late 1990s, the efficacy of Bosentan was tested in patients with idiopathic pulmonary arterial hypertension or associated with connective tissue diseases in the III-IV NYHA functional class. These data have also been confirmed in patients with IAP associated with congenital heart defects and in patients in the NYHA functional class II. In addition, a clinical study was recently concluded which included the use of this drug in patients with chronic thromboembolic IP not susceptible to surgery. The data showed a significant improvement in cardiac function and pulmonary pressure. The drug is generally well tolerated, it starts with the dose of 62.5 mg twice a day and after four weeks, if no adverse events occur, it increases at the dose of 125 mg twice daily.

Side effects

is generally well tolerated; In about 10% of patients, an increase in hepatic enzymes is observed which tends to normalize by reducing the dosage or interrupting the treatment. For this reason, the use of Bosentan is not recommended in patients with moderately or severely altered liver function or in patients with basal values of elevated transaminases. For the possibility of liver toxicity patients have to perform a control of blood tests each month for liver function. Reported side effects include nasal congestion, migraine, increased blood flow on the skin and face (redness to the face) and swelling in the lower limbs. It is thought that this medicine may have some interaction with the anticoagulant, which involves an increase in the dose to reach the therapeutic INR. Tracleer is marketed in all States of the European Union, the United States, Canada and Australia.

2. AMBRISENTAN (Volibris)

It is a selective ET-a receptor antagonist of long-acting endothelin and has no major interactions with other drugs. It is taken orally and its effects, documented in clinical studies, are overlapping with those obtained with other drugs in the endothelin receptor antagonist family. It has been shown to improve stress tolerance, clinical status and cardiac function in patients with idiopathic IAP and associated with connective diseases in II-III NYHA functional class. Ambrisentan has less interaction with other drugs and causes liver toxicity more rarely. It still requires monthly control of transaminases and is administered in a single daily dose, starting with 5 or 10 mg.



Phosphodiesterase 5 inhibitors

This category of drugs works by blocking the phosphodiesterase-5, the enzyme that promotes the transformation of GMP into GMPc (an enzyme is a protein that facilitates chemical reactions). The increase in intracellular GMPc causes short-term vasodilation and chronically an antiproliferative effect on smooth muscle cells.

1. SILDENAFIL (Revatio)

Initially this drug, known by the commercial name of Viagra, had been developed to treat patients with heart disease such as angina. An unexpected "side effect" was discovered during its use: it helped to improve erection in man. This molecule is most commonly known for its use in the treatment of erectile dysfunction (impotence). When Sildenafil was marketed on the market in 1998, its use was considered by doctors also for the treatment of IP. The drug was approved in Italy under the trade name Revatio, for the treatment of the idiopathic IAP and associated with connective diseases in II-III functional Class NYHA, at a dosage of 20 mg three times a day that can be increased to 80 mg three times a Day. Its intake implies an increase of the tolerance to the effort and an improvement of the cardiac function. Some studies suggest a favorable effect in the forms of severe IP secondary to pulmonary and in thromboembolic forms not susceptible to surgery.

Mechanism of Action

Sildenafil causes a relaxation of the smooth musculature of the blood vessels, which in turn has the effect of increasing the blood flow. This happens thanks to the inhibition of the enzyme "phosphodiesterase-5" often shortened in PDE-5. Sildenafil gives rise to a complex chain of events involving the nervous system and the release of L'alcu NI Chemical messengers in the tissues. One of these messengers is called "Cyclic GMP", which induces the blood vessels to dilate by stretching out the muscular layer that is found in their walls. Normally the action of cyclic GMP in the body is interrupted by the action of PDE-5. Sildenafil, by inhibiting the action of PDE-5, extends the action of cyclic GMP. In this way the blood vessels remain dilated for a longer time and the blood flow improves. Several clinical studies have evaluated the efficacy of this drug in patients with IP. The results of this work are encouraging, in fact they have shown that thanks to Sildenafil some patients with IP have improved their physical exercise capacity, with reduction of the pressure in the pulmonary artery and an improvement of the function Heart. In 2006, therefore, the drug was marketed for the treatment of the IAP under the name "Revatio". 

2. TADALAFIL (approximately)

It is also a phosphodiesterase-5 inhibitor, taken orally. Its efficacy in improving stress tolerance and cardiac function is stackable to that achieved with high dosages of Sildenafil. Even this molecule, with the commercial name of Cialis, was previously marketed with indication for erectile dysfunction. Only recently was approved in Italy, with the name of roughly, for the treatment of patients with idiopathic pulmonary arterial hypertension and associated with connective tissue diseases in II and III functional class at dosage of 40 mg once a day. All the medications described herein have been effective in the forms of idiopathic pulmonary arterial hypertension and in some forms associated with other pathologies (e.g. connective diseases). There are uncontrolled studies that suggest a possible efficacy also in other forms of pulmonary arterial hypertension (IP associated with congenital heart defects, HIV infections, use of anorectics, liver disease) and pulmonary hypertension Secondary to distal pulmonary embolism.



Surgeries for the treatment of pulmonary hypertension:

1. Pulmonary endarterectomy

This type of surgery can be performed in the forms of chronic thromboembolic pulmonary hypertension or Thromboembolic Pulmonary Hypertension (CTEPH). This type of pulmonary hypertension is due to a single episode of not perfectly cured pulmonary embolism (EP) or recurrent episodes. The appearance of CTEPH can therefore represent one of the possible evolutions of an EP, a disease that can progress in several ways:

  • Complete healing with dissolution of Tromboembolo (minority of patients);
  • Partial healing, with an almost complete dissolution of the blood clot (most cases); 
  • Incomplete dissolution with persistent obstruction of part of the pulmonary arteries with onset of pulmonary hypertension (CTEPH, small minority of cases).

Often patients with CTEPH report that they have suffered from one or more episodes of acute EP, other times They are episodes that were not recognized as EP and the treatment was late. The real incidence of CTEPH is unknown. In the United States approximately 600000 cases of EP per year occur, with a mortality of 8-25%; It is believed that about 0.1-0.5% of survivors go to CTEPH. A recent Italian study estimated that about 3% of patients with EP could develop CTEPH after 2 years from the EP episode. The symptoms of the disease are equal to other forms of pulmonary hypertension (wheezing under strain or even resting, signs of water retention). It is important to arrive at an accurate diagnosis of CTEPH because if the lesions are close to the origin of the pulmonary artery it is possible to perform a surgery of unclogging of the arteries (pulmonary endarterectomy). The surgery is quite complex, but the results are very good: in the majority of cases it is possible to obtain a normalization of the pulmonary pressure values. So the risk of intervention is largely overcome by benefits. There are no age limits and older patients (80 years old) may also be operated as long as they do not have other major diseases (renal failure, pulmonary emphysema). In Italy The center that has the most experience is the cardiac surgery of the hospital S. Matteo di Pavia. Patients who have been operated must follow a lifetime anticoagulant therapy and often have to undergo the placement of a cavalent filter (a parasol that is placed in a large vein that brings blood from the legs and abdomen to the heart ; This system prevents blood clots, which can form in the veins, to reach the pulmonary circle). In cases where the obstructions of the pulmonary vessels are too distant to be removed surgically, there are currently no effective medicines, but there are promising experiences with the drugs used in the forms of arterial hypertension Idiopathic pulmonary.

2. Lung transplant

It represents the ultimate weapon for the treatment of the most severe forms of pulmonary hypertension that do not respond to medication therapy. To achieve optimum results it is important that the transplant is not performed too early or too late (in the latter case the patient would have an excessively high risk). It is therefore important that doctors who treat pulmonary hypertension are in contact with a center that performs lung transplantation and decide together with the surgeon when to insert the patient's waiting list (it must be taken into account that the average wait before Performing a lung transplant is between 18 and 24 months. In order to be put on the list for lung transplant you have to have some characteristics (age of 60 years for transplantation of both lungs, absence of other serious diseases, such as tumors, good hepatic and renal function) and be in discreet General conditions and good psychological balance. Obviously the new lungs must be of an adequate size for the height of the receiver and there must be a certain compatibility between the donor and the recipient (same blood type). Surgery is usually performed by transplanting one organ at a time (sequential bilateral transplantation) starting with the most damaged lung. After surgery, the patient receives a therapy that "accepts" the new organ (immunosuppressive therapy) and avoids "rejection crisis". The current therapies are quite effective, but they expose the patient to the risk of infection. For this reason the transplant patient must be checked periodically to recognize both a possible rejection phase and possible infections. Overall the results are good and the majority of the patients succeed in resuming an active life.