Miscellaneous noteworthy drugs

CHAPTER 107


Miscellaneous noteworthy drugs




Drugs for pulmonary arterial hypertension


Pulmonary arterial hypertension (PAH) is a rare, progressive, and potentially fatal disease of the small pulmonary arteries. The condition is defined by a sustained elevation of pulmonary arterial pressure of more than 25 mm Hg at rest or more than 30 mm Hg during exercise, with a mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mm Hg. The primary vascular changes in PAH are vasoconstriction, proliferation of smooth muscle cells and endothelial cells, and pulmonary thrombosis. Cell proliferation and vascular remodeling lead to a progressive increase in pulmonary vascular resistance. The ultimate result is right ventricular failure and death. Although the pathogenesis of PAH is not fully understood, a hormone known as endothelin-1 may play a critical role (see below).


Traditional treatment consists of three drugs: warfarin, a diuretic, and a calcium channel blocker. Warfarin prevents thrombosis. Diuretics reduce fluid retention, and thereby reduce cardiac preload, which in turn reduces symptoms of right-heart failure. Calcium channel blockers dilate constricted pulmonary arteries, and can thereby reduce pulmonary hypertension. However, only 20% of patients respond to calcium channel blockers, hence use of these drugs is limited to this small group.


For many patients, PAH becomes progressively worse despite drug therapy, and hence surgical intervention may be required. Options include single-lung, double-lung, and heart-lung transplantation. These surgeries are high risk, with a mortality rate of 16% to 29%. Five-year survival is 40% to 45%.


Since 1995, seven new drugs for PAH have been approved: epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, sildenafil, and tadalafil (Table 107–1). All seven promote pulmonary vasodilation. In addition, they may delay or reverse pulmonary vascular remodeling. Also, all seven are very expensive. Discussion below is limited to these seven drugs.




Prostacyclin analogs


Three derivatives of prostacyclin are approved for PAH: epoprostenol, treprostinil, and iloprost. All three mimic the actions of endogenous prostacyclin, a compound that promotes vascular relaxation, suppresses growth of vascular smooth muscle cells, and inhibits platelet aggregation. Like prostacyclin itself, the analogs bind with cell-membrane receptors and thereby stimulate synthesis of cyclic AMP, an intracellular second messenger that mediates prostacyclin effects. In patients with PAH, the prostacyclin analogs lower pulmonary arterial resistance, decrease pulmonary arterial pressure, increase exercise tolerance, and improve short-term survival.



Epoprostenol

Epoprostenol [Flolan], approved in 1995, was the first prostacyclin available for PAH. Administration is complex and inconvenient, and adverse effects are common. The drug has a very short half-life (less than 6 minutes) and is unstable at room temperature. As a result, it must be given by continuous IV infusion, using a portable pump that can keep the drug cold. Administration is done through a central venous catheter. The infusion rate is low initially, and then gradually increased to a typical maintenance rate of 20 to 40 ng/kg/min. The most common side effects are flushing (58%), headache (49%), and nausea and vomiting (32%). These responses are dose dependent and generally mild. Of greater concern, patients are at risk of catheter-related sepsis. Also, if the pump fails or the catheter becomes dislodged, the resulting interruption of drug delivery can be life threatening.



Treprostinil

Treprostinil was approved for parenteral therapy of PAH in 2002, and then for inhalation therapy of PAH in 2009. Products for parenteral therapy are marketed as Remodulin, and products for inhalation therapy are marketed as Tyvaso. For parenteral therapy, treprostinil is usually administered by continuous subQ infusion, but if needed, it can be infused through a central venous line instead. Treprostinil has a much longer half-life than epoprostenol (4 hours vs. 6 minutes) and much greater heat stability.


Compared with infused epoprostenol, infused treprostinil [Remodulin] has three major advantages. First, because treprostinil is heat stable, it doesn’t require cooling during the infusion. Second, because treprostinil has a prolonged half-life, maintaining a precise infusion rate is less critical. And third, because treprostinil can be infused subQ, the risk of sepsis associated with a central venous catheter is obviated. However, subQ treprostinil is not free of problems: local pain occurs in 85% of patients, and other local reactions (eg, erythema, induration, rash) occur in 83% of patients. Local pain is often dose limiting. Other side effects include jaw pain, diarrhea, edema, and nausea.


For inhalation therapy, treprostinil [Tyvaso] is dosed using the Tyvaso Inhalation System, which delivers 6 mcg with each inhalation. The initial dosage is 18 mcg (3 inhalations) 4 times a day (at 4-hour intervals during waking hours), for a total of 72 mcg/day. The target maintenance dosage is 54 mcg (9 inhalations) 4 times a day, for a total of 216 mcg/day. The most common adverse effects of inhaled treprostinil are cough (54%), headache (41%), throat irritation (25%), nausea (19%), flushing (17%), and dizziness (6%).




Endothelin-1 receptor antagonists


Endothelin-1 (ET-1) is a small peptide hormone that promotes vasoconstriction and proliferation of endothelial cells. In patients with PAH, the level of ET-1 in the pulmonary vasculature is elevated as much as 10-fold. Furthermore, the degree of ET-1 elevation corresponds with the degree of PAH severity. Endothelin-1 acts through two types of receptors, known as endothelin type A (ETA) receptors and endothelin type B (ETB) receptors. Activation of ETA receptors causes vasoconstriction and cell proliferation, whereas activation of ETB receptors causes vasodilation.


Endothelin-1 receptor antagonists (ERAs) can reduce the adverse impact of ET-1 on lung function. Two ERAs are available: bosentan [Tracleer] and ambrisentan [Letairis, Volibrisimage]. In patients with PAH, these drugs can improve exercise tolerance and delay symptom progression. Unfortunately, the drugs can also cause serious adverse effects, especially liver injury and fetal malformation.



Bosentan




Adverse effects.

The most serious adverse effects are liver injury and teratogenesis. Bosentan can also cause headache, flushing, peripheral edema, nasal congestion, anemia, and reduced sperm production.






Drug interactions.

Bosentan is subject to significant drug interactions. Inhibitors of CYP2C9 and CYP4A4 have the potential to raise bosentan levels, thereby increasing the risk of toxicity.


Bosentan itself is an inducer of CYP2D6, and hence can accelerate the metabolism of certain other drugs. Important among these are warfarin (an anticoagulant that many people with PAH use) and oral contraceptives.


Two drugs—cyclosporine and glyburide—must not be taken with bosentan. Cyclosporine (an immunosuppressant) can greatly increase bosentan levels, and glyburide (a drug for type 2 diabetes) increases the risk of liver injury.








Preparations, dosage, and administration.


Bosentan [Tracleer] is supplied in tablets (62.5 and 125 mg). For patients who weigh 40 kg or more, the dosage is 62.5 mg twice daily for 4 weeks, and then 125 mg twice daily thereafter for maintenance. For patients who weigh less than 40 kg, the dosage is 62.5 mg twice daily initially, and remains at 62.5 mg twice daily for maintenance. In patients with elevated transaminase levels, dosage should be adjusted as follows:



To reduce the risk of liver injury and possible fetal exposure, bosentan must be prescribed through the Tracleer Access Program.



Ambrisentan


Ambrisentan [Letairis, Volibrisimage], approved in 2007, is much like bosentan with regard to actions, indications, and adverse effects. Both drugs block receptors for ET-1; both are taken to improve exercise tolerance and delay symptom progression in PAH; and both can cause severe birth defects. The drugs differ primarily in two respects. First, in contrast to bosentan, ambrisentan does not injure the liver. And second, whereas bosentan blocks ETA and ETB receptors, ambrisentan is selective for ETA receptors. However, we don’t know if this selectivity improves clinical outcome. As with bosentan, pregnancy must be ruled out before starting ambrisentan, and sexually active women must use two reliable forms of contraception. Like bosentan, ambrisentan can cause peripheral edema, headache, flushing, and anemia. In contrast to bosentan, ambrisentan does not reduce levels of warfarin. Ambrisentan is supplied in 5- and 10-mg film-coated tablets, which may be taken with or without food. Dosing begins at 5 mg once a day and, if this dosage is tolerated, may be increased to 10 mg once a day. Ambrisentan is not recommended for patients with moderate or severe hepatic impairment (because blood levels of the drug may become excessive). Owing to the risk of birth defects, ambrisentan is available only through a restricted distribution program, known as the Letairis Education and Access Program (LEAP).




Phosphodiesterase type 5 inhibitors


The phosphodiesterase type 5 (PDE5) inhibitors reduce pulmonary arterial pressure by causing dilation of pulmonary blood vessels. Two PDE5 inhibitors—sildenafil and tadalafil—are approved for PAH. Both drugs were originally developed for erectile dysfunction (ED). The basic pharmacology of these drugs and their use for ED are discussed in Chapter 66 (Drugs for Erectile Dysfunction and Benign Prostatic Hyperplasia). Consideration here is limited to their use in PAH.



Sildenafil

Sildenafil, sold as Revatio, was approved for oral therapy of PAH in 2005, and then for IV therapy in 2009. The same drug, sold as Viagra, has been available since 1998 for oral therapy of men with erectile dysfunction (ED).


How does sildenafil work? It causes selective inhibition of PDE5, the enzyme that inactivates cyclic GMP (cGMP). In arterioles of the lung and other tissues, endogenous nitric oxide triggers synthesis of cGMP, which in turn promotes vasodilation. Hence, by inhibiting PDE5, sildenafil can preserve cGMP, and can thereby enhance vasodilation mediated by nitric oxide. In patients with PAH, sildenafil reduces pulmonary arterial pressure and pulmonary vascular resistance. The drug may also suppress proliferation of pulmonary vascular smooth muscle cells.


Sildenafil is generally well tolerated. The most common adverse effects are headache, flushing, and dyspepsia. Transient visual disturbances and priapism (prolonged, painful erection) occur infrequently. Very rarely, men have experienced sudden hearing loss or sight-threatening nonarteritic ischemic optic neuropathy. However, in both cases, a causal relationship has not been established.


Sildenafil can cause mild hypotension when used alone, and significant hypotension when combined with certain drugs. Combined use with alpha-adrenergic blockers can cause symptomatic postural hypotension. Of much greater concern, combined used with nitrates (eg, nitroglycerin, isosorbide dinitrate) can drop blood pressure enough to threaten life. Accordingly, concurrent use of sildenafil and nitrates is contraindicated.


Sildenafil is metabolized by CYP3A4 (the 3A4 isozyme of cytochrome P450). As a result, CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir) can raise sildenafil levels, and CYP3A4 inducers (eg, rifampin, phenytoin) can lower its level.


For treatment of PAH, sildenafil is available in two formulations: 20-mg tablets for oral therapy, and a solution (10 mg/12.5 mL) for IV therapy. Both formulations are sold as Revatio. The oral dosage is 20 mg 3 times a day, taken with or without food. The IV dosage is 10 mg 3 times a day, given by bolus injection.






Drugs for neonatal respiratory distress syndrome


Respiratory distress syndrome (RDS) is the primary cause of morbidity and mortality in premature infants. The underlying cause is deficiency of lung surfactant, a complex mixture of phospholipids and apoproteins that lowers surface tension on the alveolar surface. Consequences of surfactant deficiency include alveolar collapse, pulmonary edema, reduced lung compliance, small airway epithelial damage, hypoxia, and ultimately respiratory failure.


Increased production of cortisol during weeks 30 to 32 of gestation initiates production of lung surfactant. However, surfactant production is not fully adequate until weeks 34 to 36. As a result, the earlier the premature infant is delivered, the greater the risk of RDS. Among infants born during weeks 26 to 28, the incidence of RDS is 60% to 80%; by weeks 30 to 32, the incidence drops to 20%.



Prenatal and postnatal glucocorticoids


When preterm delivery cannot be prevented, injecting the mother with glucocorticoids can accelerate fetal lung maturation, and can thereby decrease the incidence and severity of RDS. Glucocorticoids act by stimulating production of fibroblast pneumocyte factor, which in turn stimulates production of surfactant by fetal pneumocytes. Glucocorticoids are effective when used during weeks 24 to 34 of gestation. Beyond week 34, fetal lungs are sufficiently mature that no benefit is gained by giving these drugs. Two drugs are recommended: dexamethasone and betamethasone. A single course consists of either (1) dexamethasone, 6 mg IM every 12 hours for four doses, or (2) betamethasone, two 12-mg IM doses, injected 24 hours apart. To be effective, the last glucocorticoid dose should be administered at least 24 hours before delivery, but no more than 7 days before. The basic pharmacology of the glucocorticoids is discussed in Chapters 60 and 72.


If pregnancy is successfully extended (eg, by giving a uterine relaxant), can repeat courses of glucocorticoids be of benefit? Possibly. Giving a repeat course every week until delivery yields better short-term outcomes than giving a single course: With repeat courses, there is a lower incidence of RDS, less need for mechanical respiratory support, and a reduction in serious neonatal morbidity. Furthermore, long-term follow-up studies done to date suggest that repeat courses are safe: Compared with children who received a single prenatal course, those who received repeat prenatal courses showed no deficit in growth, blood pressure, neurocognitive function, or developmental scores, and no increase in neurodevelopmental complications. However, although repeat courses may not cause long-term harm, there is no proof that repeat courses offer any long-term benefits. Accordingly, until more conclusive data on long-term outcomes become available, it may be prudent to avoid routine use of repeat courses.


Although the risk/benefit ratio for prenatal glucocorticoids appears favorable, the risk/benefit ratio for postnatal glucocorticoids is not. Yes, postnatal glucocorticoids are effective for prevention and treatment of chronic lung disease in infants. However, there is a high price to pay: Treatment impairs growth, neuromotor development, and cognitive function. In one study, researchers evaluated 8-year-old children who had received dexamethasone when they were infants. Compared with children who had not received dexamethasone, the treated children were 1.5 inches shorter, had smaller heads, and did less well on tests of motor skills, visual-motor integration, and intelligence. In 2002, both the American Academy of Pediatrics and the Canadian Paediatric Society recommended against routine use of systemic postnatal dexamethasone for prevention and treatment of chronic lung disease in infants.



Lung surfactant


Lung surfactant, administered by direct intratracheal instillation, is indicated for prevention and treatment (rescue therapy) of RDS. Surfactant therapy lowers the surface tension forces that cause alveolar collapse, and thereby rapidly improves oxygenation and lung compliance and reduces the need for supplemental oxygen and mechanical ventilation. Treatment decreases neonatal mortality by 33%.


In the United States, three preparations of lung surfactant are available: poractant alfa, calfactant, and beractant. Current data are insufficient to recommend any one drug over the others. Initial doses for prevention or treatment of RDS are as follows:



Because the effects of a single dose are often transient, repeated dosing may be needed. For poractant alfa, repeat doses should be 1.25 mL/kg—half the initial dose. For calfactant and beractant, repeat doses are the same as the initial dose.


Adverse effects result primarily from the administration process. Bradycardia and oxygen desaturation, which occur secondary to vagal stimulation and airway obstruction, are most common. If these occur, it may be necessary to temporarily suspend administration. Other adverse effects include pulmonary hemorrhage, mucus plugging, and endotracheal tube reflux.


Is there an effective alternative to using lung surfactant combined with mechanical ventilation in preterm infants? The answer is “Yes,” as shown in the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT). In this trial, preterm infants were treated with either continuous positive airway pressure (CPAP) or with surfactant plus mechanical ventilation. The result? The incidence of death, bronchopulmonary dysplasia, and other major outcomes were the same in both groups.



Drugs for cystic fibrosis


Cystic fibrosis (CF) is an inherited disorder that primarily damages the lungs, pancreas, and sweat glands. Some patients also develop liver disease. About 30,000 U.S. citizens have the disease. Fifty years ago, most children diagnosed with CF died before the age of 5. Today, the survival time is 37 years, with some living into their 40s and beyond. Drugs cannot cure CF, but they can reduce symptoms and retard progression of injury.



Pathophysiology of cystic fibrosis


The underlying cause of CF is mutation of the gene that codes for a particular type of chloride channel, referred to as the cystic fibrosis transmembrane regulator (CFTR). In cells that have defective CFTRs, the normal transmembrane flow of chloride ions, sodium ions, and water is disrupted. In the lungs, exocrine glands (eg, pancreas), and other structures, disruption of ion and water flux alters secretions.





Lungs.

Today, destruction of lung tissue is the major cause of morbidity and mortality among patients with CF. In the cells that line the airway, defective CFTRs impair secretion of chloride and enhance reabsorption of water and sodium. As a result, mucus becomes thick and viscous, causing plugging of the airway and promoting chronic bacterial colonization. All patients eventually develop active pulmonary infection; the most common pathogens are Pseudomonas aeruginosa and Staphylococcus aureus. Infection elicits an inflammatory response that is mediated primarily by neutrophils. Accumulation of DNA from dead neutrophils further increases the viscosity of sputum. Over time, chronic bronchitis and associated inflammation cause progressive destruction of lung tissue. In 95% of patients, death from cardiorespiratory failure ultimately ensues.




Drug therapy


Drugs are used to alleviate symptoms of CF and delay progression of injury to the lungs. Agents employed include pancreatic enzymes, fat-soluble vitamins, antibiotics, dornase alfa, and ibuprofen. Gene therapy is under investigation.




Pulmonary drugs


Inhaled antibiotics for chronic suppressive therapy.

Antibiotics are used long-term to suppress chronic infection with P. aeruginosa. The preferred route is inhalation. Why? Because this route achieves high concentrations in the airway while minimizing the risk of systemic toxicity. However, because treatment is prolonged, resistance is a concern. Two antibiotics—tobramycin and aztreonam—are approved for chronic inhalation therapy of P. aeruginosa infection. Both drugs improve pulmonary function, reduce the density of P. aeruginosa in sputum, and decrease the risk of hospitalization. In a trial that compared these drugs directly, aztreonam was more effective. Both drugs cost about $5000 for a 28-day supply.


With tobramycin [TOBI], the dosage is 300 mg every 12 hours in repeating cycles of 28 days on and 28 days off. Each dose takes 10 to 15 minutes to administer. Common adverse effects include cough, wheezing, and hoarseness. In contrast to IV aminoglycosides, inhaled tobramycin is unlikely to cause hearing loss, although it can cause tinnitus (ringing in the ears). The basic pharmacology of tobramycin and other aminoglycosides is discussed in Chapter 87.


With aztreonam [Cayston], the dosage is 75 mg 3 times a day in repeating cycles of 28 days on and 28 days off. Each dose takes 2 to 3 minutes to administer, making aztreonam more convenient than tobramycin. Principal adverse effects are cough, nasal congestion, and wheezing. The basic pharmacology of aztreonam is presented in Chapter 85.




Inhaled dornase alfa.

Dornase alfa [Pulmozyme], a purified preparation of recombinant human deoxyribonuclease, decreases the viscosity of sputum in patients with CF. The drug is administered by inhalation, using an approved nebulizer. Benefits derive from breaking down extracellular DNA that has accumulated in the lungs secondary to death of neutrophils. With daily use, dornase alfa can improve pulmonary function and decrease infection in some patients. The drug is generally well tolerated. Adverse effects include hoarseness, pharyngitis, laryngitis, rash, chest pain, and conjunctivitis. Dosing is begun at 2.5 mg once daily and may be increased to 2.5 mg twice daily if needed. To remain effective, dornase alfa must be administered every day for life. Unfortunately, treatment is expensive. A year’s supply of dornase alfa costs over $12,000. The nebulizer costs another $2000.





Drugs for sickle cell anemia


Sickle cell anemia (SCA) is an inherited blood disorder characterized by abnormal hemoglobin, chronic anemia, periodic painful episodes, and reduced life expectancy. The underlying cause is a mutation in the gene that codes for hemoglobin (Hb). People who inherit two copies of the gene (one from each parent) produce an altered form of Hb, known as HbS. (People with just one copy are carriers, but do not make HbS.) When HbS is fully oxygenated, there is no problem. However, when HbS gives up its oxygen, molecules of HbS can polymerize, forming long, rigid, rod-like chains. As a result, red blood cells (RBCs) assume a sickle (crescent) shape, and hence cannot pass through tiny blood vessels. As more RBCs get stuck, blood flow stops, thereby depriving tissues of required nutrients and oxygen. The result is severe pain, referred to as a vaso-occlusive crisis. Pain location depends on where vessel blockage occurs (eg, hands and feet, joints and extremities, abdomen). The crisis may last a few hours to a few weeks. Some patients have 15 or more painful episodes a year, whereas others may have 1 a year or less. Over time, vaso-occlusive events produce progressive organ damage and premature death. The median age at death is 42 for men and 48 for women. In many cases, death results from pulmonary arterial hypertension. Management of this condition is discussed above.


In addition to vaso-occlusive events, people with SCA experience chronic anemia (shortage of RBCs). Why? Unlike normal RBCs, which persist about 120 days, sickled RBCs die in 10 to 20 days. Because RBC loss is unusually rapid, replacements cannot be made fast enough, and hence a chronic shortage results.


Who is vulnerable to SCA? Worldwide, millions of people have the disease. In the United States, about 72,000 people have SCA. Most are African Americans (about 1 in 700 carry two copies of the sickle cell gene, and 1 in 14 carry one copy). In addition, SCA afflicts between 1 in 1000 to 1400 Hispanic Americans. The disease is not found among white Americans.


Researchers believe that the sickle cell mutation arose in a region where malaria is endemic. There is evidence that, in people with one copy of the gene, malaria is less deadly than in people who do not have the gene. As a result, those who carried the gene were more likely to survive, and hence could pass the advantage on to their children. Of course, in areas like the United States, where malaria rarely occurs, the gene offers no survival advantage—and, when two copies are inherited, the gene becomes a threat to survival.


Treatment consists of transfusions, analgesics, glucocorticoids, and hydroxyurea. Blood transfusions help correct anemia and reduce painful episodes. Analgesics and glucocorticoids can alleviate pain. Hydroxyurea can reduce the incidence and severity of painful episodes and, perhaps more importantly, it can prolong life.



Analgesics and glucocorticoids


For patients undergoing an acute crisis, analgesics and hydration are the cornerstone of treatment. Unfortunately, most patients generally fail to receive adequate pain relief. If the pain is moderate, a nonopioid analgesic (acetaminophen or a nonsteroidal anti-inflammatory agent) may be sufficient. However, if pain is severe, intensive therapy with an opioid is required. Parenteral (IV or IM) morphine and meperidine have been employed. Patient-controlled analgesia may be especially effective. The basic pharmacology of the opioids is discussed in Chapter 28.


High doses of intravenous methylprednisolone (a glucocorticoid) can shorten the duration of a sickle cell crisis. The drug should be used together with, not instead of, an opioid. Unfortunately, when glucocorticoids are discontinued, rebound pain may occur. The basic pharmacology of the glucocorticoids is discussed in Chapters 60 and 72.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. Orientation to pharmacology
  2. Drug therapy of infertility
  3. Drugs for the ear
  4. Pharmacodynamics

Stay updated, free articles. Join our Telegram channel
Tags:
Jul 24, 2016 | Posted by in NURSING | Comments Off on Miscellaneous noteworthy drugs

Full access? Get Clinical Tree
Get Clinical Tree app for offline access