Page 349 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 335

contractions of the uterus that lead to ischemic pain. NSAIDs increased in a graded dose-dependent manner, based on recur-
successfully inhibit the formation of these prostaglandins (see rence, persistence, or worsening of symptoms. Several prostacy-
Chapter 36) and so relieve dysmenorrhea in 75–85% of cases. clin analogs with longer half-lives have been developed and used
Some of these drugs are available over the counter. Aspirin is also clinically. Iloprost (half-life about 30 minutes) is usually inhaled
effective in dysmenorrhea, but because it has low potency and is six to nine times per day (2.5–5 mcg/dose), although it has
quickly hydrolyzed, large doses and frequent administration are been delivered by intravenous administration outside the USA.
necessary. In addition, the acetylation of platelet COX, causing Treprostinil (half-life about 4 hours) may be delivered by subcu-
irreversible inhibition of platelet TXA synthesis, may increase the taneous or intravenous infusion or by inhalation. Recently, two
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amount of menstrual bleeding. oral prostacyclin receptor agonists were approved by the US Food
and Drug Administration (FDA): selexipag (a prodrug rapidly
Male Reproductive System converted to active prostacyclin agonist) and an oral preparation
of treprostinil. Other drugs used in pulmonary hypertension are
Intracavernosal injection or transurethral suppository therapy discussed in Chapter 17.
with alprostadil (PGE ) is a second-line treatment for erectile
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dysfunction. Injected doses are 2.5–25 mcg; suppositories are B. Peripheral Vascular Disease
recommended to start at 125 mcg or 250 mcg, up to 1000 mcg. A number of studies have investigated the use of PGE and PGI
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Penile pain is a frequent side effect, which may be related to the compounds in Raynaud’s phenomenon and peripheral arterial
algesic effects of PGE derivatives; however, only a few patients disease. However, these studies are mostly small and uncontrolled.
discontinue the use because of pain. Prolonged erection and pria- Currently, these therapies do not have an established place in the
pism are side effects that occur in less than 4% of patients and treatment of peripheral vascular disease.
are minimized by careful titration to the minimal effective dose.
When given by injection, alprostadil may be used as monotherapy C. Patent Ductus Arteriosus
or in combination with either papaverine or phentolamine.
Patency of the fetal ductus arteriosus depends on COX-2-derived
Renal System PGE acting on the EP receptor. At birth, reduced PGE levels,
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a consequence of increased PGE metabolism, allow ductus arte-
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Increased biosynthesis of prostaglandins has been associated with riosus closure. In certain types of congenital heart disease (eg,
one form of Bartter’s syndrome. This is a rare disease character- transposition of the great arteries, pulmonary atresia, pulmonary
ized by low-to-normal blood pressure, decreased sensitivity to artery stenosis), it is important to maintain the patency of the
angiotensin, hyperreninemia, hyperaldosteronism, and excessive neonate’s ductus arteriosus until corrective surgery can be carried
+
loss of K . There also is an increased excretion of prostaglandins, out. This can be achieved with alprostadil (PGE ). Like PGE ,
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especially PGE metabolites, in the urine. After long-term adminis- PGE is a vasodilator and an inhibitor of platelet aggregation,
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tration of COX inhibitors, sensitivity to angiotensin, plasma renin and it contracts uterine and intestinal smooth muscle. Adverse
values, and the concentration of aldosterone in plasma return to effects include apnea, bradycardia, hypotension, and hyperpy-
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normal. Although plasma K rises, it remains low, and urinary rexia. Because of rapid pulmonary clearance (the half-life is about
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wasting of K persists. Whether an increase in prostaglandin 5–10 minutes in healthy adults and neonates), the drug must be
biosynthesis is the cause of Bartter’s syndrome or a reflection of a continuously infused at an initial rate of 0.05–0.1 mcg/kg/min,
more basic physiologic defect is not yet known. which may be increased to 0.4 mcg/kg/min. Prolonged treatment
has been associated with ductal fragility and rupture.
Cardiovascular System In delayed closure of the ductus arteriosus, COX inhibitors are
often used to inhibit synthesis of PGE and so close the ductus.
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A. Pulmonary Hypertension Premature infants in whom respiratory distress develops due to
PGI lowers peripheral, pulmonary, and coronary vascular resis- failure of ductus closure can be treated with a high degree of suc-
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tance. Pulmonary hypertension is characterized by an increase cess with indomethacin. This treatment often precludes the need
in vascular resistance in the pulmonary blood vessels. PGI has for surgical closure of the ductus.
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been used to treat pulmonary hypertension arising from primary
lung disease and that arising from heart or systemic diseases. Blood
In addition, prostacyclin has been used successfully to treat
portopulmonary hypertension, which arises secondary to liver As noted above, TXA promotes platelet aggregation while PGI ,
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disease. The first commercial preparation of PGI approved for and perhaps also PGE and PGD , inhibit aggregation. Chronic
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treatment of pulmonary hypertension (epoprostenol) improves administration of low-dose aspirin (81 mg/d) selectively and irre-
symptoms, prolongs survival, and delays or prevents the need versibly inhibits platelet COX-1, and its dominant product TXA ,
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for lung or lung-heart transplantation. Side effects include flush- without modifying the activity of nonplatelet COX-1 or COX-2
ing, headache, hypotension, nausea, and diarrhea. The extremely (see Chapter 34). TXA 2 , in addition to activating platelets, ampli-
short plasma half-life (3–5 minutes) of epoprostenol necessitates fies the response to other platelet agonists; hence, inhibition of its
continuous intravenous infusion through a central line for long- synthesis inhibits secondary aggregation of platelets induced by
term treatment. Intravenous infusion dosage of epoprostenol is adenosine diphosphate, by low concentrations of thrombin and