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Pulmonary Pharmacology V Pharmacologic Therapy of Pulmonary Vascular Disease John S. Lazo, Ph.D. Department of Pharmacology E-1340 Biomedical Science Tower firstname.lastname@example.org REFERENCES Basic & Clinical Pharmacology. Lange. Katzung, Ed., 9th Edition. McGraw Hill. 2004. “The Eicosanoids.” pp.298-412 and “Nitric Oxide, Donors & Inhibitors” pp. 313-318-. Reasonable. Rubin, L.J. and Badesch, D.B. Evaluation and management of the patient with pulmonary arterial hypertension. Annuals of Internal Medicine. 143:282-292, 2005. Describes the current consensus concerning the management of pulmonary hypertension with case studies. Olschewski,,et al. Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacology & Therapeutics. 102:139-153, 2004. Good review of mechanisms and pharmacological characteristics of prostacyclin analogs with clinical data. Remuzzi, G., et al. New therapeutics that antagonize endothelin: Promises and Frustrations. Nature Reviews Drug Discovery. 1:986- 1001, 2002. The definitive text on the development of ET receptor antagonists LEARNING OBJECTIVES To understand the fundamental signal transduction pathways implicated in pulmonary vasoconstriction and vasodilatation. To know the classes of drugs used to treat pulmonary hypertension, their absorption, distribution, metabolism, and side effect profiles. To appreciate potential future pharmacological approaches and challenges for the treatment of pulmonary hypertension CHALLENGES FOR THE PHARMACOLOGICAL TREATMENT OF PULMONARY HYPERTENSION Pulmonary arterial hypertension (PAH) is hemodynamically defined as an elevated mean pulmonary vascular pressure (>25 mm Hg) with a normal pulmonary capillary or left arterial pressure (<15 mm Hg), which can be caused by an isolated increase in pulmonary arterial pressure or by increases in both pulmonary arterial & pulmonary venous pressure. Until recently, management of PAH was generally ineffective in alleviating symptoms or improving survival. The asymptomatic aspects of PAH, the complexity of differential diagnosis, involvement of coexistent cardiopulmonary disease, and the relative small patient population all represent challenges for the development efforts for PAH. During the past decade a substantial improvement in our understand of the pathogenesis of PAH has occurred with new pharmacological treatments being tested & approved. PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH The pulmonary circulation has a remarkable capacity to regulate its vascular tone to adapt to physiologic changes. Vasoactive regulation plays an important role in local blood flow regulation in relation to ventilation (V/Q matching). Hypoxic pulmonary vasoconstriction results from inhibition of pulmonary vascular smooth muscle K+ channel conductance, leading to cellular depolarization and an influx of Ca2+ ions through voltage-gated calcium channels. Contraction of vascular smooth muscle is the force that narrows the pulmonary vessel suggesting the pulmonary endothelium produces the signal for muscular contraction. PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH (cont.) In PAH, there is media thickening and hypertrophy, resulting in a muscle layer in an arteriole that is usually nonmuscularized. The resulting chronic vasoconstriction and fibroblast proliferation leads to the initiation of remodeling in the intimal and medial layers of the arteriole. PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH (cont.) Furchgott & others in the 1980s using isolated vascular smooth muscle preparations found vasodilation following acetylcholine or carbachol treatment but paradoxical vasoconstriction when the vascular endothelium was stripped or removed from the preparation. This short-lived vasodilator substance was called endothelium- derived relaxing factor (EDRF) because it promoted relaxation of precontracted smooth muscle preparations. EDRF was subsequently discovered to be nitric oxide (NO). Products of inflammation and platelet aggregation (e.g., serotonin, histamine, bradykinin, purines and thrombin) exert all or part of their actions by stimulating the production of NO. NO diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase to generate cGMP that leads to smooth muscle relaxation. Endothelium-derived vasoactive substances platelets platelets Tbm TGFb1 Ach Ach ET-1 Tbm ADP AI AII BK inactive products T TFBR M M ETB T AT1 P B ACE ACE NOS pET-1 ET-1 cyclooxygenase EDHF Endothelium ECE L-Arg NO TXA2 PGH2 PGI2 ETB IP AT1 ETA GC TX Vascular smooth muscle GTP cGMP Contraction Relaxation PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL FUNCTION AND PHARMACOLOGICAL TARGETS for PAH (cont.) The endothelial cell produces vasoconstrictors, such as ET-1 and TXA2, and catalyzes the conversion of angiotensin I to angiotensin II. ET-1 is the most potent known vasoconstrictor; it causes prolonged vasoconstriction and increases vascular tone, increasing pulmonary vascular resistance (PVR). These vasoactive molecules act on local vascular smooth muscle, mostly in a paracrine fashion, although TXA2 also stimulates platelet aggregation, which can result in in situ thrombosis and increased PVR. Endothelium-derived vasoactive substances platelets platelets Tbm TGFb1 Ach Ach ET-1 Tbm ADP AI AII BK inactive products T TFBR M M ETB T AT1 P B ACE ACE NOS pET-1 ET-1 cyclooxygenase EDHF Endothelium ECE L-Arg NO TXA2 PGH2 PGI2 ETB IP AT1 ETA GC TX Vascular smooth muscle GTP cGMP Contraction Relaxation Regulation of ET-1 synthesis and ET-receptor mediated smooth muscle contraction PGI2, NO, heparin, EGF AII, steroids, TGFb1, hypoxia, Thrombin Smooth muscle Relaxation Contraction PHARMACOLOGY OF PULMONARY HYPERTENSION No other area of pharmacology provides you with a wider array of delivery modalities!!! There are underlying physiological issues that limit the pharmacological options in PAH. 1. pulmonary hypertension results from loss of normal cross-sectional area of the pulmonary vasculature, and this loss of capacitance may limit right ventricular cardiac output. Although the mechanism is different, the physiologic effect is similar to that of aortic stenosis. Designing feasible approaches to increase the cross-sectional are of the pulmonary vasculature are difficult. 2. Limiting right ventricular cardiac output, limits left ventricular cardiac output, because the left ventricle cannot pump more blood than it receives. The reduction in biventricular cardiac output underlies the unique difficulties in the treatment of pulmonary hypertension. Patients with pulmonary hypertension frequently have low systemic blood pressure, and cannot tolerate agents that lead to systemic vasodilation. PHARMACOLOGY OF PULMONARY HYPERTENSION Endothelial cells in both the pulmonary and systemic circulation share many of the similar receptors and produce the same vasoactive molecules, so agents that might dilate the pulmonary vasculature, often act more prominently on the systemic vasculature. Differences in receptor type and density and in the quantitative production of vasoactive molecules in different vascular beds, exploiting these differences therapeutically has been the goal of modern therapy. SPECIFIC AGENTS Nitric Oxide Prostacyclin Analogs Epoprostenol Treprostinil Iloprost Endothelin Antagonists Bostentan Sitaxsentan Phosphodiesterase Inhibitors Sildenafil Calcium Channel Antagonists Combination Therapy Nitric Oxide Chemistry. Nitric oxide, (NO. or simply NO) is a highly diffusible, colorless, odorless, stable gas composed of one atom each of nitrogen and oxygen. NO (trade name: INOmax) is available as a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%). Synthesis. NO is synthesized from L-arginine by a family of three heme-containing enzymes that are collectively called nitric oxide synthase (NOS). One form, endothelial NOS, is constitutive and resides in the endothelium and synthesizes NO over short periods in response to receptor-mediated increases in cellular Ca2+. Mechanism of Action. NO relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3′, 5′-monophosphate (cGMP), which then leads to vasodilation. Epithelial cell Alveolus NO NO NO Endothelial cells NO NO NO Intravascular space Synthesis of PGI2 and other eicosanoids Nitric Oxide Absorption, Distribution and Metabolism. NO is absorbed systemically after inhalation and traverses the pulmonary capillary bed where it combines with hemoglobin that is 60-100% oxygen-saturated. At this level of oxygen saturation, NO combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate (NO3-). At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. The rapid binding to and inactivated by hemoglobin permit selective pulmonary vasodilation. Because NO is administered by inhalation, the vasodilation occurs in alveolar units that are well ventilated, so V/Q matching and systemic oxygenation tend to improve. Unfortunately, the half life of NO is between 2-6 seconds, and administration requires a pressurized delivery system with extensive monitoring and backup power, as abrupt discontinuance may lead to rebound pulmonary hypertension. Because of these limitations, the use of NO is limited to patients in the intensive care unit, primarily neonates with persistent PAH of the newborn. Inhaled NO may also be used diagnostically in adults with PAH to identify the subset with vascular reactivity. Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the NO dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration. Synthesis of PGI2 and other eicosanoids Cell membrane Phospholipase A2 Arachidonic acid 5-Lipogenase Prostaglandin G2 5-HPETE Prostaglandin H2 Leukotrienes PGI2 PGE2 TXA2 Chemical Structures of Prostacyclin Analogs HO O OH O O HO PGI2 Epopstenol Arachidonic acid HO O O H3 C OH O HO OH HO O HO Iloprost Beraprost Treprostinil Japan HO CH 3 HO CH3 HO HO Prostacyclin Analogs: Epoprostenol Absorption. Epoprostenol is administrated iv and has a half-life in human blood of ~6 minutes; it must be delivered into the central venous circulation to achieve selective pulmonary vasodilation. Hence this medication requires a chronic indwelling central venous catheter and a portable infusion pump. Metabolism. Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Epoprostenol is metabolized to two primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which are essentially pharmacologically inactivity. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans. Elimination. ~90% of the administered drug is eliminated in the urine. Toxicity. Abrupt withdrawal of epoprostenol may lead to rebound pulmonary vasoconstriction, and at least one death has been attributed to a sudden interruption of epoprostenol therapy. Other adverse effects (in descending order of prevalence) include dizziness, headache, jaw pain, flushing, diarrhea, tachycardia, and anxiety. Less common, but potentially more serious complications are thrombo-cytopenia and sepsis related to the indwelling catheter. Mechanism of Action. Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. Prostacyclin Analogs:Treprostinil Absorption. Treprostinil is relatively rapidly and completely absorbed after subcutaneous infusion using a pump system, with an absolute bioavailability approximating 100%. Steady- state concentrations occurred in ~10 hours. Distribution. The volume of distribution of the drug in the central compartment is approximately 14 L/70 kg ideal body weight. Treprostinil has a half-life of 2-4 hours. The longer half-life means that pump malfunction, or accidental dislodgement of the infusion catheter are less serous for patients using treprostinil than for those receiving epoprostenol. The access site must be moved every 2 or 3 days, and 85% of patients experience pain at the infusion site and for some it is intolerable. Metabolism. Treprostinil is substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described but the biological activity and metabolic fate of these metabolites are unknown. Elimination. Biphasic: ~ 80% excreted in the urine, ~5% as unchanged drug. Approximately 10% of a dose is excreted in the feces. Toxicity. Other adverse effects are similar to those experienced with epoprostenol and include flushing, nausea, diarrhea, jaw pain, and headache. Mechanism of Action. Like epoprostenol, the major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. Prostacyclin Analogs:Iloprost Chemistry. A synthetic analogue of prostacyclin comprising a mixture of the 4R and 4S diastereomers at a ratio of approximately 50:50. Absorption. The hemodynamic effects of iloprost last 30-60 minutes, and it is administered via drug aerosol 6 or 9 times daily. The absolute bioavailability of inhaled iloprost has not been determined. Distribution. The volume of distribution at steady-state is 0.7 to 0.8 L/kg following iv infusion. Metabolism. Oxidized to an inactive metabolite, which is found in the urine. Elimination. ~70% eliminated in the urine and ~10% in the feces. Toxicity. Complications of therapy include flushing, jaw pain, and syncope and are generally less pronounced than seen with epoprostenol Mechanism of Action. Like epoprostenol, the major pharmacological actions of Iloprost are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. The improvement in patient performs is significant but modest. The two diastereoisomers of iloprost, 4S and 4R isomer differ in potency in dilating blood vessels, 4S isomer is substantially more potent than the 4R isomer. Figure 6. Iloprost-mediated change in 6 min walk distance 30 min post inhalation in PAH patients. Endothelin Antagonists ET-1 signal transduction mechanisms Ca2+ Ca2+ Endothelin Antagonists: Bostentan Chemistry. Bostentan, the first clinically approved endothelin antagonist belonging. Cl CH 3 O O O O S NH OCH 3 S N N O (H3 C)3C N H N O S N O N OH O O Bosentan Sitaxsentan Endothelin Antagonists: Bostentan Absorption, Distribution, Metabolism and Elimination. The absolute bioavailability of bosentan is about 50% and is unaffected by food. The volume of distribution is about 18 L/ 70 kg. Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. After oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half- life (T½) is about 5 hours. Bosentan has 3 metabolites, 1 of which is pharmacologically active and may contribute 10-20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19. After multiple oral dosing, plasma concentrations decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto- induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Toxicity. Hepatic toxicity is the major clinical adverse effect, with elevation of hepatic transaminases to greater than 3 times the upper limit of normal in 11-14% of patients. Liver injury was more common in patients taking glyburide (an oral antiglycemic agent), so concomitant administration is contraindicated. Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and cyclosporine A is contraindicated. Bosentan causes dose-dependent reductions in hemoglobin. Therapy has been associated with flushing. Finally, bosentan is teratogenic in animals, and pregnancy while take the medication is strongly discouraged. Induction of CYP3A4 and P2C9 by bosentan is likely to decrease the plasma level of a number of drugs, including oral contraceptives, oral hypoglycemic agents, warfarin, and statins, although clinical experience with these combinations is limited. Mechanism of Action. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. PDE5 Inhibitors: Sildenafil O CH 3 N O O HN N S N N N H3 C O CH 3 CH 3 Sildenafil Viagra Sildenafil is an orally administered cGMP PDE 5 inhibitor approved for use in treatment of erectile dysfunction. In normal volunteers, sildenafil attenuated the increase in pulmonary arterial pressure associated with hypoxia with no effect on systemic blood pressure. In small studies with primary and secondary PAH patients sildenafil has improved exercise tolerance and pulmonary arterial pressure, but the available studies are small; further research is necessary. PDE5 Inhibitors: Sildenafil Absorption. Orally active with a bioavailability of ~40%. Half-life = 2.4 hours. Distribution. Widely distributed with a volume of distribution of ~1 L/kg. Peak biological activity occurs at ~ 1 hour. Metabolism. Hepatic metabolism is via CYP3A4 (major route) and CYP2C9 (minor route). Thus, you need to be concerned with drug-drug interactions such as with cimetidine, erythromycin, etc. Elimination. 80% appears in the feces; 13% in the urine. Toxicity. Reported side effects are minor and include headache, nasal congestion, and visual disturbance. However, serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, and hypertension, have occurred with use of sildenafil for other indications. Mechanism of Action. A selective inhibitor of PDE5: potency is PDE1 (> 80-fold); PDE2 and PDE4 (> 1000 times); PDE3 (about 4000 times), and PDE6 (about 10 times). PDE3 controls cardiac contractility and PDE6, an enzyme found in the retina, may be involved in color vision abnormalities reported for the higher dose of sildenafil. The active metabolite of sildenafil has approximately 50% potency for PDE5, and contributes approximately 20% of sildenafil's effect. By diminishing the effect of PDE5, sildenafil facilitates the effect of NO, increases cGMP levels and relaxes smooth muscle relaxes. Calcium Channel Antagonists Calcium antagonists block the influx of Ca2+ into the vascular smooth muscle cell through voltage-operated calcium channels, reducing he intracellular free Ca2+ concentration and promoting vasodilation. Calcium channel blockers, however, have properties that could worsen underlying PAH, including negative inotropic effects on right ventricular function. Although widely used, the effectiveness of calcium channel blockers is limited to the small subset of subjects with PAH who demonstrate large hemodynamic improvements with acute administration. Hemodynamic improvements in response to calcium channel antagonists may merely identify subjects with a better prognosis, and not indicate a beneficial effect of the drugs. Use of these agents without initial monitoring of pulmonary pressures and vasoreactivity is potentially dangerous. Combination Therapy Because endothelin antagonists and PDE5 inhibitors each act through distinct pathways, combination therapy is attractive. Combining medications may enhance efficacy or allow drugs to be used at lower doses, thereby minimizing toxicity. Alternatively, the medications might combine in unanticipated ways and increase toxicity. Studies to examine the combined effects of two or more agents are currently underway. Conclusions To understand the fundamental signal transduction pathways implicated in pulmonary vasoconstriction and vasodilatation. NO, PGI2, ET-1 & TXA2 are important mediators of smooth muscle tone in the pulmonary vasculature. To know the classes of drugs used to treat pulmonary hypertension, their absorption, distribution, metabolism, and side effect profiles. NO, PGI2 (Epoprostenol), analogs (Treprostinil & Iloprost), ET-1 antagonists (Bostentan), PDE5 antagonists (Sildenafil). Some iv, sc pump, inhalation or oral. To appreciate potential future pharmacological approaches and challenges for the treatment of pulmonary hypertension. ETA receptor selective ET-1 antagonists. PDE5 inhibitors & combination therapy.
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