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Pulmonary Pharmacology

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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
                lazo@pitt.edu
                      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.