40 Pharmacology 5: Therapy of Pulmonary Vascular Disease Flashcards Preview

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Flashcards in 40 Pharmacology 5: Therapy of Pulmonary Vascular Disease Deck (27)
1

Challenges for the pharmacological treatment of pulmonary arterial hypertension (PAH)

  • Pulmonary arterial hypertension (PAH)
  • PAH can be caused by...
  • Challenges for PAH management

  • Pulmonary arterial hypertension (PAH)
    • Elevated mean pulmonary vascular pressure (>25 mm Hg) 
    • Normal pulmonary capillary or left arterial pressure (<15 mm Hg)
  • PAH can be caused by...
    • An isolated increase in pulmonary arterial pressure
    • Increases in both pulmonary arterial and pulmonary venous pressure
  • Challenges for PAH management
    • The asymptomatic aspects of PAH
    • The complexity of differential diagnosis
    • Involvement of coexistent cardiopulmonary disease
    • The relative small patient population

2

Brief review of pulmonary vascular structure, endothelial function, and pharmacological targets for PAH

  • The pulmonary vascular bed 
  • The pulmonary circulation has a remarkable capacity to...
  • Vasoactive regulation 
  • Hypoxic pulmonary vasoconstriction results from...
  • Although contraction of vascular smooth muscle narrows pulmonary vessels, the pulmonary endothelium signals
  • In PAH, there is...

  • The pulmonary vascular bed
    • A high-flow, low-resistance circuit 
    • Can accommodate the entire cardiac output at a pressure that is normally less than 20% of the pressure in the systemic circulation
  • The pulmonary circulation has a remarkable capacity to...
    • Regulate its vascular tone to adapt to physiologic changes
  • Vasoactive regulation
    • Plays an important role in the local regulation of blood flow 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
  • Although contraction of vascular smooth muscle narrows pulmonary vessels, the pulmonary endothelium signals
    • Muscular contraction
  • In PAH, there is...
    • Media thickening and hypertrophy, resulting in development of a muscle layer in an arteriole
    • The resulting chronic vasoconstriction and fibroblast proliferation leads to the
      initiation of remodeling in the intimal and medial layers of the arteriole

3

Brief review of pulmonary vascular structure, endothelial function, and pharmacological targets for PAH

  • The central role of the endothelium 
  • Vasodilation follows...
  • Vasoconctriction follows...
  • Endothelium-derived relaxing factor (EDRF) 
  • Production of NO
  • In addition to NO, the endothelial cell produces...
  • The endothelial cell catalyzes...
  • ET-1 
  • These vasoactive molecules act...

  • The central role of the endothelium
    • Regulating vascular smooth muscle action
  • Vasodilation follows...
    • Acetylcholine or carbachol treatment
  • Vasoconctriction follows...
    • Vascular endothelium being stripped or removed from the preparation
  • Endothelium-derived relaxing factor (EDRF) 
    • Short-lived vasodilator substance
    • Promoted relaxation of precontracted smooth muscle preparations
    • Subsequently discovered to be nitric oxide (NO)
  • Production of NO
    • Stimulation allows products of inflammation and platelet aggregation (e.g., serotonin, histamine, bradykinin, purines and thrombin) to exert all or
      part of their actions
    • Diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase to generate cGMP that leads to smooth muscle relaxation
  • In addition to NO, the endothelial cell produces...
    • Other vasodilators, including prostacycline (PGl2)
    • Vasoconstrictors, such as endothelin 1 (ET-1) and thromboxane A2 (TXA2) 
  • The endothelial cell catalyzes...
    • The conversion of angiotensin I to angiotensin II
  • ET-1
    • The most potent known vasoconstrictor
    • Causes prolonged vasoconstriction and increases vascular tone, increasing pulmonary vascular resistance (PVR)
    • Mediated by ET receptors
  • These vasoactive molecules act...
    • On local vascular smooth muscle, mostly in a paracrine fashion
    • TXA2 also stimulates platelet aggregation, which can result in in situ thrombosis and increased PVR

4

Pharmacology of pulmonary hypertension

  • Underlying physiological issues that limit the pharmacological options in PAH
    • Pulmonary hypertension results from...
    • Limiting right ventricular cardiac output...
  • Patients with pulmonary hypertension frequently...
  • Agents that might dilate the pulmonary vasculature...
  • There are differences in...

  • Underlying physiological issues that limit the pharmacological options in PAH
    • Pulmonary hypertension results from loss of normal cross-sectional area of the pulmonary vasculature
      • This loss of capacitance may limit right ventricular cardiac output
      • The physiologic effect is similar to that of aortic stenosis
    • Limiting right ventricular cardiac output limits left ventricular cardiac output
      • 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
    • Cannot tolerate agents that lead to systemic vasodilation
  • Agents that might dilate the pulmonary vasculature...
    • Often act more prominently on the systemic vasculature
    • Endothelial cells in both the pulmonary and systemic circulation share many of the similar receptors and produce the same vasoactive molecules
  • There are differences in...
    • Receptor type and density
    • The quantitative production of vasoactive molecules in different vascular beds

5

Specific agents:
Nitric oxide:
Chemistry, synthesis, and mechanism of action

  • Chemistry
  • Synthesis
  • Mechanism of Action

  • Chemistry
    • Hhighly diffusible, colorless, odorless, stable gas composed of one atom each of nitrogen and oxygen
    • Available as a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%)
  • Synthesis
    • Synthesized from L-arginine by a family of three heme-containing enzymes that are collectively called nitric oxide synthase (NOS)
    • One form: endothelial NOS
      • Constitutive
      • Resides in the endothelium
      • 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
    • Activates guanylate cyclase
    • Increases intracellular levels of cGMP
    • Leads to vasodilation

6

Specific agents:
Nitric oxide:
Absorption, distribution, and metabolism

  • NO is absorbed systemically after...
  • At this level of oxygen saturation, nitric oxide combines predominantly with...
  • At low oxygen saturation, nitric oxide can combine with...
  • The rapid binding to and inactivated by hemoglobin provide...
  • Because NO is administered by inhalation, the vasodilation occurs in...
  • The half life of NO is...
  • Administration requires...
  • Because of these limitations, the use of NO is limited to patients...
  • Inhaled NO may also be used diagnostically in...
  • Nitrate 

  • 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, nitric oxide 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 provide...
    • The inhaled gas to exhibit 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
  • The half life of NO is...
    • Between 2-6 seconds
  • 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 pulmonary hypertension of the newborn
  • Inhaled NO may also be used diagnostically in...
    • Adults with pulmonary hypertension to identify the subset with vascular reactivity
  • Nitrate
    • The predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled
    • Cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration

7

Prostacyclin analogs:
Eicosinoids

  • Such as prostacyclin (PGI2)
  • Derived from arachadonic acid and other 20- carbon fatty acids when phospholipase A2 is activated by injury or other stimuli

8

Prostacyclin analogs:
Epoprostenol:
Chemistry, absorption, distribution, metabolism, and elimination

  • Chemistry
  • Absorption and distribution
    • Administrated ...
    • Half-life
    • Must be delivered into...
    • Requires...
    • Hydrolysis
    • Degradation
  • Metabolism
  • Elimination

  • Chemistry
    • PGI2, a naturally occurring prostaglandin
  • Absorption and distribution
    • Administrated IV
    • Half-life in human blood of ~6 minutes
    • Must be delivered into the central venous circulation to achieve selective pulmonary vasodilation
    • Requires a chronic indwelling central venous catheter and a portable infusion pump
    • Rapidly hydrolyzed at neutral pH in blood
    • Subject to enzymatic degradation
  • Metabolism
    • Metabolized to two primary inactive metabolites, which are essentially inactive
    • Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans
  • Elimination
    • Urinary elimination accounts for 90% of the administered compound

9

Prostacyclin analogs:
Epoprostenol:
Toxicity and mechanism of action

  • Toxicity
    • Abrupt withdrawal of epoprostenol may lead to...
    • Other adverse effects
    • Less common, but potentially more serious complications
  • 2 major pharmacological mechanisms of actions

  • Toxicity
    • Abrupt withdrawal of epoprostenol may lead to rebound pulmonary vasoconstriction
      • At least one death has been attributed to a sudden interruption of epoprostenol therapy
    • Other adverse effects (in descending order of prevalence)
      • Dizziness, headache, jaw pain, flushing, diarrhea, tachycardia, and anxiety
    • Less common, but potentially more serious complications
      • Thrombocytopenia and sepsis related to the indwelling catheter
  • 2 major pharmacological mechanisms of actions
    • Direct vasodilation of pulmonary and systemic arterial vascular beds
    • Inhibition of platelet aggregation

10

Prostacyclin analogs:
Treprostinil:
Chemistry, toxicity, and mechanism of action

  • Chemistry
  • Toxicity
  • Mechanism of action

  • Chemistry
    • Analog of PGI2
  • Toxicity
    • Other adverse effects are similar to those experienced with epoprostenol
    • 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
      • Inhibition of platelet aggregation

11

Prostacyclin analogs:
Treprostinil:
Absorption, distribution, metabolism, and elimination

  • Absoprtion
    • Absorbed after...
    • Bioavailability
  • Distribution
    • Steady-tate concentrations
    • Volume of distribution
    • Half-life
    • Access site
    • At the infusion site
  • Metabolism
    • Location
    • Metabolites
  • Elimination

  • Absoprtion
    • Relatively rapidly and completely absorbed after subcutaneous infusion using a pump system
    • Absolute bioavailability approximating 100%
  • Distribution
    • Steady-state concentrations occurred in ~10 hours
    • The volume of distribution of the drug in the central compartment is approximately 14 L/70 kg ideal body weight
    • 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
    • 85% of patients experience pain at the infusion site, which is intolerable in some (<10% in reported trials)
  • Metabolism
    • Substantially metabolized by the liver
    • Five metabolites
  • Elimination
    • Biphasic, with ~ 80% of an administered dose being excreted in the urine: 5% unchanged drug
    • Approximately 10% of a dose is excreted in the feces

12

Prostacyclin analogs:
Iloprost:
Chemistry, absorption, distribution, metabolism, and elimination

  • Chemistry
  • Absorption, distribution, and metabolism
    • Hemodynamic effects last...
    • Administered via...
    • Volume of distribution at steady-state
    • Oxidized to...
  • Elimination

  • Chemistry
    • Synthetic analog of prostacyclin
    • 50:50 mixture of the 4R and 4S (active) diastereomers
  • Absorption, distribution, and metabolism
    • The hemodynamic effects last 30-60 minutes
    • Administered via drug aerosol 6 or 9 times daily
    • Volume of distribution at steady-state is 0.7 to 0.8 L/kg, following intravenous infusion
    • Oxidized to an inactive metabolite, which is found in the urine
  • Elimination
    • ~70% of the drug is eliminated in the urine
    • ~10% of a dose is excreted in the feces

13

Prostacyclin analogs:
Iloprost:
Toxicity and mechanism of action

  • Toxicity
  • Mechanism of action
    • Major pharmacological actions
    • Improvement in patient performance
    • Two diastereoisomers

  • Toxicity
    • Complications of therapy include flushing, jaw pain, and syncope
    • Generally less pronounced than seen with epoprostenol infusions
  • Mechanism of action
    • Like epoprostenol, the major pharmacological actions are...
      • Direct vasodilation of pulmonary and systemic arterial vascular beds
      • Inhibition of platelet aggregation
    • The improvement in patient performance is statistically significant but physiologically 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

14

Endothelin antagonists:
Endothelin 1 (ET-1)

  • Form of endothelium
  • The synthesis is regulated by...
    • Derived from...
  • Dose-dependence
  • When infused intravenously, ET-1 causes...
    • The depressor response results from...
    • The pressor response is due to...
  • Other actions
  • Potent mitogen for...
  • Neurohormone effects are mediated by...
  • ET-1 concentrations are elevated in...

  • Predominant form secreted by the endothelium
  • The synthesis is regulated both by positive and negative factors
    • Derived from a 212 amino acid precursor protein known as prepro-ET-1 or big ET-1
  • Dose-dependent paracrine or autocrine vasoconstriction in most vascular beds
  • When infused intravenously, ET-1 causes a rapid and transient decrease arterial blood pressure, followed by a prolonged increase
    • The depressor response results from release of prostacyclin and NO from the vascular endothelium
    • The pressor response is due to direct constriction of vascular smooth muscle
  • Other actions
    • Bronchial smooth muscle constriction
    • Positive chronotropic and inotropic cardiac effects
    • Tenal vasoconstriction leading to decreases in salt and water excretion
  • Potent mitogen for...
    • Vascular smooth muscle cells
    • Cardiac myocytes
    • Glomerular mesangial cells
  • Neurohormone effects are mediated by...
    • Binding to ETA and ETB receptors in the endothelium and vascular smooth muscle
  • ET-1 concentrations are elevated in...
    • Plasma and lung tissue of patients with pulmonary arterial hypertension
    • Suggests a pathogenic role for ET-1 in this disease

15

Endothelin antagonists

  • The endothelin receptors, ETA and ETB
  • ETA 
    • Affinity
    • Location
    • Mediates...
  • ETB
    • Affinity
    • Location
    • Mediates...
  • The signal transduction mechanisms triggered by binding of ET-1 to ETA receptors lead to...
  • Because the ET-1 is such a potent vasoconstrictor, there has been considerable interest in developing inhibitors of the ET receptor for disorders including...

  • The endothelin receptors, ETA and ETB
    • Have different distributions
    • Use different signal transduction pathways to yield distinct effects
  • ETA
    • Has high affinity for ET-1
    • Found primarily on smooth muscle cells
    • Mediates vasoconstriction
  • ETB
    • Has equal affinity for ET-1 and ET-3
    • Is located primarily on vascular endothelial cells
    • Mediates the release of prostacyclin and NO
  • The signal transduction mechanisms triggered by binding of ET-1 to ETA receptors lead to...
    • An increase in intracellular calcium concentration by several mechanisms
  • Because the ET-1 is such a potent vasoconstrictor, there has been considerable interest in developing inhibitors of the ET receptor for disorders including...
    • Systemic hypertension, PAH, heart failure and renal disease

16

Endothelin antagonists:
Bostentan (Tracleer):
Chemistry, absorption, distribution, metabolism, and elimination

  • Chemistry
  • Absorption and distribution
    • Bioavailability
    • Volume of distribution
    • Bound to...
  • Metabolism
    • Maximum plasma concentrations
    • Metabolites
    • Inducer of...
    • Plasma concentrations
    • Steady-state
  • Elimination

  • Chemistry
    • First clinically approved endothelin antagonist
  • Absorption and distribution
    • The absolute bioavailability of bosentan is about 50% and is unaffected by food
    • The volume of distribution is about 18 L/ 70 kg
    • Highly bound (>98%) to plasma proteins, mainly albumin
  • Metabolism
    • After oral administration, maximum plasma concentrations are attained within 3-5 hours and the terminal elimination half-life (T½) is about 5 hours
    • 3 metabolites, 1 of which is pharmacologically active and may contribute 10-20% of the effect of bosentan
    • 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
  • Elimination
    • Eliminated by biliary excretion following metabolism in the liver
    • Less than 3% of an administered oral dose is recovered in urine

17

Endothelin antagonists:
Bostentan (Tracleer):
Toxicity and mechanism of action

  • Toxicity
    • Major clinical adverse effect
    • More common in patients taking glyburide
    • Coadministration of cyclosporine A and bosentan
    • Dose-dependence
    • Therapy has been associated with...
    • In animals and pregnancy
    • Induction of CYP3A4 and P2C9
  • Mechanism of action

  • 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
    • 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
    • A specific and competitive antagonist at endothelin receptor types ETA and ETB
    • Slightly higher affinity for ETA receptors than for ETB receptors

18

Endothelin antagonists:
Ambrisentan (Letairis):
Chemistry, toxicity, and mechanism of action

  • Chemistry
    • Molecular formula
    • Molecular weight
  • Toxicity
  • Mechanism of action

  • Chemistry
    • Molecular formula of C22H22N2O4
    • Molecular weight of 378.42
  • Toxicity
    • Treatment with endothelin receptor antagonists has been associated with dose-dependent liver injury
      • Thus, liver function needs to be monitored and liver chemistries measured prior to initiation of ambrisentan
    • Hepatic toxicity is not a major adverse effect
  • Mechanism of action
    • High affinity ETA receptor antagonist 
    • High selectivity for the ETA versus ETB receptor

19

Endothelin antagonists:
Ambrisentan (Letairis):
Absorption, distribution, metabolism, and elimination

  • Absorption and distribution
    • Rate
    • Bioavailability
    • Half-life
  • Metabolism
  • Elimination
    • Mainly by...
    • Potential drug-drug interactions

  • Absorption and distribution
    • Rapidly absorbed with peak concentrations of 2 hours
    • Bioavailability is unaffected by food
    • Half-life is ~9 hours
  • Metabolism
    • Metabolized by CYP3A4, CYP2C19 and uridine 5”-diphosphate glucuronosyltransferase (UGTs) 1A9S, 2B7S and 1A3S
  • Elimination
    • Mainly by non-renal pathways
    • Potential drug-drug interactions
      • Interactions with cyclosporine A (an inhibitor of CYP3A4)
      • Ketoconazole (an inhibitor of CYP3A)
      • Omeprazole (an inhibitor of CYP2C19)

20

Endothelin antagonists:
Sitaxsentan (Thelin)

  • Potent...
  • More selective for...
  • Improves...
  • Side effects
  • Induces...
  • Approval

  • Potent endothelin-receptor antagonist
    • Oral bioavailability
    • A long duration of action
  • More selective as an antagonist for ETA compared with ETB receptors
    • Should provide better pulmonary vasodilation relative to bosentan
  • Improves exercise tolerance and cardiac output
  • Side effects
    • Similar to bosentan
    • Include hepatotoxicity, headache, nausea, peripheral edema and nasal congestion
  • Induces CYP2C9 with attendant changes in metabolism of multiple drugs, including warfarin and oral contraceptives
  • Not FDA approved in the US

21

Phosphodiesterase inhibitors

  • NO promotes vasodilation by...
  • The effects of cGMP 
  • The predominant PDE in the pulmonary vasculature
  • Inhibitors of cGMP specific phosphodiesterase...
  • In addition, PDE 5 gene expression and activity are increased in...

  • NO promotes vasodilation by...
    • Increased levels of cGMP in vascular smooth muscle
  • The effects of cGMP
    • Brief, because of rapid degradation of cGMP by phosphodiesterases (PDE)
  • The predominant PDE in the pulmonary vasculature
    • The cGMPspecific PDE 5
  • Inhibitors of cGMP specific phosphodiesterase...
    • Augment pulmonary vasodilation in response to NO
  • In addition, PDE 5 gene expression and activity are increased in...
    • PAH, providing rationale for the use of inhibitors in this condition

22

Phosphodiesterase inhibitors:
Sildenafil:
Chemistry, absorption, distribution, metabolism, elimination

  • Chemistry
    • Trade name
    • Administration
    • Attenuates...
    • In patients with PAH and pulmonary hypertension resulting from chronic pulmonary thromboembolism...
  • Absorption and distribution
    • Bioavailability
    • Half-life
    • Distribution
    • Peak biological activity
  • Metabolism
  • Elimination

  • Chemistry
    • Trade name: Viagra
    • Orally administered cGMP PDE 5 inhibitor approved for use in treatment of erectile dysfunction
    • Attenuates the increase in pulmonary arterial pressure associated with hypoxia with no effect on systemic blood pressure
    • In patients with PAH and pulmonary hypertension resulting from chronic pulmonary thromboembolism, treatment has been associated with improvements in exercise tolerance and pulmonary arterial pressure
  • Absorption and distribution
    • Orally active with a bioavailability of ~40%
    • Half-life of 2.4 hours
    • 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)
    • Need to be concerned with drug-drug interactions such as with cimetidine, erythromycin, etc
  • Elimination
    • 80% appears in the feces
    • 13% in the urine

23

Phosphodiesterase inhibitors:
Sildenafil:
Toxicity and mechanism of action

  • Toxicity
    • Minor side effects 
    • Serious cardiovascular events
  • Mechanism of action
    • PDE5
    • PDE3
    • PDE6
    • Active metabolite

  • Toxicity
    • Minor side effects
      • Headache, nasal congestion, and visual disturbance
    • Serious cardiovascular events
      • Myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, and hypertension
  • Mechanism of action
    • Selective inhibitor of PDE5
      • Potency is PDE1 (> 80- fold); PDE2 and PDE4 (> 1000 times); PDE3 (about 4000 times), and PDE6 (about 10 times)
      • By diminishing the effect of PDE5, sildenafil facilitates the effect of NO, increases cGMP levels and relaxes smooth muscle relaxes
    • PDE3 controls cardiac contractility
    • 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

24

Phosphodiesterase inhibitors:
Tadalafil:
Chemistry, absorption, distribution, metabolism, and elimination

  • Chemistry
  • Absorption and distribution
    • Activity
    • Half-life
    • Distribution
    • Biological activity
  • Metabolism
  • Elimination

  • Chemistry
    • Orally administered cGMP PDE 5 inhibitor 
    • Approved for use in treatment of erectile dysfunctionand PAH
  • Absorption and distribution
    • Orally active
    • Half-life of 17.5 hours
    • Widely distributed with a volume of distribution of ~0.9 L/kg
    • Peak biological activity occurs at ~ 2 hour
  • Metabolism
    • Hepatic metabolism is via CYP3A4
    • Need to be concerned with drug-drug interactions such as with cimetidine, erythromycin, etc.
  • Elimination
    • Of the administered dose, 61% appears in the feces; 36% in the urine

25

Phosphodiesterase inhibitors:
Tadalafil:
Toxicity and mechanism of action

  • Toxicity
    • Similar to...
    • Minor
    • Serious
  • Mechanism of action

  • Toxicity
    • Side effects are similar to sildenafil and cialis
    • They are minor and include headache, nasal congestion and flushing
    • Serious cardiovascular events may occur if associated to organic nitrates and alpha adrenergic receptor antagonists
  • Mechanism of Action
    • A selective inhibitor of PDE5
    • Can also inhibit PDE11, a widely distributed PDE isoform
    • By diminishing the effect of PDE5, tadalafil facilitates the effect of NO, increases cGMP levels and relaxes smooth muscle

26

Calcium channel antagonists

  • Mechanism of action
  • Properties that could worsen underlying PAH
  • Effectiveness of calcium channel blockers 
  • Hemodynamic improvements in response to calcium channel antagonists 
  • Use of these agents without initial monitoring of pulmonary pressures and vasoreactivity

  • Mechanism of action
    • Block the influx of Ca2+ into the vascular smooth muscle cell through voltage-operated calcium channels
    • Reduces the intracellular free Ca2+ concentration
    • Promotes vasodilation
  • Properties that could worsen underlying PAH
    • Negative inotropic effects on right ventricular function
  • Effectiveness of calcium channel blockers
    • Widely used
    • 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
    • May not indicate a beneficial effect of the drugs
  • Use of these agents without initial monitoring of pulmonary pressures and vasoreactivity
    • Potentially dangerous

27

The future?

  • Since prostacyclin, 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
  • Clinical studies to examine the combined effects of two or more agents are currently

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