DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Naloxone. Naloxone is a competitive opioid antagonist that is indicated
only if ventilatory depression is due to overdose of opioids.
Flumazenil. Flumazenil is a benzodiazepine receptor antagonist that
can reverse respiratory depression due to overdose of benzodiazepines
(Gross et al., 1996).
PHARMACOTHERAPY OF PULMONARY
ARTERIAL HYPERTENSION
Pulmonary arterial hypertension (PAH) is characterized
by vascular proliferation and remodeling of small
pulmonary arteries, resulting in a progressive increase in
pulmonary vascular resistance, which may lead to right
heart failure and death (Morrell et al., 2009). PAH involves
dysfunction of pulmonary vascular endothelial and smooth
muscle cells and their interplay and results from an imbalance
in vasoconstrictor and vasodilator mediators.
Vasodilators are the mainstay of drug therapy for
PAH (Barnes and Liu, 1995). However, the vasodilators
used to treat systemic hypertension are problematic:
they lower systemic blood pressure, which may result
in reduced pulmonary perfusion. Calcium channel
blockers, such as nifedipine, are poorly effective, but a
few patients may benefit. There have been important
advances in the development of more selective pulmonary
vasodilators, based on a better understanding of
the pathophysiology of PAH (McLaughlin et al., 2009).
In PAH, there is an increase in the vasoconstrictor mediators
endothelin-1, thromboxane A 2
, and serotonin, and
a decrease in the vasodilating mediators prostacyclin
(PGI 2
), NO, and VIP (Figure 36–13) (Humbert et al.,
2004). Therapies aim at antagonizing the vasoconstrictive
mediators and enhancing vasodilation. Because different
classes of vasodilators work through different
mechanisms, it may be possible to increase efficacy
while reducing adverse effects by using combinations
of agents from different classes in therapy of PAH.
Primary (idiopathic and familial) pulmonary hypertension
(PPAH), where there is no identifiable cause, is uncommon. Most cases
of pulmonary hypertension are associated with connective tissue disorders,
such as systemic sclerosis, or they are secondary to hypoxic lung
diseases, such as interstitial lung disease and COPD, where chronic
hypoxia leads to hypoxic pulmonary vasoconstriction. Secondary pulmonary
hypertension in COPD rarely requires specific therapy. In secondary
pulmonary hypertension due to chronic hypoxia, the initial
treatment is correction of hypoxia using supplementary O 2
therapy,
including ambulatory oxygen, with the aim of increasing O 2
saturation
to >90%. Right heart failure is treated initially with diuretics.
Anticoagulants are indicated for the treatment of pulmonary hypertension
secondary to chronic thromboembolic disease, but they may also
be indicated for patients with severe pulmonary hypertension who have
an increased risk of venous thrombosis.
Prostacyclin. Prostacyclin (PGI 2
; Epoprostenol) is produced by
endothelial cells in the pulmonary circulation and directly relaxes
pulmonary vascular smooth muscle cells by increasing intracellular
cyclic AMP concentrations (see Chapter 33). Reduced
prostacyclin production in PAH has led to the therapeutic use of
epoprostenol and other stable prostacyclin derivatives (Gomberg-
Maitland and Olschewski, 2008). Functionally and physiologically,
PGI 2
opposes the effects of TXA 2
.
Intravenous epoprostenol (FLOLAN, others) is effective in lowering
pulmonary arterial pressures, improving exercise performance,
and prolonging survival in PPAH. Because of its short plasma t 1/2
,
prostacyclin must be administered by continuous intravenous infusion
using an infusion pump. Common side effects are headache, flushing,
diarrhea, nausea, and jaw pain. Continuous intravenous infusion is
inconvenient and very expensive. This has led to the development of
more stable prostacyclin analogs. Treprostinil (REMODULIN) is given by
continuous subcutaneous infusion or as an inhalation (TYVASO), consisting
of four daily treatment sessions with nine breaths per session.
Oral beraprost sodium appears to be somewhat less effective and its
effect seems to diminish after 3 months of therapy, so it has not been
approved in most countries. Iloprost (VENTAVIS) is a stable analog that
is given by inhalation, but it needs to be given by nebulizer six to nine
times daily. It is associated with the vasodilator side effects of prostacyclin,
including syncope. It may also cause cough and bronchoconstriction
because it sensitizes airway sensory nerves.
Endothelin Receptor Antagonists
Endothelin-1 (ET-1) is a potent pulmonary vasoconstrictor that is
produced in increased amounts in PAH. ET-1 contracts vascular
smooth muscle cells and causes proliferation mainly via ET A
receptors.
ET B
receptors mediate the release of prostacyclin and NO from
endothelial cells. Several endothelin antagonists are now on the market
for the treatment of PPAH (see Chapter 26).
Bosentan (TRACLEER) was the first ET antagonist developed
and is a antagonist of both ET A
and ET B
receptors. Several longterm
clinical trials have now established the efficacy of oral bosentan
in reducing symptoms and improving mortality in PPAH.
Starting dose is 62.5 mg twice daily for 4 weeks, then increasing to
the maintenance dose of 125 mg twice daily. The drug is generally
well tolerated. Adverse effects include abnormal liver function tests,
anemia, headaches, peripheral edema, and nasal congestion. Given
the risk of serious liver injury, liver aminotransferases should be
monitored monthly. A class effect is a risk of testicular atrophy and
infertility; bosentan is potentially teratogenic.
Ambrisentan (LETAIRIS) is selective ET A
receptor antagonist.
It is given orally once daily at a dose of 5-10 mg. The theoretical
advantage of blocking only ET A
receptors is that ET B
receptors may
continue to stimulate release of PGI 2
and NO, giving a greater therapeutic
effect. However, its clinical efficacy is similar to that of
bosentan, as are its adverse effects. Use of ambrisentan also requires
monthly monitoring of liver aminotransferases. Sitaxsentan (not
available in the U.S.) is similar to ambrisentan but may be less likely
to cause liver dysfunction.
Phosphodiesterase 5 Inhibitors
Nitric oxide activates soluble guanylate cyclase to increase cyclic
GMP, which is hydrolyzed to 5GMP by PDE5 (Chapter 27).
Elevation of cGMP in smooth muscle causes relaxation (Chapter 3),
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CHAPTER 36
PULMONARY PHARMACOLOGY