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Tx para la hipertensión arterial pulmonar - Coggle Diagram
Tx para la hipertensión arterial pulmonar
NO and Simulators of cGMP and PKG signaling
NO
Is biosynthesized from the terminal N L-argenine by the enzyme nitric oxidase synthase. Endogenous NO levels are reduced in px with PAH
IS A SELECTIVE PULMONARY VASODILATOR
ADME
Soluble gas.
INHALED
Must be compressed and stored with an inert gas such as N2 to minimize the exposure to O2
Increases the PaO2 by vsadilating better ventilated lung regions from poorly inflated lung areas
Half life (2-6 s), is primarily a result of the rapid inactivation of NO by hemoglobin binding and oxidation to nitrite
the nitrite + oxyhemoglobin
Formation of nitrate and met-hemoglobin
Nitrite identified as the predominant NO metabolite excreted in the urine
Clinical Use
Can acutely lower PAP and PVR without altering systemic arterial pressure
USED FOR:
Tx of term and near-term neonates + persistent pulmonary hypertension and acute hypoxemic resp failure
Existe una disminución de la pulmonary vascular resistance de un 30% during the inhalation of NO
Adverse Effects and Precautions
High doses of inhaled NO are lethal
Methemoglobinemia
noisy breathing, hematuria, atelectasis
Riociguat
A direct activator of soluble guanylate cyclase
is the first in line class stimulator of sGC. It sensitizes sGC to endogenous NO.
Clinical Use
It significantly delayed time to clinical worsening for patients with PAH
patients with chronic thromboembolic pulmonary hypertension
Adverse Reactions and Precautions
Riociguat + nitroglycerin
hypotension + syncope
Riociguat + PDE5 inhibitors
hypotension + syncope
embryo fetal toxicyty, hypotension, bleeding
Serious adverse effects
headche, dyspepsia, dizziness, nausea, diarrhea, vomiting, anemia, reflux, constipation, palpitations, nasal congestion, epistaxis, dysphagia, adbominal distension y peripherial edema
PDE5 Inhibitors
PDE5 Inhibitors
is an isoform that is relatively specif for cGMP, is abundant in pulmonary artery smooth muscle cell
Sildenafil
Mechanism of action
mimics the purine ring of cGMP and selective inhibitor of PDE5
By inhibiting cGMP hydrolysis, elevates cellular levels of cGMP and augments signaling through the cGMP-PKG pathway
provided guanylyl cyclase is active
ADME
is rapidly absorbed and reaches a peak plasma concetration 1 hr after VO
Cleared by the hepatic CYP3A and CYP2C9
is major active metabolite: N-desmethyl sildenafil
half lives of about 4 h
Bound to plasma prot and excreted into feces and into the urine
Clinical Use and Adverse Effects and Precautions
5-20 mg x 3 times per day improves excersice capcity, functional class, and hemodynamics
Sildenafil + Epoprostenol
resulted in delayed time to clinical worsening of PAH
Bosentan
decreases in plasma levels of sidenafil
Protease inhibitors used in HIV therapy; erythormycin; cimetidine;
inhibit sildenafil metabolism, thereby prolonging the t1/2 and elevating blood levels of sildenafil
potentiate the hypotensive effects of nitrate vasodilators, producing dangerously low blood pressure
THE USE WITH NITRATE IS CONTRAINDICATED
Headache, flushing, transient blue-green tinting of vision due to inhibition of retinal PDE6
Prostacyclin Receptor Agonists
synthesized in and released from vascular endothelial cellas and exerts relazant and antiproliferative effects on vascular smooth muscle cells.
PGI2 is considered an endotheliaum derieved relaxing factor.
its mechanism of action: prastacyclin binds to the IPR in the plasma membrane of pulmonary artery smooth muscle cell and activates the Gs- AC- cAMP- PKA pathway
DECREASING CA+2 via activating K channels , causing hyperpolarization and repolarization leading to closure of volatage dependent Ca+2 channel
causing smootn muscle relaxation and vasodilation
it also esert an antiproliferative eddect in PASMCs by inhibiting the hedgehog, ERK/p21 and Akt/mTOR
Epoprostenol (Prostacyclin)
FIRST SYNTHETIC PGI2, has dose-dependent inhibitory effects on systemic vascular resistance and pulmonary vascular resistance, with increase in cardiac ourput for px with PAH
Short life (3-5 min), use of pump system for IV
reamains a mainstay of pAH tratment, particularly in advanced stages of the disease
Adverse effects
myalgias, pain in extremities, jaw pain, nausea, headaches, abdominal discomfort, diarrhea, flusing, dizziness and hypotension
Trepostinil
IV, SC, inhalation, VO
The inhalated formulation has more potent vasodilating effects
Monotherapy with extended-release oral formulations of treprostinil are effective in px with PAH with moderate functional impairments
Iloprost
The first PGI2 analogue available in an inhaled formulation
Designed to target the pulmonary vasculature with minimal systemic sude effects
Selexipag
Orally active, selective IPR agonist
Hydrolyzed in the liver to an active metabolite ACT-33679
Ion channel blockers and openers
Nifedipine, Amlodipine y Dilitiazem
Used only in PAH px with positive vasodilator testing
Dilitiazem: significant chronotropic and inotropic effects; avoid in bradycardia
ENDOTHELIN AND ENDOTHELIN RECEPTOR ANTAGONISTS
ERA
is apotent endothelium-derived, constrinting factor. The constrictor response is mediated by the ETa receptor located on PASMCs, this activates the Gq- PLC- IP3- Ca2+ and DAG-Ca+2- PKC pathways
release on intracellular Ca+2 and produces vasoconstriction
Side effects: heache, pulmonary edema, nasal congestion, pharyngitis, testicular atrophy and infertility
Bosentan and Ambrisentan may increase liver transaminases, CONTRAINDICATED in px with liver disease
Metabolized by CYP3A4 and CYPs2C9 and 2c19
ARE TERATOGENS and should be used with caution in women of childbearing age. NOT BE USED IN PREGNANT WOMEN.
Bosentan
VO effective, competitive antagonist of ETa and ETb receptors. In px wit PAH (II-IV), improves symptoms, functional capacity and pulmonary hemodynamic parameters. Excretion in the bile.
Macitentan
VO active, competitive ETa and ETb receptor antagonist. Improves the time to disease progression or death in PAH and improves symptoms, funcitonal capcity and pulmonary hemodynamic measurements
Ambrisentan
Is a relatively selective ETa Antagonist
Receptor Tyrosine Kinase Inhibitors
Imatinib
treatment of chronic myelogenous leukemia by targetinh the ABL TKR. The compound targets PDGF receptor that has been linked to vascular hyperthropy in the development of PAH