Vasodilators Flashcards
Vasodilator classes
-Cyclic GMP modulators
-K channel agonists
-endothelin receptor antagonists
-PGI2 analogs- IP receptor agonists
Why does inc K channel opening relax vasc smooth muscle?
-K flux set membrane potential
-the longer K channels are open, the closer the membrane potential is to the K equilibrium potential
-the closer the membrane potential is to the K equilibrium potential, the harder it is to depolarize membrane enough to open gated Ca channels
K channel agonists/openers
-minoxidil
-diazoxide
-adenosine?
-regulate membrane potential
-reduce Ca channel activity
Minoxidil
-activated in vivo by sulfotransferase 1A1
-K opener
-use w loop diurtics and beta blockers
-potent
-effective in severe, drug resistant HTN
-cAMP PDE inhibition may be efficacy
-give orally or topically for hair growth
-hypertrichosis
Diazoxide
-K-opener
-used IV to tx acute HTN
-very potent (resistnant HTN)
-inhibits release of insulin form pancreatic B cells
-used orally for hypoglycemia 2’ to hyperinsulinemia
Adenosine
-binds A1 (GPCR)
-inc conductance of a K channel (hyperpolarization and relaxation)
-give IV coronary stress test
-also for supraventricular arrhythmias
Hyperpolarization of vasc smooth muscle by adenosine
-A1 receptor
-G-protein activated inwardly rectifyin K channel
-Gby binds and activates GIRK-conducts K efflux and membrane hyperpolarization
Drugs that stimulate nitric oxide production
Nitric Oxide Synthase
-NOS in vascular endothelium
-NO diffuses to vasc smooth muscle
-nNOS
-iNOS
-eNOS in vasc endothelium activated by Ca-CAM
-exogenous NO can relax smooth muscle
Nitric oxide-cyclic GMP pathway
-eNOS found in endothelial cells of vasculature
-NO referred to as EDRF
-guanylate cyclase found in vasc smooth muscle
-exogenously applies NO can directly relax smooth muscle
Acetylcholine relaxes smooth muscle via NO
Nitric oxide binds to
-heme in iron prosthetic group in guanylate cyclase
=stimulate production of cGMP and activating cGKI (protein kinase G)
-
how does protein kinase G relax smooth muscle?
-inhibition of L-type Ca channels (Cav1.2)
-stimulation of Ca activated K channels (BKca)
-dec MLC phosphorylation (myosin phosphatase 1)
-enhanced Ca uptake in to ER (phospholamban
Organic nitrates
-non-selective vasodilators
-breakdown to nitric oxide (bioactivation)
-dont require functional endothelium
-acute or chronic admin
Organic nitrate drugs
-amylnitrite
-glyceryl trinitrate (GTN)
-pentaerythritol tetranitrate (PETN)
-isosorbide dinitrate
-isosorbide mononitrate
-nitroprusside
PK of organic nitrates
-GTN 3min <1% bioavailability
-ISDN 10 min 20%
-5-ISMN 280 min 100%
-give sublingually in tx of acute attacks of angina
-tolerance occurs w continuous administration
Tolerance to glyceryl trinitrate
-munitions workers
-monday headaches
-slide 21 mech
genetics of glycerol trinitrate
-glu504 polymorphism
-glu504 metabolize glycerol trinitrate
-lack of efficacy in large % of Asian population
-the lys 504 allele also accounts for alcohol intolerance as acetaldehyde metabolism also reduced
Differences in activation of GTN and ISMN/ISDN
mech of cell damage initiated by hyperglycemia
-AGE precursor methylglyoxal inhibits vasorelaxation stimulated by acetylcholine/nitric oxide
Sodium nitroprusside (SNP)
-give IV for acute managemnet of HTN crisis and severe heart failure
-dilates veins and arterioles
-metabolized in erythrocytes to NO, 4CN, and cyanmethemoglobin (limits duration)
-CN can inhibit oxidative metabolism = lactic acid accumulation
-CN converted to less toxic SCN- by rhodanase, excreted via kidney
-may be used for detox
Hydrazaline
-nitrate
-dilates arterioles preferentially
-can induce lupus-like syndrome
-give orally or IV
-combined w B-blocker, diuretic
hydralazine combo w ISDN in BiDil
-antioxidant activity potentiates vasodilatory activity of ISDN
-BiDil decreases mortality in black people w CHF
Human type B Natriuretic peptide (BNP)
-cleaved by Neprilysin
-synthesized and secreted from heart muscle in response to inc blood volume
-binds to and activates membrane-bound gunaylate cyclase in vasc smooth muscle and endothelial cells
BNP mech
Sacubritril
-combo w ARB valsartan (entresto) ARNI
-oral BID
-prodrug activated by esterases
-prevents breakdown of BNP enhancing its action
-NOT USED W ACEi
-use to tx heart failure
-inhibitor of neprilysin (protease)
Drugs that inhibit breakdown of cGMP/AMP: phosphodiesterase inhibitors
-amrinone (PDE3 cAMP)
-milrinone (PDE3 cAMP)
-dipyridamole (PDE5 cGMP)
-sildenafil (PDE5 cGMP)
mech for controlling smooth muscle tone
-Ca channel pathway
-GPCR pathway:
-inc cAMP PDE3 makes cAMP to AMP
Amrinone and milrinone
-give IV
-inotropic
-vasodilatory effect on smooth muscle
-used maily in CHF
sildenafil (PDE5 inhibitors)(viagra)
-inhibit cGMP
-10 fold selectivity over PDE6 inhibition (retina)
-bluish vision
-lack of systemic vasodilation
-corpus cavernosum
levitra (vardenafil)
-shorter time to onset than viagra
-more selective for PDE5 than viagra
tadalafil (cialis)
-more selective than viagra
-longer duration of action
PDE5 inhibitor contraindication
-DO NOT USE w organic nitrates
-precipitous drop in blood pressure
=both drugs inc cGMP accumulation
-cGMP also inhibits PDE3
=inc cAMP levels
-both stimulate vasodilation
Vasodilators used in Pulmonary arterial HTN (PAH)
-endothelin antagonists
-PGI2 analogs
-guanylyl cyclase activators
-PDE5 inhibitors
-activin neutralizers
endothelin signaling
-increased in PAH
vasoconstrictor (endothelin) ANTAgonists
-Bosentan (Tracleer)
-Macitentan (Opsumit)
Ambrisentan (Letairis)
Bosentan (traccleer) and Macitentan (opsumit)
-specific low MW
-endothelin receptor antagonists
-block both ETA (VSM and ETB (VSM + endothel receptor)
Ambrisentan (letairis)
-blocks only ETA receptors
-approved for PAH
Vasoconstrictor ANTAgonist contraindications (-sentan)
-contraindicated in pregnancy
-hepatotoxicity (bosentan)
-only available to females thru special programs
Prostacyclin analogs
-PGI2 (epoprostenol; 3-5min t1/2) IV
-Treprostinil (Remodulin 4h) PO or IV
-Iloprost (Ventavis 30 min) inhalation
-selexipag (uptravi 6-13h) PO or IV
-tx PAH
Allosteric activator of sGC
-Riociguat (adempas)
-for PAH
-potentiates the effect of NO
-stimulates sGC activity allosterically
-inc cGMP concentration in VSM
Riociguat
-allosteric activator of sGC
-not combo w nitrates of PDE5s
-dont use if pregnant
-risk of hemorrhage
-substrate for P-gp, CYP1A1,3A
-only available to females thru special programs
PDE5 inhibitors for PAH
-sildenafil and tadalafil are both indicated for PAH
-both thought to enhance effect of NO
Sotatercept-CSRK (winrevair)
-activin type IIA-Fc
-binds/neutralizes activin and other TGF ligands
-for PAH
-reduces proliferation of vas smooth muscle cells
-reduces pulmonary vasc resistance
-inj SQ q3weeks
Sotatercept-CSRK (winrevair) potential toxicities
-erythrocytosis
-thrombocytopenia
-bleeding
-terrtogen
-impaired fertility
-HA, rash, nosebleed, telangiectasia
PAH
