Vasodilators Flashcards
Classification
Arteriolar dilators
Venodilators
Arteriolar dilators: def and effects
relax SM cells of systemic arterioles
↓ peripheral vascular resistance/impedance
↓ systemic BP, systolic intraventricular P and myocardial wall stress
* ↓ force opposing contraction of myocardial fibers
* ↑ contractility → ↑SV
Arteriolar dilators: drugs
- Amlodipine
- Hydralazine
Venodilators: def and effects
relax SM cells in systemic veins
↑ capacitance of systemic venous reservoir
Blood redistribution from /PVs → veins
* ↓ ventricular diastolic and PVP
* ↓ edema formation
Effect depend on
o Vascular bed it influences: systemic, pulmonary
o Relative potency
Direct acting vasodilators: drugs
Hydralazine
endralazine, cadralazine, minoxidil, dipyridamole, pinacidil
Types of vasodilators
Nitrates
Direct acting
Ca2+ channel blockers
Adrenergic R blockers
ACEi
Ang II R blockers
PDEi
ET1 antagonists
K+ channels opener
PGI analog
O2
Hydralazine: MOA
- Multifactorial mechanism
o SMcell hyperpolarization → opening of K+ channels
o Inhibit IP3 induced released of Ca2+ from SR
o Stimulates NO formation by vascular endothelium → cGMP mediated vasodilation
o ↑ [prostacyclin] in systemic arterioles
↓ resistance in renal, coronary, cerebral, mesenteric vascular bed > skeletal - ↑ renal blood flow: ↑ digoxin excretion + ↑ furosemide delivery
Hydralazine: effect
- Arteriolar vasodilator
o ↓ regurgitant flow
o ↑ forward Ao flow
o ↑ venous O2 tension
Hydralazine: PharmacoK
- Metabolism
o Hepatic metabolism: 1st pass
o Not excreted by kidneys, but biotransformation affected by renal failure (↑[]) - Pharmacokinetics
o PO: effect in 1h, peak 3h, duration 8-10h
o Hemodynamic effects are dose dependent
Hydralazine: side effects
o Hypotension
o Reflex tachycardia → baroR reflex
Nitrates: drugs
o Nitroglycerin/isisorbide dinitrate: venous and coronary dilator, weak arteriolar
o Nitroprusside: balanced vasodilator
o Nesiritide: balanced vasodilator
Act on guanylate cyclase (similar to NO)
Hu recombinant of B-type natriuretic peptide
Nitrates: MOA
- Organic nitrate → exogenous source of NO
o Short lived free radical
o Action: Nitrate enter vessel → mononitrates converted → NO2 by mitochondrial aldehyde dehydrogenase-2 (mito ALDH) → addition of -SH group → p450 reductase creates NO → stimulate guanylate cyclase → ↑cGMP formation → SM cell relaxation
S-nitrolysation of intracell prots → post translational modifications → alter physiologic properties
Generation of peroxynitrite (ONOO-) → from NO + superoxide O 2- - Inhibit conversion of GTP → GMP
- Can lead to toxicity
- ↑ by AngII
Nitrates: effects
↓afterload: ↓ SVR
↓ preload: ↑ venous capacitance → pooling of blood
* ↓ mechanical stress on ventricular walls
* ↓ O2 consumption
Vasodilate intact + damaged endothelium
* Some vascular agents will require intact endothelium
Modulator of myocardial relaxation (cGMP)
* Improve diastolic fct by ↑ troponin I phosphorylation of titin
Inhibit/reverse platelet aggregation
Nitrate tolerance MOA
Prolonged nitrate tx
* Formation of peroxynitrite → inhibit endothelial nitric oxide synthase (NOS)
* Endothelial dysfct from free radicals
CCB: action
Ca2+ channel blocker
o Inhibit L-type, voltage sensitive Ca2+ channels
Negative inotrope
Nodal inhibition
↓PVR and SVR
Role of Ca2+ in SM cells
regulate contractile mechasnism independently of Troponin C
Ca2+ - calmomodulin → myosin light chain kinase (MLCK) stimulation → Pi of myosin light chain → actin-myosin interaction → contraction
cAMP inhibits MLCK
Types of CCB
Dihydropyridines
Non-dihydropyridines
Dihydropyridines: drugs
- Short acting: nifedipine
o Induce rapid vasodilation
o But rapid reflex adrenergic activation → tachycardia + vasoconstriction
↑ myocardial O2 consumption - Long acting: amlodipine, extended release nifedipine, felodipine, isradipine
o Fewer side effects
o Amlodipine
Arteriolar vasodilator
PO: peak effect 4-7days, 30h ½ life
Non-dihydropyridines: drugs
Diltiazem and verapamil
Adrenergic R blockers types
Alpha-R blockers
Beta-R blockers
Alpha-R blockers: drugs
Prazosin
phenoxybenzamine, phentolamine
Prazosin MOA
o α1-R blocker (no α2 blockade)
o PDE inhibition peripherally
Prazosin effect
- Arteriolar and venous (++) dilator
- No reflex tachycardia
B R blockers types
B1, B2, B3
B1 R blockers: action
- Heart muscle
- Action: G protein coupled R
o Adenylate cyclase → cAMP → prot kin A activation → Pi of Ca2+ protein → open Ca2+ channels
↑ myosin ATPase activity → ↑ rate of myocardial contraction
↑ activation of troponin C → ↑ contractility
Pi of phospholamban → ↑ rate of Ca2+ reuptake → ↑ relaxation rate
↑ SA node pacemaker
↑ conduction speed
o Vagal activation → activate prot G inhibitory system
B2 R blockers: action and effect
- Bronchial and vascular SM
o 20-25% of cardiac B-R
o Upregulation in HF - Lead to hypotension and vasodilation
B3 R blockers: action and effect
- Endothelial
- Vasodilation induced by NO
Features of B-R blockade
- Turnoff mechanism after B-R stimulation
o B-R kinase activation (BARK or GRK-2) → Pi of R →B-arrestin recruitment →desensitization of stimulated R = uncoupling from G sprot → internalization
o If sustained → lysosomal destruction of internalized R
Downregulation of R density
Exacerbated in CHF: catecholamine + iatrogenic stimulation (dobutamine) - Tachyphylaxis: progressive loss/↓ of therapeutic efficacy
Clinical use of B blcokade
o No longer recommended for use to treat systemic hypertension
o ↓ renin levels → not logical to combine to ACEi or ARB
ACEi drugs
Benazepril, Enalapril, Lisinopril
ACEi action
inhibition of Angiotensin Converting Enzyme (ACE)
o Bind its zinc ion-containing active site
o Angiotensin II: potent vasoconstrictor → ↓[AngII]
Allow systemic arteriolar and venous relaxation
↓Na+ and H2O reabsorption (↓AngII mediated aldosterone release)
o Local renin-angiotensin system in many tissues
Kidney, brain, blood vessels, myocardium, cardiac valves
o ↓bradykinin metabolism
↑ prostacyclin and PGE2 → vasodilation
ACEi in dogs
- Drugs studied in dogs
o Prodrugs: enalapril, benazepril, quinapril, ramipril
o Active drugs: captopril, lisinopril
Ang II R blockers drugs
Losartan, telmisartan, valsartan, irbesartan
Ang II R blockers: action and effects
- Block binding of AngII to AT-1 R
- Similar effect to ACEi
o No bradykinin effect
PDEi types
PDEi5
PDEi3
PDEi5 drugs
Sildenafil, tadalafil
PDEi5 MOA and effect
- Block action of PDE5 enzyme → ↑cGMP in SM
- PDE5 specific to pulmonary vessels
PDEi3 MOA and effect
- Block action of PDE3 enzyme → ↑cAMP in SM of systemic arterioles
o Systemic vasodilation
o ↓ afterload
ET1 R antagonist drugs
Bosentan (non selective), ambrisentan (selective ET-A)
ET1 effects
- Endothelin-1: produced by vascular endothelium
o Potent vasoconstrictor
heart: ↑HR and contractility
o Bind ET-A and ET-B receptors on SMcells
Coupled to G protein
ET-A activation → formation of IP3 → Ca2+ release by SR → vasoconstriction
ET-B activation → stimulat NO formation → vasodilation
o ET-1 induce transient relaxation (ET-B), then prolonged vasoconstriction (ET-A)
ET-1 R antagonists effects
o Vasodilation
o Cardiac inhibition
K+ channel opener drugs
Minoxidil
K+ channels opener: MOA
- Activate ATP sensitive K+ channels in vascular SM
o Hyperpolarization → close voltage gated Ca2+ channels → ↓intra [Ca2+]
o ↓ Ca2+ available to combine w calmomoduline → ↓ MLCK activation → ↓ MLC Pi
o Vasodilation
K+ channels opener: effects
- Effective on small arteries and arterioles
K+ channels opener: side effects
o Reflex bradycardia
o Fluid retention/edema
PGI analog drugs
Epoprostenol, treprostinil, iloprost
PGI analog action
- Synthetized from arachidonic acid
- Action
o Antiplatelet/aggregation effects
o Vasodilation
o Antiproliferative effects → ↑ cAMP
O2 effect
- Potent vasodilator
