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12. Pharmacology > Vasodilators > Flashcards

Vasodilators Flashcards

1
Q

Classification

A

Arteriolar dilators
Venodilators

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2
Q

Arteriolar dilators: def and effects

A

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

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3
Q

Arteriolar dilators: drugs

A
  • Amlodipine
  • Hydralazine
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4
Q

Venodilators: def and effects

A

relax SM cells in systemic veins
 ↑ capacitance of systemic venous reservoir
 Blood redistribution from /PVs → veins
* ↓ ventricular diastolic and PVP
* ↓ edema formation

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5
Q

Effect depend on

A

o Vascular bed it influences: systemic, pulmonary
o Relative potency

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6
Q

Direct acting vasodilators: drugs

A

Hydralazine
endralazine, cadralazine, minoxidil, dipyridamole, pinacidil

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7
Q

Types of vasodilators

A

Nitrates
Direct acting
Ca2+ channel blockers
Adrenergic R blockers
ACEi
Ang II R blockers
PDEi
ET1 antagonists
K+ channels opener
PGI analog
O2

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8
Q

Hydralazine: MOA

A
  • 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
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9
Q

Hydralazine: effect

A
  • Arteriolar vasodilator
    o ↓ regurgitant flow
    o ↑ forward Ao flow
    o ↑ venous O2 tension
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10
Q

Hydralazine: PharmacoK

A
  • 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
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11
Q

Hydralazine: side effects

A

o Hypotension
o Reflex tachycardia → baroR reflex

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12
Q

Nitrates: drugs

A

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

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13
Q

Nitrates: MOA

A
  • 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
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14
Q

Nitrates: effects

A

 ↓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

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15
Q

Nitrate tolerance MOA

A

 Prolonged nitrate tx
* Formation of peroxynitrite → inhibit endothelial nitric oxide synthase (NOS)
* Endothelial dysfct from free radicals

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16
Q

CCB: action

A

Ca2+ channel blocker
o Inhibit L-type, voltage sensitive Ca2+ channels
 Negative inotrope
 Nodal inhibition
 ↓PVR and SVR

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17
Q

Role of Ca2+ in SM cells

A

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

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18
Q

Types of CCB

A

Dihydropyridines
Non-dihydropyridines

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19
Q

Dihydropyridines: drugs

A
  • 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
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20
Q

Non-dihydropyridines: drugs

A

Diltiazem and verapamil

21
Q

Adrenergic R blockers types

A

Alpha-R blockers
Beta-R blockers

22
Q

Alpha-R blockers: drugs

A

Prazosin
phenoxybenzamine, phentolamine

23
Q

Prazosin MOA

A

o α1-R blocker (no α2 blockade)
o PDE inhibition peripherally

24
Q

Prazosin effect

A
  • Arteriolar and venous (++) dilator
  • No reflex tachycardia
25
Q

B R blockers types

A

B1, B2, B3

26
Q

B1 R blockers: action

A
  • 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
27
Q

B2 R blockers: action and effect

A
  • Bronchial and vascular SM
    o 20-25% of cardiac B-R
    o Upregulation in HF
  • Lead to hypotension and vasodilation
28
Q

B3 R blockers: action and effect

A
  • Endothelial
  • Vasodilation induced by NO
29
Q

Features of B-R blockade

A
  • 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
30
Q

Clinical use of B blcokade

A

o No longer recommended for use to treat systemic hypertension
o ↓ renin levels → not logical to combine to ACEi or ARB

31
Q

ACEi drugs

A

Benazepril, Enalapril, Lisinopril

32
Q

ACEi action

A

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

33
Q

ACEi in dogs

A
  • Drugs studied in dogs
    o Prodrugs: enalapril, benazepril, quinapril, ramipril
    o Active drugs: captopril, lisinopril
34
Q

Ang II R blockers drugs

A

Losartan, telmisartan, valsartan, irbesartan

35
Q

Ang II R blockers: action and effects

A
  • Block binding of AngII to AT-1 R
  • Similar effect to ACEi
    o No bradykinin effect
36
Q

PDEi types

A

PDEi5
PDEi3

37
Q

PDEi5 drugs

A

Sildenafil, tadalafil

38
Q

PDEi5 MOA and effect

A
  • Block action of PDE5 enzyme → ↑cGMP in SM
  • PDE5 specific to pulmonary vessels
39
Q

PDEi3 MOA and effect

A
  • Block action of PDE3 enzyme → ↑cAMP in SM of systemic arterioles
    o Systemic vasodilation
    o ↓ afterload
40
Q

ET1 R antagonist drugs

A

Bosentan (non selective), ambrisentan (selective ET-A)

41
Q

ET1 effects

A
  • 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)
42
Q

ET-1 R antagonists effects

A

o Vasodilation
o Cardiac inhibition

43
Q

K+ channel opener drugs

A

Minoxidil

44
Q

K+ channels opener: MOA

A
  • 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
45
Q

K+ channels opener: effects

A
  • Effective on small arteries and arterioles
46
Q

K+ channels opener: side effects

A

o Reflex bradycardia
o Fluid retention/edema

47
Q

PGI analog drugs

A

Epoprostenol, treprostinil, iloprost

48
Q

PGI analog action

A
  • Synthetized from arachidonic acid
  • Action
    o Antiplatelet/aggregation effects
    o Vasodilation
    o Antiproliferative effects → ↑ cAMP
49
Q

O2 effect

A
  • Potent vasodilator

12. Pharmacology (10 decks)

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