Vasodilators

Question 1

Classification

Answer 1

Arteriolar dilators
Venodilators

Question 2

Arteriolar dilators: def and effects

Answer 2

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

Question 3

Arteriolar dilators: drugs

Answer 3

• Amlodipine
• Hydralazine

Question 4

Venodilators: def and effects

Answer 4

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

Question 5

Effect depend on

Answer 5

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

Question 6

Direct acting vasodilators: drugs

Answer 6

Hydralazine
endralazine, cadralazine, minoxidil, dipyridamole, pinacidil

Question 7

Types of vasodilators

Answer 7

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

Question 8

Hydralazine: MOA

Answer 8

• 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

Question 9

Hydralazine: effect

Answer 9

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

Question 10

Hydralazine: PharmacoK

Answer 10

• 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

Question 11

Hydralazine: side effects

Answer 11

o Hypotension
o Reflex tachycardia → baroR reflex

Question 12

Nitrates: drugs

Answer 12

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

Question 13

Nitrates: MOA

Answer 13

• 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

Question 14

Nitrates: effects

Answer 14

 ↓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

Question 15

Nitrate tolerance MOA

Answer 15

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

Question 16

CCB: action

Answer 16

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

Question 17

Role of Ca2+ in SM cells

Answer 17

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

Question 18

Types of CCB

Answer 18

Dihydropyridines
Non-dihydropyridines

Question 19

Dihydropyridines: drugs

Answer 19

• 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

Question 20

Non-dihydropyridines: drugs

Answer 20

Diltiazem and verapamil

Question 21

Adrenergic R blockers types

Answer 21

Alpha-R blockers
Beta-R blockers

Question 22

Alpha-R blockers: drugs

Answer 22

Prazosin
phenoxybenzamine, phentolamine

Question 23

Prazosin MOA

Answer 23

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

Question 24

Prazosin effect

Answer 24

• Arteriolar and venous (++) dilator
• No reflex tachycardia

Question 25

B R blockers types

Answer 25

B1, B2, B3

Question 26

B1 R blockers: action

Answer 26

* 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

Question 27

B2 R blockers: action and effect

Answer 27

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

Question 28

B3 R blockers: action and effect

Answer 28

* Endothelial * Vasodilation induced by NO

Question 29

Features of B-R blockade

Answer 29

* 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

Question 30

Clinical use of B blcokade

Answer 30

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

Question 31

ACEi drugs

Answer 31

Benazepril, Enalapril, Lisinopril

Question 32

ACEi action

Answer 32

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

Question 33

ACEi in dogs

Answer 33

* Drugs studied in dogs o Prodrugs: enalapril, benazepril, quinapril, ramipril o Active drugs: captopril, lisinopril

Question 34

Ang II R blockers drugs

Answer 34

Losartan, telmisartan, valsartan, irbesartan

Question 35

Ang II R blockers: action and effects

Answer 35

* Block binding of AngII to AT-1 R * Similar effect to ACEi o No bradykinin effect

Question 36

PDEi types

Answer 36

PDEi5 PDEi3

Question 37

PDEi5 drugs

Answer 37

Sildenafil, tadalafil

Question 38

PDEi5 MOA and effect

Answer 38

* Block action of PDE5 enzyme → ↑cGMP in SM * PDE5 specific to pulmonary vessels

Question 39

PDEi3 MOA and effect

Answer 39

* Block action of PDE3 enzyme → ↑cAMP in SM of systemic arterioles o Systemic vasodilation o ↓ afterload

Question 40

ET1 R antagonist drugs

Answer 40

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

Question 41

ET1 effects

Answer 41

* 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)

Question 42

ET-1 R antagonists effects

Answer 42

o Vasodilation o Cardiac inhibition

Question 43

K+ channel opener drugs

Answer 43

Minoxidil

Question 44

K+ channels opener: MOA

Answer 44

* 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

Question 45

K+ channels opener: effects

Answer 45

* Effective on small arteries and arterioles

Question 46

K+ channels opener: side effects

Answer 46

o Reflex bradycardia o Fluid retention/edema

Question 47

PGI analog drugs

Answer 47

Epoprostenol, treprostinil, iloprost

Question 48

PGI analog action

Answer 48

* Synthetized from arachidonic acid * Action o Antiplatelet/aggregation effects o Vasodilation o Antiproliferative effects → ↑ cAMP

Question 49

O2 effect

Answer 49

* Potent vasodilator