Vasodilators

Dr. Ashley Stokes

Veterinary Clinical Pharmacology
 Vasodilators

n Primary use is for cardiac disease

n Goals of use are to improve hemodynamics,

reduce edema formation, improve cardiac
output, and improve tissue perfusion

n Vasodilators do this by dilating arterioles

(decreases resistance) and/or venules
(decreases circulating blood volume)
 Vasodilators
n *Heart failure*
– Causes decreased CO &
tissue perfusion
– Body’s reaction/
compensatory mechanisms
§Increase blood pressure = main goal
– Initial – stimulates sympathetic nervous system
§ Increased heart rate and vasoconstriction
– Long-term – stimulates renin-angiotensin system (stimulated
by decreased renal perfusion)
§ Vasoconstriction and increased Sodium/water retention
§Short-term ok; long-term makes the heart work too hard
(due to increased resistance & increased blood volume)
 Vasodilators
n Common veterinary uses of vasodilators
– Heart failure associated with mitral regurgitation
– Hypertension
§ i.e. cats with chronic renal failure
– Equine laminitis/navicular disease
 Vasodilators

n Types of vasodilators
– Arteriodilators
§ reduce afterload
– Venodilators
§ reduce preload
– Mixed vasodilators
 MECHANISM OF PRELOAD AFTERLOAD
DRUG CLASS VASODILATING ACTION REDUCTION REDUCTION

Organic nitrates (Nitroglycerin) Nitric oxide-mediated +++ +

vasodilation
Nitric oxide donors Nitric oxide-mediated +++ +++
(Nitroprusside) vasodilation
Angiotensin converting enzyme Inhibition of angiotensin ++ ++
inhibitors (Enalapril, generation; decreased
Benazepril) bradykinin degradation
Angiotensin receptor blockers Blockade of angiotensin receptors ++ ++
(Iosartan) inhibitors

Phosphodiesterase (Milrinone, Inhibition of cyclic AMP degradation ++ ++

Inamrinone, Pimobendan)

Direct-acting (Hydralazine) Unknown, may block Ca2+ + +++

movement?
Subtype-selective
1-adrenergic Selective
1-adrenergic receptor +++ ++
receptor antagonists (Prazosin) blocker

Non-subtype-selective
-adrenergic Non-selective
-adrenergic receptor +++ +++

receptor antagonists blockade
(Phentolamine)

Vasodilating /
1 adrenergic receptor Selective
1-adrenergic receptor ++ ++

antagonists (Carvedilol) blockade

Ca2+ channel blocking drugs Inhibition of L-type Ca2+ + +++

(Amlodipine) channels

-adrenergic receptor agonists Stimulation of vascular
2- ++ +
(Isoxsuprine) adrenergic receptors
Vasodilators
n Complications from
vasodilator use
– *Hypotension*
§ May be dose-dependent
– Adjust dose
§ May be due to decreased renal/hepatic fxn
– Adjust dose (may need to readjust up as fxn improves)
– Reflex-enhanced sympathetic activity
– Electrolyte imbalances
n Monitoring is essential
– i.e. blood pressure, electrolytes, renal/hepatic fxn
 Vasodilators
n Arteriodilators
– Hydralazine
§ Used for mitral
regurgitation & other
cardio-vasc diseases
§ MOA - ?? May decrease
Ca2+ movement into
smooth muscle cells
§ Usually given PO 10 mg
– Side effect = GI 25 mg
disturbances common!
50 mg
May need to stop
administration because of 100 mg
this!
 Vasodilators
n Venodilators
– Nitroglycerine
§ Concentrated form !
§ Diluted to 2-10% medical use
§ Diverts blood into systemic venous
pools via nitric oxide
§ IV, PO, transdermal
– IV – fast, low doses = venodilation, high
doses = veno & arteriodilation, short
half-life
– PO – only 10% bioavailability
– Transdermal – patch or ointment, clip
area, wear gloves
§ Side effect = tolerance
– Use intermittently
Vasodilators
n Nitroglycerine - nitric oxide
mediated vasodilation
1) Drug metabolized into nitric oxide
(NO) in vascular smooth muscle.
2) NO molecules activate an
enzyme, guanylyl cyclase (GC).
3) GC converts guanosine
triphosphate (GTP) to cyclic
guanosine monophosphate
(cGMP).
4) cGMP causes calcium ions to
enter storage area of the cell. The
lowered concentrations of calcium
ions (Ca2+) set off a cascade of
cellular reactions that cause the
cell’s contractile filaments (myosin
and actin) to slide apart.
5) Smooth muscle cells relax.
6) Blood vessel dilates.
 Vasodilators

n Venodilators
– Isoxsuprine
§ Direct relaxation of vascular
smooth muscle, beta-adrenergic
receptor agonist
§ Tx of navicular disease &
laminitis in horses
§ Requires long-term treatment
(i.e. months) to see effects
 Vasodilators

n Mixed Arterio/Venodilators
– Prazosin
§ Blocks alpha1 receptor
– Remember role of sympathetic
nervous system in heart failure
§ Used for pulmonary & systemic
hypertension
§ Side effect = severe hypotension!!
– Especially small
dogs & cats!
 Vasodilators
n Mixed Arterio/
Venodilators
– Nitroprusside
§ NO mediated activity
§ Different pathway
from NG activity
§ Another name of drug (metabolite) (metabolism in liver)
is sodium nitroferricyanide
§ Used for hypertensive emergencies (i.e. acute
congestive heart failure)
§ IV only, must dilute in 5% dextrose, protect from light
§ Side effects = hypotension!!
= cyanide toxicity with use >16 h!!
– Monitor blood pressure, acid/base
– Treat with thiosulfate if cyanide toxicity – note why
 Vasodilators
n Mixed Arterio/
Venodilators
– Pimobendan (Vetmedin)
§ New in US
§ Phosphodiesterase inhibitor –
increases cAMP
§ Used as adjunctive therapy for
congestive heart failure in dogs
§ Increased cAMP leads to
increased intracellular Ca++
§ In arteries and veins (smooth
muscle) – increased Ca++ = dilation
§ In heart (cardiac muscle) –
increased Ca++ = increased
contractility (inotropic)
§ Oral formulation only
 Vasodilators
Renin-angiotensin-aldosterone system
A series of reactions designed to help regulate blood
pressure.
1. When blood pressure falls (for systolic, to 100 mm
Hg or lower), the kidneys release the enzyme renin
into the bloodstream.
2. Renin splits angiotensinogen,
angiotensinogen, a large protein that
circulates in the bloodstream, into pieces. One
piece is angiotensin I.
3. Angiotensin I, which is relatively inactive, is split
into pieces by angiotensin-converting enzyme
(ACE). One piece is angiotensin II, which is very
active.
4. Angiotensin II, a hormone, causes the muscular
walls of small arteries (arterioles) to constrict,
increasing blood pressure. Angiotensin II also
triggers the release of the hormone aldosterone
from the adrenal glands.
5. Aldosterone causes the kidneys to retain salt
(sodium) and excrete potassium. The sodium
causes water to be retained, thus increasing blood
volume and blood pressure
 (Illustration: Craig Zuckerman)

1. ACE converts angiotensin I to angiotensin II, which constricts blood vessels.

2. ACE inhibitors block conversion of angiotensin I - angiotensin II, thereby relaxing blood
vessels.
3. ACE inhibitors also decrease the breakdown of bradykinin,
bradykinin, also relaxing blood vessels.
4. Angiotensin II binds to receptors on vascular smooth muscle cells, causing vasoconstriction.
5. ARBs (angiotensin II receptor blockers) inhibit this binding to receptors, relaxing blood
vessels.
 Vasodilators
n ACE Inhibitors
– Arterio & venodilators
– Also reduce aldosterone release
– Commonly used for heart failure
§ Especially canine DCM & feline HCM
§ Often given with diuretics
– Commonly used for hypertension secondary to renal
disease
– Oral administration
§ on empty stomach provided best bioavailability
– Monitor for hypotension, electrolyte imbalances, and
renal fxn
– Use with caution in pregnant animals!
 Vasodilators
Captopril Benazepril

n ACE Inhibitors
– Captopril
§ Thought to improve all stages of heart failure
§ PO – good bioavailability
§ Metabolized in liver/excreted renally
§ Side effects = anorexia & vomiting
– Enalapril and Benazepril used more commonly
– Benazepril
§ Heart failure in dogs & chronic renal disease
induced hypertension in cats
§ Metabolized in liver to active form
§ Newer drug, fewer side effects than Captopril
§ Currently approved in UK/Canada
 Vasodilators

n ACE Inhibitors
– Enalapril
§ One of the most clinically studied drugs in
veterinary species
§ Most common ACE inhibitor for mild,
moderate, severe CHF in dogs and cats
(especially mitral regurgitation and DCM in
dogs)
§ Metabolized in liver/excreted liver & kidneys
§ PO most commonly used (IV available –
used for treatment of cardiogenic shock)
 Vasodilators
n Calcium channel blockers
– Contraction of vascular smooth
muscle is dependent upon the
influx of Ca2+
– Ca2+ channel blockers reduce this
influx allowing relaxation of
vascular smooth muscle
(especially arterial)
– 5 classes of drugs in this group
§ One group is the dihydrophyridines
– Group with greatest arteriodilation
effect
– Amlodipine is in this group
 Vasodilators

n Calcium channel blockers

– Amlodipine
§ Drug of choice for hypertension
secondary to chronic renal disease/failure
§ Also used to treat hypertension secondary
to hyperthyroid thyrotoxic cardiomyopathy
§ PO administration
 Vasodilators Objectives
n How do the various classes of vasodilators
counter the acute and chronic cardiovascular
changes associated with heart failure
(understand general mechanisms)?
n What are the major side effects of vasodilator
use?
n Vasodilator table in these PowerPoint notes
(underlined groups especially)
– For these agents know: mechanism of action, drug
class, arterio/venous/both dilation, major drug-
specific side effects
 MECHANISM OF PRELOAD AFTERLOAD
DRUG CLASS VASODILATING ACTION REDUCTION REDUCTION

Organic nitrates (Nitroglycerin) Nitric oxide-mediated +++ +

vasodilation
Nitric oxide donors Nitric oxide-mediated +++ +++
(Nitroprusside) vasodilation
Angiotensin converting enzyme Inhibition of angiotensin ++ ++
inhibitors (Enalapril, generation; decreased
Benazepril) bradykinin degradation
Angiotensin receptor blockers Blockade of angiotensin receptors ++ ++
(Iosartan) inhibitors

Phosphodiesterase (Milrinone, Inhibition of cyclic AMP degradation ++ ++

Inamrinone, Pimobendan)

Direct-acting (Hydralazine) Unknown, may block Ca2+ + +++

movement?
Subtype-selective
1-adrenergic Selective
1-adrenergic receptor +++ ++
receptor antagonists (Prazosin) blocker

Non-subtype-selective
-adrenergic Non-selective
-adrenergic receptor +++ +++

receptor antagonists blockade
(Phentolamine)

Vasodilating /
1 adrenergic receptor Selective
1-adrenergic receptor ++ ++

antagonists (Carvedilol) blockade

Ca2+ channel blocking drugs Inhibition of L-type Ca2+ + +++

(Amlodipine) channels

-adrenergic receptor agonists Stimulation of vascular
2- ++ +
(Isoxsuprine) adrenergic receptors