Vasodilators

Vasodilators (for MD Pharmacology)
Dr. Advaitha

Usage of Vasodilators
• Systemic hypertension
• Heart failure
• Peripheral vascular disease
• Raynaud's disease
• Pulmonary hypertension.

Directly acting vasodilators :
1. Calcium channel blockers : Nifedipine,
diltiazem, verapamil.
2.KATP channel activators : Minoxidil and
Diazoxide.
Newer ones (coronary vasodilators) ---
- Nicorandil, Pinacidil, cromakalin.

Directly acting contd..
3.Drugs that increase cytoplasmic cyclic
nucleotide concentrations by:
a) Increasing adenylyl cyclase activity
-prostacyclin (epoprostenol).
-β2-adrenoceptor agonists.
-Adenosine.

b) Increasing guanylyl cyclase activity
-nitrates (glyceryl trinitrate, nitroprusside)
-Inhibiting phosphodiesterase activity (sildenafil)
- Natiuretic Peptide analogues ( Nesiritide)

Indirectly acting vasodilators :
1.Drugs that interfere with the sympathetic
nervous system
α1-blockers (Phentolamine, Phenoxybenzamine).
α2 agonists ( clonidine)
D1 receptor agonist : Fenoldopam

2.Drugs that block the renin-angiotensin system:
– Renin inhibitors ( aliskiren)
– ACE inhibitors (ramipril)
– AT1 receptor antagonists (losartan).

Indirectly acting contd..
3. Drugs or mediators that stimulate endothelial
NO release
acetylcholine, bradykinin
4.Drugs that block the endothelin system:
– Blocks endothelin synthesis –Phosphoramidon
(endothelin-1 converting enzyme inhibitor) –not
approved
– Endothelin-1 receptor antagonists (Bosentan).

Miscellaneous drugs
• Vasodilators whose mechanism is uncertain
-- alcohol, propofol and hydralazine.
• Drugs in Peripheral vascular disease
--Pentoxifylline, Cilastozole
• Diuretics : Frusemide ( I.V only )

Our focus !
• Vasodilator Peptides and related drugs
• Gaseous vasodilator : Nitric Oxide
• Direct vasodilators
1. Arteriolar -hydralazine, minoxidil, diazoxide.
2. Venodilator : nitroglycerine
3. Arteriolar + venous –nitroprusside.

Gaseous Vasodilator – Nitric oxide
• NO is now known as a critical endogenous
cell-signaling molecule.
• It has an increasing number of potential
therapeutic applications.
• Endogenous, NO is produced from L-arginine
by a enzymes called NO synthases
(neural, inducible and endothelial).

• NO activates the guanylyl cyclase, increasing
cellular cyclic GMP .
• In the vasculature, basal release of NO
produced by endothelial cells is a primary
determinant of resting vascular tone.
• NO is also synthesized in response to shear
stress or a variety of vasodilating agents

Properties :
• Vasodilation
• Inhibits platelet aggregation and adhesion.
• In the immune system, it serves as an effector of
macrophage-induced cytotoxicity.
• Overproduction of NO is a mediator of
inflammation.

• NO has been implicated in mediating central
nociceptive pathways

Metabolism :
• NO is rapidly inactivated in the circulation by
oxyhaemoglobin.
• Also, reaction of NO + heme iron = nitrosyl-hemoglobin.

• Small quantities of methemoglobin are also
produced.
(These are converted to the ferrous form of
heme iron by cytochrome b5 reductase)
• The majority of inhaled NO is excreted in the
urine in the form of nitrate

Therapeutic Uses :
• Inhaled NO is FDA-approved for only one
indication---
persistent pulmonary hypertension of the
newborn
• It is also used in adult and neonatal respiratory
distress.
Adverse effects :
• Methaemoglobinaemia
• Pulmonary toxicity.

Vasodilator peptides
• Natriuretic Peptide
• Vasoactive intestinal peptide (VIP)
• Substance P
• Neurotensin
• Calcitonin Gene-related Peptide
• Adrenomedullin

• Natriuretic Peptide :
These are
• Atrial natriuretic peptide (ANP)
• B- type natriuretic peptide (BNP)
• C-type natriuretic peptide (CNP)
• Urodilatin
The inner medullary collecting duct (IMCD) is
major site of action of natriuretic peptides.

ANP BNP CNP
Site of
synthesis
Cardiac atrial
cells+++, ventricular
cells++, central and
peripheral neurons
Ventricular
cells ++++
Vascular
endothelium, CNS,
kidney
Factors
stimulating
release
Atrial stretch, ECF
expansion, Heart
Failure, Primary
aldosteronism
Volume
expansion
Not clear
actions Natiuresis, diuresis,
decrease in BP
(vasodilation)
same as
ANP
Vasodilator, lesser
natriuretic and
diuretic effects.
uses Diagnostic /
Prognostic marker in
heart failure
In CHF

ANPA
(Receptors)
ANPB ANPC
Location On the surface
of target cells
Same as
ANPA
Vascular
endothelium
Ligand ANP,BNP CNP ANP, BNP, CNP
Mechani
-sm
Increases cGMP
levels, decrease
in free Ca2+
conc.
-do- not clear
function previous table Previous
table
Removal of ANP, BNP
and CNP from
circulation.
“ clearance receptor”

Note on Urodilatin :
• Is like ANP, synthesised in distal tubule of
kidney from ANP precursors.
• It produces natriuresis, diuresis and
vasodilation.

Mechanism & Site of action of Natriuretic
Peptide:
• The IMCD is the final site along the nephron
where Na+ is reabsorbed.
• There is a cyclic nucleotide gated cation (CNG)
channel in IMCD.

• This channel is highly selective for cations over
anions, has equal permeability for Na+ and K+.
• CNG Channel is inhibited by cGMP, PKG, and
atrial natriuretic peptides (ANP).
• Also, ANP stimulate membrane-bound guanylyl
cyclase activity and elevate cellular cGMP

• This leads to natriuresis at the level collecting
duct.

Pharmacokinetics of natriuretic peptides :
Shorter T-half .
metabolized by neutral endopeptidase (NEP-
24.11) in kidney, Liver and Lungs and
Also removed by ANPC receptor

Drugs :
• Carperitide -Human recombinant ANP, available
only in Japan.
• Nesiritide- Recombinant BNP are currently
available therapeutic agents of this class
• Ularitide ( phase 3 trial)– Synthetic urodilatin

Nesiritide :
• Recombinant BNP.
• Increases cGMP in vascular smooth muscle
resulting in
-- Vasodilation and reduction in pulmonary
capillary wedge pressure.
--- No effect on cardiac contractility.
Pharmacokinetics :
• Half life – 18-23 min
• Diuretic effect : I.V infusion 60 min.

• Haemodynamic effect : 2-4 hr ( after I.V bolus)
• Metabolism : by neutral endopeptidases in
brush border of kidney
Indication :
• Acutely decompensated CHF with dyspnoea at
rest.
Dose : 0.01 mcg/kg/min I.V infusion

Adverse effects :
• Hypotension
• Raised serum creatinine.
• Headache.

Vasopeptidase inhibitors
• These inhibits neutral endopeptidases 24.11
and ACE (also).
• So increases level of ANP and BNP and
decreases Angiotensin II.
• Resulting in enhanced vasodilation with Na+
and water excretion.

Drugs : ( None approved)
• Omapatrilat,
• Sampatrilat and
• fasidotrilat.
• All improved cardiac function in HF and BP in
HTN.
• But they caused angioedema, cough and
dizziness.

Direct vasodilators
Hydralazine
• Hydralazine (1-hydrazinophthalazine) was one
of the first orally active antihypertensive drugs
marketed.

Mechanism of Action
• Hydralazine directly relaxes arteriolar smooth
muscle.
• Molecular targets/mechanisms that explain its
capacity to dilate arteries remain uncertain.

Evidence shows that
• Hydralazine inhibits IP3-induced release of Ca2+
from intracellular storage sites in arteries.
ultimately fall in intracellular calcium
concentrations
leading to diminished contraction.

• Hydralazine promotes arterial dilation by
opening high conductance Ca2+-activated K+
channels.
• Also, it has nitric oxide–enhancing actions
• It does not relax venous smooth muscle.

Pharmacological Effects
• It is confined to the cardiovascular system.
• Involves selectivereduction of blood pressure in
coronary, cerebral, and renal circulations, with
smaller effect in skin and muscle.

Postural hypotension is not a common problem
(Because of preferential dilation of arterioles
over veins)
• However , vasodilation is associated with
baroreceptor-mediated reflexes, to results in
Increased heart rate and contractility.
Increased plasma renin activity, and fluid
retention.

Pharmacokinetics :
• Hydralazine is well absorbed.
• But the systemic bioavailability is low due to first
pass metabolism.
(16% in fast acetylators and 35% in slow
acetylators).
• Hydralazine is N-acetylated in the bowel and the
liver.

• The t1/2 is 1 hour.
• Duration of action : 12 hrs (accumulation in artery
wall)
• Peak hypotensive effect : within 30-120 minutes
of PO

Toxicity and Precautions
• Headache , nausea, flushing, hypotension.
• Stimulation of the sympathetic nervous
system :
Palpitations, tachycardia, dizziness, and angina
pectoris.
Myocardial ischemia (baroreceptor reflex-induced
,increased O2 demand)
So I.V Hydralazine is not preferred in HTN with
CAD

• Salt retention + high-output congestive heart
failure (if the drug is used alone)
So it is better tolerated when combined with
beta blocker and diuretic.
• Drug -induced lupus syndrome ( usually after 6
months).

Uses
• No more first line drugs for essential
hypertension.
If used, it is with combination diuretics and
Beta- blockers.
Dose : 25-100 mg twice daily. Max 200mg.

• Mainly used In hypertensive emergencies :
10–50 mg at 30-min intervals I.V.
It is preferred in - preeclampsia.

• In CHF :
It reduces ventricular afterload by reducing
pulmonary and systemic vascular resistance.
 Recently demonstrated,
combination therapy with isosorbide dinitrate
, reduces CHF mortality.

Minoxidil
• Discovered in 1965.
• Hypotensive action of minoxidil was a
significant advance in the treatment of
hypertension.
• It has proven to be efficacious in patients with
the most severe and drug-resistant forms of
hypertension.

Mechanism of Action :
• Minoxidil is not active in vitro.
• It is metabolized by hepatic sulfotransferase to
the active molecule, minoxidil N-O sulfate.
• Minoxidil sulfate activates the ATP-modulated
K+ channel in smooth muscle.
• By opening K+ channels, thereby permitting K+
efflux, it cause hyperpolarization and
relaxation of smooth muscle.

• Minoxidil produces arteriolar vasodilation
with essentially no effect on the capacitance
vessels.
• It increases blood flow to skin, skeletal muscle,
the gastrointestinal tract, and the heart more
than to the CNS.

• It is a renal artery vasodilator.
Renal function improves in patients who take
minoxidil for the treatment of hypertension.
(especially if renal dysfunction is secondary to
hypertension)

Pharmacokinetics :
• Minoxidil is well absorbed. BA : 90%
• Initial effect : 1 hour after PO
• Plasma t1/2 of 3-4 hours.
• Duration of action is 2- 5 days.
• Metabolism : liver , via Glucuronidation

Adverse effects
Hypertrichosis (80 %) : after extended period
(probably a consequence of K+ channel
activation)
Growth of hair occurs on the face, back, arms,
and legs.
Fluid and salt retention

Cardiovascular effects : similar to Hydralzine
 Abnormal ECG (60%) : Flattened and inverted T,
similar to other K+ channel openers.
Others : rashes, Stevens-Johnson syndrome

Uses
• Severe hypertension : is best reserved for the
treatment that
Responds poorly to other antihypertensive
medications.
HTN with renal insufficiency in male patients.

They are concurrently used with a diuretic
and beta blockers.
Dose : 2.5mg , 10 mg PO
• Topical solution 2%, 5%: It is used in male
pattern baldness and Alopecia Areata.

Diazoxide
• Diazoxide was used in the treatment of
hypertensive emergencies.
• Fell out of favor -risk of marked falls in blood
pressure when large bolus doses of the drug
were used.
• Current use : treat patients with
hypoglycemia ( inoperable islet cell adenoma).
Dose : 50mg/ml oral suspension

Nitroglycerine
• Organic nitrates/ nitrovasodilators/ nitric
oxide donors : Nitroglycerine etc.
• They lead to the formation of the reactive
gaseous free radical NO and related
compounds.
• The exact mechanism of denitration to
liberate NO is an active area of investigation.

Mechanism of action :
• Phosphorylation of the myosin light chain
regulates the maintenance of the contractile
state in smooth muscle.
• NO activate guanylyl cyclase, increase the
cellular level of cyclic GMP, activate Protein
Kinase G (PKG).

• Activated PKG and leads to
dephosphorylation of the myosin light chain.
• This promotes vasorelaxation .

Pharmacological action :
• Low concentrations of nitroglycerin
preferentially dilate veins more than arterioles.
• Decreased venous return, leads to fall in left
and right ventricular chamber size and end-diastolic
pressures.

• Systemic arterial pressure may fall slightly.
• Heart rate is unchanged or may increase
slightly in response to a decrease in blood
pressure.

• Pulmonary vascular resistance and cardiac
output are slightly reduced.
• Very low Doses , (that do not alter systemic
arterial pressure) may still produce arteriolar
dilation in the face and neck.
• This result in a facial flush, or dilation of
meningeal arterial vessels, cause headache.

• Basis for the differential response of arterial
versus venous tissues remains unclear.
• However , at Higher doses, there is further
venous pooling and may decrease arteriolar
resistance as well.
• This decreases SBP , DBP and CO

• Coronary vessel : Nitrates preferrentially relax
bigger conducting coronary arteries than
arterioles and resistance vessels.
So has favourable redistribution to ischemic
areas in angina patients
• Heart : No direct stimulant or depressant action
on heart.

Uses :
• Angina (including prinzmetal’s): An initial dose
of 0.3 mg nitroglycerin often relieves pain
within 3 minutes.
• MI : To relieve ischemic pain and pulmonary
congestion. Intravenous 5–200 mcg/min
• CHF/ LVF : To decrease preload.
• Biliary colic & Esophageal spasm : to relieve
pain.

• Post operative Hypertension : (drug of choice)
• Cyanide Poisoning : methaemoglobin
generated by nitrates has greater affinity for
cyanide.
Used along with Sod. Thiosulphate.

Adverse effects :
• Headache is common .
• Transient episodes of dizziness, weakness,
postural hypotension.
• Drug rash.
• Tolerance

Sodium Nitroprusside
Mechanism of Action
• It is a nitrovasodilator that acts by releasing
NO.
• NO activates the guanylyl cyclase– cyclic
GMP– PKG pathway, leading to vasodilation.
• So It mimicks the production of NO by
vascular endothelial cells, which is impaired in
many hypertensive patients .

• Tolerance develops to nitroglycerin but not to
nitroprusside.

• Nitroprusside dilates both arterioles and
venules.
• So causes : venous pooling and reduced
arterial impedance.
• In normal subjects ,venous pooling affects
cardiac output (more than does the reduction
of afterload) so here, cardiac output tends to
fall.

• In contrast, in patients with severely impaired
left ventricular function and diastolic
ventricular distention
the reduction of arterial impedance is the
predominant effect, leading to a rise in cardiac
output.

• It is a nonselective vasodilator, and regional
distribution of blood flow is little affected by the
drug.
• Renal blood flow and glomerular filtration are
maintained.
• Unlike , other arteriolar vasodilators,
Only a modest increase in heart rate and an overall
reduction in myocardial O2 demand.

Pharmacokinetics :
• The drug must be protected from light and
given by continuous intravenous infusion to be
effective.
• Onset of action is within 30 seconds.
• Peak hypotensive effect : 2 minutes
• The effect disappears within 3 minutes when
the infusion is stopped.

• Metabolized in Blood (100%). Ferrous ion in
nitroprusside reacts with sulphydryl compounds
in RBCs .This releases Cyanide.
• Cyanide is further metabolized by rhodanase in
liver to form thiocyanate.
• It is eliminated almost entirely in the urine.

Uses
• It is used primarily to treat hypertensive
emergencies.
Dose : 2–4 mcg/kg/min; maximum 10
mcg/kg/min for 10 min
• Acute aortic dissection (to lower blood
pressure )

• To improve cardiac output in CHF, especially
in hypertensive patients with pulmonary
edema.
• To induce controlled hypotension during
anesthesia to reduce bleeding in surgical
procedures.

Adverse effects
Common ones :
• Hypotension, bradyarrhythmia, tachyarrhythmia .
• Headache, restlesness.
• Injection site irritation.

Serious ones :
• Cyanide poisoning :
Management - concomitant administration of
sodium thiosulfate can prevent accumulation of
cyanide.
• Thiocynate toxicity : (seen in renal failure)
anorexia, nausea, fatigue, disorientation, and
toxic psychosis
Management - Haemodialysis
• Raised intracranial pressure

References :
• Rang and Dale
• Goodman & Gilman
• HL Sharma and KK Sharma
• KD Tripathi
• Harrison’s principles of Internal medicine
Thank you

Vasodilators

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Vasodilators