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Gaseous Vasodilator – Nitric oxide
• NO is now known as a critical endogenous
• It has an increasing number of potential
• 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
• Inhibits platelet aggregation and adhesion.
• In the immune system, it serves as an effector of
• Overproduction of NO is a mediator of
• NO has been implicated in mediating central
• NO is rapidly inactivated in the circulation by
• Also, reaction of NO + heme iron = nitrosyl-hemoglobin.
• Small quantities of methemoglobin are also
(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
persistent pulmonary hypertension of the
• It is also used in adult and neonatal respiratory
Adverse effects :
• Pulmonary toxicity.
• Natriuretic Peptide :
• Atrial natriuretic peptide (ANP)
• B- type natriuretic peptide (BNP)
• C-type natriuretic peptide (CNP)
The inner medullary collecting duct (IMCD) is
major site of action of natriuretic peptides.
ANP BNP CNP
cells++, central and
Atrial stretch, ECF
actions Natiuresis, diuresis,
decrease in BP
uses Diagnostic /
Prognostic marker in
Location On the surface
of target cells
Ligand ANP,BNP CNP ANP, BNP, CNP
in free Ca2+
-do- not clear
function previous table Previous
Removal of ANP, BNP
and CNP from
“ clearance receptor”
Note on Urodilatin :
• Is like ANP, synthesised in distal tubule of
kidney from ANP precursors.
• It produces natriuresis, diuresis and
Mechanism & Site of action of Natriuretic
• 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
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
• 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
• Recombinant BNP.
• Increases cGMP in vascular smooth muscle
-- Vasodilation and reduction in pulmonary
capillary wedge pressure.
--- No effect on cardiac contractility.
• 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
• Acutely decompensated CHF with dyspnoea at
Dose : 0.01 mcg/kg/min I.V infusion
• 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)
• Sampatrilat and
• All improved cardiac function in HF and BP in
• But they caused angioedema, cough and
• Hydralazine (1-hydrazinophthalazine) was one
of the first orally active antihypertensive drugs
Mechanism of Action
• Hydralazine directly relaxes arteriolar smooth
• 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
leading to diminished contraction.
• Hydralazine promotes arterial dilation by
opening high conductance Ca2+-activated K+
• Also, it has nitric oxide–enhancing actions
• It does not relax venous smooth muscle.
• 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
• However , vasodilation is associated with
baroreceptor-mediated reflexes, to results in
Increased heart rate and contractility.
Increased plasma renin activity, and fluid
• Hydralazine is well absorbed.
• But the systemic bioavailability is low due to first
(16% in fast acetylators and 35% in slow
• Hydralazine is N-acetylated in the bowel and the
• The t1/2 is 1 hour.
• Duration of action : 12 hrs (accumulation in artery
• Peak hypotensive effect : within 30-120 minutes
Toxicity and Precautions
• Headache , nausea, flushing, hypotension.
• Stimulation of the sympathetic nervous
Palpitations, tachycardia, dizziness, and angina
Myocardial ischemia (baroreceptor reflex-induced
,increased O2 demand)
So I.V Hydralazine is not preferred in HTN with
• 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
• No more first line drugs for essential
If used, it is with combination diuretics and
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.
combination therapy with isosorbide dinitrate
, reduces CHF mortality.
• Discovered in 1965.
• Hypotensive action of minoxidil was a
significant advance in the treatment of
• It has proven to be efficacious in patients with
the most severe and drug-resistant forms of
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
• 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
• 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
Hypertrichosis (80 %) : after extended period
(probably a consequence of K+ channel
Growth of hair occurs on the face, back, arms,
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
• Severe hypertension : is best reserved for the
Responds poorly to other antihypertensive
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 was used in the treatment of
• Fell out of favor -risk of marked falls in blood
pressure when large bolus doses of the drug
• Current use : treat patients with
hypoglycemia ( inoperable islet cell adenoma).
Dose : 50mg/ml oral suspension
• Organic nitrates/ nitrovasodilators/ nitric
oxide donors : Nitroglycerine etc.
• They lead to the formation of the reactive
gaseous free radical NO and related
• 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
• Systemic arterial pressure may fall slightly.
• Heart rate is unchanged or may increase
slightly in response to a decrease in blood
• 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
• 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
• Post operative Hypertension : (drug of choice)
• Cyanide Poisoning : methaemoglobin
generated by nitrates has greater affinity for
Used along with Sod. Thiosulphate.
Adverse effects :
• Headache is common .
• Transient episodes of dizziness, weakness,
• Drug rash.
Mechanism of Action
• It is a nitrovasodilator that acts by releasing
• 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 dilates both arterioles and
• So causes : venous pooling and reduced
• In normal subjects ,venous pooling affects
cardiac output (more than does the reduction
of afterload) so here, cardiac output tends to
• In contrast, in patients with severely impaired
left ventricular function and diastolic
the reduction of arterial impedance is the
predominant effect, leading to a rise in cardiac
• It is a nonselective vasodilator, and regional
distribution of blood flow is little affected by the
• Renal blood flow and glomerular filtration are
• Unlike , other arteriolar vasodilators,
Only a modest increase in heart rate and an overall
reduction in myocardial O2 demand.
• The drug must be protected from light and
given by continuous intravenous infusion to be
• 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.
• It is used primarily to treat hypertensive
Dose : 2–4 mcg/kg/min; maximum 10
mcg/kg/min for 10 min
• Acute aortic dissection (to lower blood
• To improve cardiac output in CHF, especially
in hypertensive patients with pulmonary
• To induce controlled hypotension during
anesthesia to reduce bleeding in surgical
Common ones :
• Hypotension, bradyarrhythmia, tachyarrhythmia .
• Headache, restlesness.
• Injection site irritation.
Serious ones :
• Cyanide poisoning :
Management - concomitant administration of
sodium thiosulfate can prevent accumulation of
• Thiocynate toxicity : (seen in renal failure)
anorexia, nausea, fatigue, disorientation, and
Management - Haemodialysis
• Raised intracranial pressure
• Rang and Dale
• Goodman & Gilman
• HL Sharma and KK Sharma
• KD Tripathi
• Harrison’s principles of Internal medicine