Vasodilators.pg.

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-arginineby 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 atrialcells+++, ventricular cells++, central and peripheral neurons

Ventricular cells ++++

Vascular endothelium, CNS,kidney

Factors stimulating release

Atrial stretch, ECFexpansion, Heart Failure, Primary aldosteronism

Volumeexpansion

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 cGMPlevels, 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 NatriureticPeptide:

• The IMCD is the final site along the nephronwhere 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 guanylylcyclase 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.

Pharmacological Effects

• 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 contractilestate 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 : methaemoglobingenerated 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.

Pharmacological Effects

• 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

Thank you

References :

• Rang and Dale

• Goodman & Gilman

• HL Sharma and KK Sharma

• KD Tripathi

• Harrison’s principles of Internal medicine