Dr Suryawan bin Tasref Department of Anaesthesiology & Intensive Care HSNZ

Dr Suryawan bin Tasref

Department of Anaesthesiology

& Intensive Care

HSNZ

VASODILATORS

CONTENT

Introduction

Classifications

Conclusion

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INTRODUCTIONvasodilator = drugs that relax the smooth muscle in blood vessels, which causes the vessels to dilate.

Dilation of arterial (resistance) vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure.

Dilation of venous (capacitance ) vessels decreases venous blood pressure

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http://cvphysiology.com/Blood%20Pressure/BP021.htm


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CLASSIFICATION Based on their site of action (arterial vs venous)

Arterial dilators--primarily dilate resistance vessels (e.g., hydralazine)

Venous dilators--primarily affect venous capacitance vessels ( e.g., nitroglycerine).

Mixed arterial and venous dilator properties ( e.g., alpha-adrenoceptor antagonists, angiotensin converting enzyme inhibitors)

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INTRO-CLINICAL USEVasodilators are used to treat hypertension, heart failure and angina

Arterial dilators that act primarily on resistance vessels are used for hypertension and heart failure, but not for angina because of reflex cardiac stimulation.

Venous dilators are very effective for angina, and sometimes used for heart failure, but are not used as primary therapy for hypertension.

Most vasodilator drugs are mixed (or balanced) vasodilators in that they dilate both arteries and veins;

there are some drugs that are highly selective for arterial or venous vasculature

http://www.cvpharmacology.com/clinical%20topics/hypertension.htm

http://www.cvpharmacology.com/clinical%20topics/heart%20failure.htm

http://www.cvpharmacology.com/clinical%20topics/angina.htm


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CLASSIFICATIONBy mechanism of action

1. Antiadrenergic Agents

2. Vasodilators

3. Renin-Angiotensin System Inhibitors

4. Calcium Channel Blocker

5. Phosphodiesterase inhibitor

6. Beta adrenoceptor agonist


Alpha-1 ReceptorsPrazosin

Phenoxybenzamine

Phentolamine

Beta ReceptorsPropanolol, Metoprolol, Atenolol, Esmolol

Alpha-Beta receptorsLabetolol


Central Nervous SystemClonidine

Methyldopa

Autonomic GangliaTrimetaphan

Nerve endingsReserpine

2. Vasodilators

Vascular Smooth MuscleHydralazine

Minoxidil

Diazoxide

Nitroprusside


Vascular Smooth MuscleVerapamil

Nifedipine

Diltiazem

4. Renin-Angiotensin System

Angiotensin Converting Enzyme InhibitorsCaptopril

Enalapril

Lisinopril

Angiotensin II Receptor AntagonistsLosartan


A number of drugs that inhibit the adrenergic nervous system are available, including some that act

centrally on vasomotor center activity

peripherally on neuronal catecholamine discharge

by blocking alpha- and/or beta-adrenergic receptors

Simplified schematic view of the adrenergic nerve ending showing that norepinephrine (NE) is released from its storage granules when the nerve is stimulated and enters the synaptic cleft to bind to alpha1 and beta receptors on the effector cell (postsynaptic). In

addition, a short feedback loop exists, in which NE binds to alpha2 and beta receptors

on the neuron (presynaptic), to inhibit or to stimulate further release, respectively

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Alpha-1 ReceptorsPrazosin

Phenoxybenzamine

Phentolamine

Beta ReceptorsPropanolol, Metoprolol, Atenolol, Esmolol

Alpha-Beta ReceptorsLabetolol

PRAZOSINquinazoline derivative produces peripheral vasodilation; vascular tone in both resistance(arterioles) and capacitance(veins) vessels is reducedresulting in decreased VR, CO and BPnot assd with reflex tachycardia (presyn alpha-2)selective and competitive postsynaptic alpha-1 receptor blockade (5000 affinity than alpha-2 receptor)

Pharmacokinetics Prazosin

administered orally (2 to 40mg/day) in divided bd doses

60% bioavailability

protein binding 90%

nearly completely metabolized by the liver

elimination half-time is about 3 hours (prolonged by cardiac failure)

Side Effects Prazosin

vertigofluid retentionorthostatic hypotension‘first dose phenomenon’ ; dizziness, faintness, syncope soon after the administration of the first dosedryness of the mouth, nasal congestion, nightmares, urinary frequency, lethargy, and sexual dysfunction

PHENOXYBENZAMINE

non-competitive and irreversible blocker

100x affinity for alpha-1

active metabolites which actually binds to the receptor; slow onset

poorly absorbed; 20-30%, dosage 40-60mg/day

elimination half-life; 24hours

indications; pre-operative preparation or long term Mx in phaechromocytoma

PHENTOLAMINE

competitive antagonismless selective alpha blocker (3-5x alpha-1)also acts at histamine and Ach receptorsadministered intravenously

as a diagnostic test for phaechromocytoma; risk of CVS collapseto ctrl HPT during surgical removal of phaechromocytoma

1. Antiadrenergic Agents (cont)

Alpha-1 ReceptorsPrazosinPhenoxybenzaminePhentolamine

Beta ReceptorsPropanolol, Metoprolol, Atenolol

Alpha-Beta ReceptorsLabetolol

Mechanism of Action

competitive antagonist

binding is reversible

chronic administration is associated with an increase in the number of beta-adrenergic receptors (up-regulation)

produces some degree of membrane stabilization in the heart

Classification selective and nonselective for beta-1 and beta-2 receptors partial or pure antagonists on the basis of the presence or absence of intrinsic sympathomimetic activity(ISA)antagonists with ISA cause less direct myocardial depression and heart rate slowing (better tolerated in patients with poor LV function)

CLASSIFICATION

Clinical Effect

negative inotropic and chronotropic effects

conduction speed (AVN) is slowed

decreased the rate of spontaneous phase 4 depolarization

antidysrhythmic effect

Side Effects

increased airway resistance

unmask the signs of hypoglycaemia

precipitate cardiac failure

PVD and Raynaud’s phenomenon

hyperkalaemia

memory loss and mental depression

withdrawal hypersensitivity; up-regulation

PROPANOLOL

non-selective blocker

lacks of ISA; pure antagonist

equal antagonism at beta-1 and beta-2

the first beta-antagonist introduced

the standard drug to which all other beta antagonists are compared

Pharmacokinetics Propanolol

rapidly and almost completely GIT absorptionextensive hepatic first-pass metabolism (70%); poor bioavailabilityextensively bound to plasma proteins (90% to 95%) clearance is by hepatic metabolism to active metabolite, 4-hydroxypropranolol (equivalent in activity to propanolol)

Pharmacokinetics Propanolol

elimination half-time is 2 to 3 hours,

elimination reduced when hepatic blood flow decreases

alterations in hepatic enzyme activity may also influence the rate of hepatic metabolism

ESMOLOL

selective beta-1 blocker; lacks of ISA

rapid-onset and ultra short-acting

preventing or treating haemodynamic instability intraoperatively in response to noxious stimulation, e.g. during intubation

Pharmacokinetics Esmolol

rapid metabolism in blood by hydrolysis of the methyl ester

inactive acid metabolites

elimination half-time 10 minutes

poor lipid solubility; limits transfer into the CNS or across the placenta

dosage: (peri-operative)= 0.5 to 1mg/kg over 15-30sec

infusion 50-300mcg/kg/min

1. Antiadrenergic Agents (cont)

Alpha ReceptorsPrazosin

Terazosin

Beta ReceptorsPropanolol, Metoprolol, Atenolol

Alpha-Beta receptorsLabetolol

LABETOLOL

Both alpha & beta (ratio1:7)

selective alpha-1 antagonist (1/5 to 1/10 as potent as phentolamine); presynaptic alpha-2 receptors are spared

nonselective beta-1 and beta-2 antagonist (1/4 to 1/3 as potent as propranolol)

useful in Mx of PIH

Pharmacokinetics Labetolol

extensive first pass metabolism30-40% bioavailabilitymetabolism is by conjugation to glucuronic acid< than 5% excreted unchanged in the urineelimination half-time is 5 to 8 hours (prolonged in liver disease and unchanged in renal dysfunction)

Dosage and Administration Labetolol

oral dose of 100-400mg per day

severe HPTmultiple bolus dose 20-40mg every 10-15 mins (up to 300mg)

continous infusion 2mg/min (up to 150mg)

intraop/postop HPT or induced hypotension during anaesthesia

lower starting multiple bolus dose of 5-10mg

Side Effects Labetolol

orthostatic hypotension (most common)

beta-antagonists effects (bronchospasm, congestive heart failure, heart block, fatigue, mental depression

fluid retention



Methyldopa



CLONIDINE

centrally acting alpha-2 agonist

stimulates alpha-2 inhibitory neurons in the medullary vasomotor center

resulting in reduction of SNS outflow from the CNS to peripheral tissues

manifested as decreases in BP, HR and CO

Pharmacokinetics Clonidine

well absorbed after oral administration

daily adult dose is 0.2 to 0.3 mg orally (bd)

60% of the drug excreted unchanged in the urine

duration of action; 8 hours

elimination half-time; 8.5 hours

Side Effects Clonidine

dry mouth

sedation

withdrawal syndrome; hyperadrenergic states resembling phaechromocytoma

retention of Na + and water

skin rashes

constipation

METHYLDOPA

serves as an alternative substrate to dopa

decarboxylated to methyldopamine and beta-hydroxylated to alpha methylnorepinephrine

inhibits SNS from the vasomotor center to the periphery

resulting in decrease SVR and BP

Pharmacokinetics Methyldopa

daily adult dose is 250 to 2000mg (bd)

incomplete absorption (25-50%)

low protein binding 15%

maximal effect within 4 to 6 hrs after an oral dose and persists for as long as 24 hrs

Side Effects Methyldopa

Sedation

Hepatic dysfunction, necrosis; maybe fatal

Positive Coombs' test (10-20%)

Rebound hypertension

Retention of Na + and water

Sexual dysfunction

Bradycardia


Central Nervous SystemClonidineMethyldopa


Nerve endingsReserpineGuanethidine

TRIMETAPHAN

peripheral vasodilator and adrenergic ganglionic blocker

directly relaxes capacitance vessels and blocks autonomic nervous system reflexes

decreases CO and SVR; hence lowering BP

increases in HR; most likely reflect PNS ganglionic blockade

Side effects Trimetaphan

Mydriasis

Reduced gastrointestinal activity; ileus

Urinary retention

Histamine release



Methyldopa



RESERPINE

interferes with the cathecholamines uptake into the storage vesicles

depletes stores of catecholamines

decreased CO and bradycardia leading to hypotension

Side Effects Reserpine

Orthostatic hypotension (prominent)

Sedation and drowsiness

Mental depression

Signs of PNS predominance include bradycardia, nasal stuffiness, xerostomia, increased gastric H+ secretion, and exaggerated gastrointestinal motility (abdominal cramps and diarrhea)

2. Vasodilators

Vascular Smooth MuscleHydralazine

Nitroprusside

HYDRALAZINE

phthalazine derivative decreases BP by a direct relaxant effect on vascular smooth muscle (on arterioles greater than veins)pronounced on the coronary, cerebral, renal, and splanchnic circulationsinterference with Ca2+ transport in vascular smooth muscle

Clinical Uses Hydralazine

usual adult dose is 20 to 40 mg qid

treatment of a hypertensive crisis; 2.5 to 10 mg IV (effect begins within 15 mins and lasts 3 to 4 hours)

Pharmacokinetics Hydralazine

extensive hepatic first-pass metabolism

metabolized partially by acetylation; slow and rapid acetylators

elimination half-time; 3 hours

< than 15% of the drug excreted unchanged in the urine

Side Effects Hydralazine

Na + and water retention vertigo, diaphoresis, nausea, and tachycardiamyocardial stimulation can evoke angina pectorislupus erythematosus-like syndrome (10% to 20%)drug fever, urticaria, polyneuritis, anemia, and pancytopenia, peripheral neuropathies

NITROPRUSSIDE

causes relaxation of arterial and venous vascular smooth muscle onset is almost immediate, and its duration is transient, continuous intravenous infusion to maintain a therapeutic effectextreme potency; necessitates careful titration of dosage and frequent monitoring of blood pressure

Mechanism of Action

produce NO, which activates the GC enzymeresults in increased conc of cGMP in smooth muscleleading to vasodilatation in arteries and veinsmay be sec to decreased Ca2+ entry into muscle cells or increased uptake by the SR

Clinical Uses Nitroprusside

hypertensive emergencies

induced hypotension during surgery

congestive cardiac failure; improve CO, due to decrease in LV impedance

rapid injection, 1 to 2 mg kg -1 IV obtund haemodynamic changes produced during intubation

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Thiocyanate

thiocyanate is cleared slowly by the kidney, with an elimination half-time of 4 to 7 days; (accumulates with prolonged therapy or in renal failure) clinical toxicity is rare (100x less toxic than cyanide)skeletal muscle weakness, nausea, and mental confusion (> 10 mg dl –1)

Cyanide Toxicity

dose-dependentshould be suspected

in any patient who is resistant to the hypotensive effects of the drug despite adequate infusion rates (up to 8 mg kg -1 min -1 IV)in a previously responsive patient who becomes unresponsive to the BP-lowering effects of the drug despite increasing doses (tachyphylaxis)

Cyanide Toxicity (cont)

mixed venous PO2 is elevated

development of metabolic acidosis

decreased cerebral oxygen use

CNS dysfunction in awake patients

Treatment of Cyanide Toxicity

immediate discontinuation

100% oxygen

NaHCO3

sodium thiosulfate, 150 mg kg -1 IV over 15 minutes, is a recommended therapy (acts as a sulfur donor to convert cyanide to thiocyanate)

Treatment of Cyanide Toxicity

severe case; slow administration of sodium nitrate, 5 mg kg -1 IV (convert Hb to metHb)

metHb acts as an antidote; converting cyanide to cyanmethemoglobin

hydroxycobalamin (vit B12); reacts with cyanide to form cyanocobalamin


Vascular Smooth MuscleVerapamil

Nifedipine

Pharmacological Effects

decreased myocardial contractility

decreased HR

decreased conduction rate through the AVN

vascular smooth muscle relaxation with assd vasodilation and reductions in SVR and BP; affect primarily arterial rather than venous vascular tone

Clinical Uses

Essential Hypertension

Supraventricular Tachydysrhythmias

Coronary Artery Vasospasm

Exercise-Induced Angina Pectoris

Cerebral Artery Vasospasm

Cerebral Protection

Myocardial Protection

NIFEDIPINEdihydropyridine derivative

arterial vasodilator (minimal effect on veins)

peripheral vasodilation and the resulting decrease in BP activate baroreceptors, leading to reflex tachycardia

Pharmacokinetics Nifedepine

absorption of an oral or SL dose is about 90%

onset within about 20 minutes

protein binding; 90%.

hepatic metabolism is nearly complete

elimination 80% in renal, remaining in bile

elimination half-time is 4 to 6 hours.

Clinical Use in Hypertension

rapid reduction in BP; orally or SL or by biting the capsule and swallowing its content

10-20mg produce significant hypotension within 15-30 mins

chronic therapyneeds tds dosing

combination with beta blocker to blunt reflex tachycardia

VERAPAMIL

synthetic derivative of papaverine

supplied as a racemic mixture

direct depressant effects on SAN and delay conduction via AVN (Tx of SVT)

mild vasodilating properties (Tx of angina and essential HPT)

Clinical Use in Hypertension

reduces elevated PVR in essential HPT

prevent significant increases in HR (effects on SAN)

chronic therapy; mild natriuretic effect, Na+ retention does not occur

dose ranges from 160 to 480 mg daily (bd)



Enalapril

Lisinopril


ACE Inhibitors

ACE converts inactive AT I to active AT IIAT II then acts to raise BP through;

Its potent vasoconstrictor effectBy stimulating secretion of aldosterone by the adrenal cortex; which acting through kidney, causes Na+ retention and expands IV volume

ACE is also responsible for the metabolism of bradykinin, which is a potent vasodilator

The four sites of action of inhibitors of the renin-angiotensin system. J-G = Juxtaglomerular apparatus; CE = converting enzyme

CAPTOPRIL

competitive inhibitor of ACE; therefore prevents the generation of AT II

inhibits AT II mediated vasoconstriction and aldosterone secretion

also inhibits breakdown of bradykinin; further contribute to its hypotensive effect

Pharmacokinetics Captopril

well absorbed after oral administration (60-70%)

onset; 15 minutes

half-life; 1.7 hrs

plasma protein binding is low (20-30%)

excreted both through metabolism and by urinary excretion of unchanged drug

Side Effects Captopril

skin rash sometimes acc. by fever and joint discomfort (10%) and pruritis

loss of taste sensation (1% to 2%)

proteinuria and elevations in [creatinine]

neutropenia (0.3%)

abrupt fall in BP after initial dose; esp in pts who are volume depleted

Side Effects Captopril

angioedema; drug-induced inhibition of the metabolism of bradykinin

cough and exacerbation of dyspnea and wheezing in COAD (kinin effects)

increase serum K + levels, esp in pts with impaired renal function



Enalapril

Lisinopril


LOSARTAN

AT II receptor blocker (type AT1); hence blocks the vasoconstrictor and aldosterone-secretion effects of AT II

25-50 mg once daily

extensive 1st pass metabolism

active metabolites is 10-40x more potent

can cause fetal morbidity and mortality

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PHOSPHODIESTERASE INHIBITOR mechanism of action

. Cyclic-AMP is broken down by an enzyme called cAMP-dependent phosphodiesterase (PDE).

Inhibition of this enzyme increases intracellular cAMP, which further inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation)

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Phosphodiesterase inhibitors

a) bypiridine derivatives

- amrinone , milrinone

b)imidazole - enoximone,pyroximone

c) methylxanthines - theophylline, caffein

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PHOSPHODIESTERASE INHIBITOR

cardiovascular action

Systemic circulation

-Vasodilatation

- Increased organ perfusion

- decreased SVR

- decreased atrial pressure

cardiopulmonary

- increased contractility & HR

-increased SV & ejection fration

- decreased ventricular pre-load

- decreased pul;monary capillary wedge pressure

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β2 adrenoceptor agonistVascular smooth muscle has β2-adrenoceptors that have a high binding affinity for circulating epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic nerves

These receptors are coupled to a Gs-protein, which stimulates the formation of cAMP.

, in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation

cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin.

increases in intracellular cAMP caused by β2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation)



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(β-agonists)-mech. of action

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Beta-AgonistsCardiac effects

• Increase contractility(positive inotropy)

• Increase relaxation rate(positive lusitropy)

• Increase heart rate(positive chronotropy)

• Increase conduction velocity(positive dromotropy)

Vascular effects

• Smooth muscle relaxation(vasodilation)

Other actions

• Bronchodilation

Hepatic glycogenolysis

• Pancreatic release of glucagon

• Renin release by kidneys

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QUESTIONS

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Thank You

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Dr Suryawan bin Tasref Department of Anaesthesiology & Intensive Care HSNZ