VASODILATORS
Dr Suryawan bin Tasref
Department of Anaesthesiology
& Intensive Care
HSNZ
CONTENT
Introduction
Classifications
Conclusion
INTRODUCTION
vasodilator = 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
3
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)
4
INTRO-CLINICAL USE
Vasodilators 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
5
CLASSIFICATION
By mechanism of action
1. Antiadrenergic Agents
2. Vasodilators
3. Renin-Angiotensin System Inhibitors
4. Calcium Channel Blocker
5. Phosphodiesterase inhibitor
6. Beta adrenoceptor agonist
6
1. Antiadrenergic Agents
Alpha-1 Receptors
Prazosin
Phenoxybenzamine
Phentolamine
Beta Receptors
Propanolol, Metoprolol, Atenolol, Esmolol
Alpha-Beta receptors
Labetolol
1. Antiadrenergic Agents
Central Nervous System
Clonidine
Methyldopa
Autonomic Ganglia
Trimetaphan
Nerve endings
Reserpine
2. Vasodilators
Vascular Smooth Muscle
Hydralazine
Minoxidil
Diazoxide
Nitroprusside
3. Calcium Channel Blocker
Vascular Smooth Muscle
Verapamil
Nifedipine
Diltiazem
4. Renin-Angiotensin System
Angiotensin Converting Enzyme Inhibitors
Captopril
Enalapril
Lisinopril
Angiotensin II Receptor Antagonists
Losartan
1. Antiadrenergic Agents
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
14
1. Antiadrenergic Agents
Alpha-1 Receptors
Prazosin
Phenoxybenzamine
Phentolamine
Beta Receptors
Propanolol, Metoprolol, Atenolol, Esmolol
Alpha-Beta Receptors
Labetolol
PRAZOSIN
quinazoline derivative
produces peripheral vasodilation; vascular tone in
both resistance(arterioles) and capacitance(veins)
vessels is reduced
resulting in decreased VR, CO and BP
not 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
vertigo
fluid retention
orthostatic hypotension
‘first dose phenomenon’ ; dizziness, faintness,
syncope soon after the administration of the first
dose
dryness 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 antagonism
less selective alpha blocker (3-5x alpha-1)
also acts at histamine and Ach receptors
administered intravenously
as a diagnostic test for phaechromocytoma; risk
of CVS collapse
to ctrl HPT during surgical removal of
phaechromocytoma
1. Antiadrenergic Agents (cont)
Alpha-1 Receptors
Prazosin
Phenoxybenzamine
Phentolamine
Beta Receptors
Propanolol, Metoprolol, Atenolol
Alpha-Beta Receptors
Labetolol
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
absorption
extensive hepatic first-pass metabolism
(70%); poor bioavailability
extensively 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 Receptors
Prazosin
Terazosin
Beta Receptors
Propanolol, Metoprolol, Atenolol
Alpha-Beta receptors
Labetolol
LABETOLOL
Both alpha & beta (ratio1:7)
selective alpha-1 antagonist (1/5 to 1/10 as
potent as phentolamine); presynaptic alpha2 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 metabolism
30-40% bioavailability
metabolism is by conjugation to glucuronic
acid
< than 5% excreted unchanged in the urine
elimination 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 HPT
multiple 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
1. Antiadrenergic Agents
Central Nervous System
Clonidine
Methyldopa
Autonomic Ganglia
Trimetaphan
Nerve endings
Reserpine
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
1. Antiadrenergic Agents
Central Nervous System
Clonidine
Methyldopa
Autonomic Ganglia
Trimetaphan
Nerve endings
Reserpine
Guanethidine
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
1. Antiadrenergic Agents
Central Nervous System
Clonidine
Methyldopa
Autonomic Ganglia
Trimetaphan
Nerve endings
Reserpine
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 Muscle
Hydralazine
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 circulations
interference 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
tachycardia
myocardial stimulation can evoke angina
pectoris
lupus 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 effect
extreme potency; necessitates careful
titration of dosage and frequent monitoring
of blood pressure
Mechanism of Action
produce NO, which activates the GC
enzyme
results in increased conc of cGMP in
smooth muscle
leading to vasodilatation in arteries and
veins
may 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-dependent
should 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
3. Calcium Channel Blocker
Vascular Smooth Muscle
Verapamil
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
NIFEDIPINE
dihydropyridine 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 therapy
needs 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)
4. Renin-Angiotensin System
Angiotensin Converting Enzyme Inhibitors
Captopril
Enalapril
Lisinopril
Angiotensin II Receptor Antagonists
Losartan
ACE Inhibitors
ACE converts inactive AT I to active AT II
AT II then acts to raise BP through;
Its potent vasoconstrictor effect
By 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 (6070%)
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
4. Renin-Angiotensin System
Angiotensin Converting Enzyme Inhibitors
Captopril
Enalapril
Lisinopril
Angiotensin II Receptor Antagonists
Losartan
LOSARTAN
AT II receptor blocker (type AT1); hence
blocks the vasoconstrictor and aldosteronesecretion 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
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)
81
Phosphodiesterase inhibitors
a) bypiridine derivatives
- amrinone , milrinone
b)imidazole - enoximone,pyroximone
c) methylxanthines - theophylline, caffein
82
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
83
β2 adrenoceptor agonist
Vascular 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 β2agonists inhibits myosin light chain kinase thereby
producing less contractile force (i.e., promoting 84
(β-agonists)-mech. of action
85
Beta-Agonists
Cardiac 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
86
QUESTIONS
87
Thank You