Transcript Sympatholytics

Adrenergic Antagonist
(Sympatholytics)
 Inhibition of sympathetic system
by blocking:
 Adrenergic receptors (reversible or
irreversible blocking of α or/and β
receptors)
 Adrenergic neurons (blocking uptake
or release)
Adrenergic Blocking Drugs





These drugs competitively inhibit α and β receptor sites.
α receptors, α1, α2.
One group of drugs is specific for both β1 and β2 receptors.
One group is specific for β2 receptors.
One group is specific for both α and β receptors.
Adrenergic Receptor Antagonist
 α-Blockers:
- Non selective: Phenoxybenzamine & Phentolamine
- α1-Blocker: Prazosin, Terazosin, Doxazosin & Tamsulosin
- α2-Blocker: Yohimbine (Sympatholytic ?)
 β-Blockers:
- Non selective: Propranolol, Timolol & Nadolol
- β1-Blocker: Atenolol, Metoprolol & Esmolol
- β1-Blocker with partial β2 agonist activity: Acebutolol & Pindolol
 α & β Blocker: Labetalol & carvidilol
Effects of α-adrenoceptor Antagonists

The most important effect is CVS effect
They block α1 receptors causing decrease in
peripheral resistance and consequently BP
The resultant hypotension provokes reflex
tachycardia


For non selective α-antagonists, the main differences between
phenoxybenzamine and phentolamine are:
 Phenoxybenzamine is a prodrug that takes few hrs for biotransformation
while phentolamine is not a prodrug
 Phenoxybenzamine bind covalently (irreversible binding) to α receptors
and so the activity last for about 28 hrs. On the other hand, phentolamine
is competitive blocker (reversible binding), so the activity last for 4hr.
–

For selective α1 blockers like prazosin (Minipress) and
terazosin, they are competitive blocker of α1 receptors
causing profound vasodilation and decrease in arterial BP.
The hypotensive effect is more dramatic than non selective.
Yohimbine blocks α2 causing increase in sympathetic
flow and so BP. is sometimes used as a sexual
stimulant.
Clinical uses of α-adrenoceptor antagonists


Hypertension: α1 selective blockers are more preferred e.g.
prazosin. They are used alone or in combination with other
antihypertensive drugs
Phaeochromocytoma: A combination of α- and β- receptor
antagonists is the most effective way of controlling the BP
e.g. phenoxybenzamine and atenolol


Flomax (tamsulosin). Used in BPH. Produces smooth
muscle relaxation of prostate gland and bladder neck.
Minimal orthostatic hypotension.
Priscoline
(tolaxoline)
used
for
Pulmonary
hypertension in newborn.
Adverse effects of α-adrenoceptor antagonists


1st dose effect: syncope. With alpha 1 blockers,
first dose syncope may occur from
hypotension. Give low starting dose and at hs.
Postural hypotension

Tachycardia (α1-selective produce less
tachycardia because they do not increase NA
release from sympathetic nerve terminal)

Prazosin may cause sodium & water retention,
therefore it is frequently used with a diuretic
Orthostatic hypotension dentistry



Orthostatic hypotension is a problem with prazosin
analogs and to a lesser extent tamsulosin.
Significantly, orthostatsis is a problem that can be
seen with any vasodilator that affects the tone on
venous smooth muscle.
This would include, organic nitrates, hydralazine,
clonidine, minixodil and the many drugs.
Orthostatic hypotension or postural hypotension
occurs when systemic arterial blood pressure falls by
more than 20 mmHg upon standing.
 In this situation, cerebral perfusion falls and an individual may
become light headed, dizzy or fatality may occur.

In changing from the supine to the standing position, gravity
tends to cause blood to pool in the lower extremities. However,
several
reflexes,
including
sympathetically
mediated
venoconstriction minimize this pooling and maintain cerebral
perfusion. If these reflex actions do not occur, then orthostatic
hypotension could result.

By blocking the alpha1-receptors associated with
venous smooth muscle, prazosin-like drugs, inhibit the
sympathetically mediated vasoconstriction associated
with postural changes. Hence, orthostatic hypotension
can occur.
Drugs like clonidine cause orthostasis due to its CNS
actions that block the sympathetic reflexes.
Vasodilators such as nitrates, minoxidil, hydralazine or
impotence medications cause orthostasis because of
their actions directly on the vasculature.


β-adrenoceptor antagonists

They are all competitive blocker, most of them are nonselective
or β1 blocking activity (cardioselective)
 β-Blockers:
- Non selective: Propranolol, Timolol & Nadolol
- β1-Blocker: Acebutolol, Atenolol, Metoprolol & Esmolol
- β1-Blocker with partial β2 agonist activity: Acebutolol & Pindolol
Beside β blocking activity, some blockers may possess one or
more of the following properties:
 Intrinsic Sympathetic Activity (ISA): i.e. they have the ability to
stimulate the occupied receptors, hence known as partial
agonist e.g. pindolol
 Membrane stabilizing activity: i.e. inhibit depolarization of
excitable membrane (by blocking Na+ channels) and so they
have antiarrhythmic and local anaesthetic action e.g.
propranolol

They have ISA
Intrinsic Sympathomimetic Activity
Effects of β-adrenoceptor antagonists

Cardiovascular:
–
–
–
Heart:
 -ve chronotropic & inotropic (↓CO, O2 consumption & HR)
 ↓excitability (antiarrhythmic effect)
 ↓Conductivity (heart block in large dose)
BV:
 Block β2 mediated VD
 No postural hypotension (No α effect)
 Reflex VC due to ↓CO & BP and so ↓ blood flow to the
periphery
BP: ↓ with no reflex tachycardia
• Reduction in CO
• Reduction in renin release
Effects of β-adrenoceptor antagonists

Bronchial smooth muscles:
• In asthma & obstructive pulmonary disease, they can cause
severe bronchoconstriction. This danger is less with β1
selective blocker

Metabolism:
• Inhibition of glycogenolysis (Caution with insulin treatment?)
• Inhibition of glucagon release
• Hypertriglyceridemia & hypercholesterolemia




Decreased production of aqueous humor in
eye
May increase VLDL and decrease HDL
Diminished portal pressure in clients with
cirrhosis
Decreased renin production.
Receptor selectivity



Acetutolol, atenolol, betaxolol, esmolol, and
metoprolol are relatively cardioselective
These agents lose cardioselection at higher
doses as most organs have both beta 1 and
beta 2 receptors.
esmolol is the most rapidly acting, short t ½ (8
minutes), given only IV for management of
arrhythmia.
Non-Receptor selectivity


Carteolol, levobunolol, metipranolol, nadolol,
propranolol, sotalol and timolol are all nonselective
Can cause bronchoconstriction, peripheral
vasoconstriction and interference with
glycogenolysis
Combination selectivity




Labetalol and carvedilol (Coreg) block alpha 1
receptors to cause vasodilation and beta 1 and
beta 2 receptors which affect heart and lungs
Both alpha and beta properties contribute to
antihypertensive effects
May cause less bradycardia but more postural
hypotension
Less reflex tachycardia
Intrinsic sympathomimetic activity




Have chemical structure similar to that of
catecholamines
Block some beta receptors and stimulate
others
Cause less bradycardia
Agents include: acebutolol, penbutolol and
pindolol
Clinical Uses of β-adrenoceptor antagonists
Cardiovascular:

•
Hypertension:
•
•
•
They are used alone or in combination.
Mixed α & β blocker, labetalol, is often used in preeclamptic
toxaemia (a form of hypertension occurring late in pregnancy)
Angina pectoris
•
•
↓ Cardiac work & O2 consumption by decreasing rate, BP and
contractility
Chronic management of stable angina (not acute treatment)
•
Cardiac arrhythmias
•
Following myocardial infarction:
•
It is preferred to give β-blocker immediately following a
myocardial infarction to reduce infarct size by blocking the
action of circulating catecholamines

Useful in pheochromocytoma in conjunction
with alpha blockers (counter catecholamine
release)
Clinical Uses of β-adrenoceptor antagonists (cont.)
•
Glaucoma: Open angel
•
•
•
•
Hyperthyroidism :
•
•
Particularly timolol, used as eye drops
↓ secretion of aqueous humor by the ciliary body
They do not affect the ability of eye to focus for near vision or
pupil size
Preoperatively in thyrotoxicosis by blocking sympathetic
stimulation that occurs in hyperthyroidism, particularly cardiac
arrhythmia
Migraine:
•
as prophylaxis by blocking catecholamine-induced VD in the
brain vasculature
Specific condtions-beta blockers



With significant bradycardia, may need
medication with ISA such as pindolol and
penbutolol
Patient with asthma, cardioselectivity is
preferred
For MI, start as soon as patient is
hemodynamically stable
Special conditions—beta blocers

Should be discontinued gradually. Long term
blockade results in increase receptor sensitivity
to epinephrine and norepinephrine. Can result
in severe hypertension. Taper 1-2 weeks.
Adverse effects of β-adrenoceptor antagonists


Bronchoconstriction
Cardiac failure (large dose), May worsen condition of
heart failure as are negative inotropes

Hypoglycemia
(with
reduced
awareness
hypoglycemia in patients receiving insulin)
of

Physical fatigue (due to reduced cardiac output and
reduced muscle perfusion in exercise)

Cold extremities
Adrenergic Neuron Antagonists

They act by:
↓NA Synthesis
e.g. α-methyltyrosine, carbidopa
& α-methyldopa
–
↓NA Storage
e.g. Resepine
–
↓NA Release
e.g.Guanthidine
–
Inhibitors of NA Synthesis

α-methyltyrosine:
–
–

It inhibits tyrosine hydroxylase
Not used clinically
Carbidopa:
–
–
It inhibits dopa decarboxylase
Its main use is an adjunct to
treatment of Parkinsonism with Ldopa
Inhibitors of NA Synthesis

α-methyldopa:
 It is taken up by noradrenergic neurons, where it is
decarboxylated and hydroxylated
transmitter, α-methyl-nor-adrenaline
to
form
the
false
 The false transmitter is released in the same way as NA but
differ in two points:
- It is less active than NA on α1 receptors and thus it is less
effective in causing vasoconstriction
- It is more active on presynaptic α2 receptors and so stimulates
autoinhibitory feedback mechanism
 It is used in treatment of hypertension
Inhibitors of NA Storage

Reserpine
 a plant alkaloid
 It acts by blocking ATP-dependent transport of NA and other
amines (e.g. 5-HT & dopamine) into synaptic vesicles,
apparently by binding to the transport protein → depletion of
NA from the adrenergic neurons
 It induces a gradual decrease in BP with concomitant slowing
of heart rate. It has slow onset and longer duration of action
(persist for many days after stopping)
 Used for hypertension resistant to other treatment
Inhibitors of NA Release

Guanthidine
 Overall, the principle action of guanthidine involves its
accumulation by the synaptic vesicles, which are then
unable to fuse with the cell membrane in the normal way, so
the exocytosis is prevented i.e. Stop the release
 It induce transient increase in BP because guanthidine
displace NA in its storage sites
 At large doses, it causes structural damage of
noradrenergic neurons
 It is no longer used clinically