Download Adrenoceptor Antagonists

Adrenoceptor Antagonists
α-Adrenoceptor Antagonists
Non-selective
Selective
 Irreversible antagonist  α -adrenergic
1
phenoxybenzamine,
antagonists:
that binds covalently
prazosin, doxazocin
to receptor, long
& tamsulosin (α1Aduration of action of
blocker)
14-48 hours
 α2-adrenergic
 Reversible competitive antagonists:
antagonist
yohimbine &
phentolamine &
rauwolscine
tolazoline
Nonselective α-receptor
antagonists
Vascular & Blood Pressure Effects
 By blocking postsynaptic α1-adrenoceptors,
they produce vasodilation, & decreased total
peripheral resistance and a fall in blood
pressure opposed by stimulation of peripheral
sympathetic activity via blockade of the
presynaptic α2-adrenoceptors
 Postural hypotension via blockade of reflex
sympathetic control of capacitance vessels
upon standing
Cardiac Effects
 Reflex tachycardia mainly via α2-receptor
blockade because the inhibitory effect on
NE release is blocked and peripheral NE
release is increased stimulating β1 cardiac
receptors
Therapeutic Uses Nonselective αReceptor Antagonists
 Treatment of pheochromocytoma which is a
tumor of adrenal gland which secretes NE &
EP leading to signs of excessive
catecholamine including hypertension,
tachycardia & arrhythmias
 Preoperative control of severe hypertension
resulting from tissue manipulation in patient
undergoing pheochromocytoma surgery
 Treatment of Raynaud’s disease
Major Side Effects αReceptor Antagonists
 Postural hypotension
 Reflex tachycardia
 Inhibition of ejaculation
 Nasal stuffiness
Selective α1-receptor
antagonists
Vascular & Blood Pressure Effects
 Blocking the vascular postsynaptic α1-
adrenoceptors, produce vasodilation, &
decrease total peripheral resistance and
a powerful fall in blood pressure
 Unopposed by blockade of the
presynaptic α2-adrenoceptors that
doesn’t occur and hence the blood
pressure lowering efficacy is high
CVS Effects
 Postural hypotension is much less
pronounced than the non-selective αblockers possibly because of lower effect
on veins
Cardiac effects
 They may cause reflex tachycardia
mediated via baroreceptors
Therapeutic Uses
 Treatment of mild hypertension alone or in
combination with other antihypertensives such
as thiazide diuretics or β-blockers in moderate
or severe hypertension
 Treatment of benign prostatic hypertrophy.
Blockade of α1-adrenoceptors at the base of
the bladder and the prostate possibly reduces
the symptoms of obstruction and the urinary
urgency
o Tamsulosin has antagonistic affinity to α1A
receptors (in vas deferens) more than to α1B in
vascular smooth muscles
Beta (β)-Adrenergic Antagonists
(β-blockers)
Non-selective βCardioselective β1adrenergic
adrenoceptor
antagonists
Antagonists
 blocking the effects  preferentially block
of sympathetic
the cardiac β1
stimulation upon all
adrenergic receptors
subtypes β-receptors with little effect on β2 propranolol, pindolol, receptors
nadolol, and timolol  metoprolol, atenolol,
acebutalol & esmolol
β-Adrenergic Antagonists with Intrinsic
Sympathomimetic Activity (ISA)
 Pindolol and acebutolol are -adrenergic
antagonists in presence of catecholamines
 In addition, they possess a partial AGONISTIC
activity on -adrenergic receptors
 Hence, they cause less bradycardia than
propranolol, and can be preferred in patients with
bradycardia
 Acebutolol is a selective -adrenergic antagonist,
but metabolised into a non-selective antagonist
Pharmacological Actions of
β-Blockers
Cardiac effects
 Negative chronotropic effects especially at
high sympathetic discharge as during
exercise
 Decreased cardiac force of contraction. Peak
cardiac tension & rate of cardiac tension rise
(contraction velocity) are reduced leading to
lowered stroke volume, and increased endsystolic (residual) cardiac volume
 As a result, the cardiac output decreases
Cardiac Effects of βBlockers
 Decreased cardiac oxygen consumption as a
result of reduced cardiac work (decreased
heart rate, ventricular systolic pressure &
contractility)
 Blocked sympathetic tone to A-V node &
hence vagal action predominates and
atrioventricular conduction velocity decreases
 Depression of pacemaker activity
(automaticity)
Vascular Effects of βblockers
Acute administration
vasoconstriction (increased peripheral
resistance)
 Unopposed α-mediated vasoconstriction in vascular
beds containing both the α- & β-adrenoceptors
 Reflex increase in sympathetic tone as a result of
reduced cardiac output
Vascular Effects of βblockers
Chronic administration
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Decreased blood pressure possibly
decreased cardiac output
antagonism of β-receptors in the CNS
blocking the facilitator presynaptic β-adrenoceptors
on sympathetic nerves
reduction of renin release from juxtaglomerular
apparatus and hence reduced angiotensin II and
aldosterone levels
Peripheral vasoconstriction through:
Unopposed α-mediated vasoconstriction in vascular
beds containing both the α- & β-adrenoceptors
Reflex increase in sympathetic tone as a result of
reduced cardiac output
Bronchiolar Smooth Muscle
 Propranolol antagonizes the β-adrenoceptor
mediated bronchodilation
 Augmenting ACh- & histamine-induced
bronchospasm; airway resistance is increased
 β-blocker bronchospasm is seriously
dangerous in asthmatics
Metabolic Effects
Fat metabolism
 β-blockers inhibit
catecholamineinduced increase in
lipolysis and the
increase of plasma
free fatty acids
Carbohydrate metabolism
 β-blockers enhance
hypoglycemia by inhibiting
catecholamine-stimulated
hepatic glycogenolysis
(important for diabetic
patients)
 After insulin injection or
exercise, β-blockers delay
the recovery of blood
glucose (hypoglycemia)
Therapeutic Uses of β-
blockers
 Treatment of hypertension: Selective β1-blockers
are preferable in asthmatic & diabetic patients and
in patients with Raynaud’s disease
 Myocardial Infarction (MI):
• β-blockers administered 1-4weeks after MI reduce
much the probability of myocardial re-ifarction
possibly by reducing cardiac work.
• β-blockers given immediately (few hours) after MI
reduces the infarct size and enhance cardiac
reperfusion and recovery; timolol, propranolol, and
metoprolol are used
Therapeutic Uses of βblockers
 Chronic Treatment of Glaucoma (Mainly Propranolol,
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timolol are used)
They decrease the formation of aqueous humor by
ciliary body reducing the IOP
They don’t affect accommodation for near vision nor
affect pupil size as cholinergic agonists do
Pilocarpine is of choice in acute attacks
Chronic Migraine: Propranolol is used in treatment
of migraine where it reduces the severity of attacks
and lowers their frequency
Possibly via inhibition of catecholamine-induced
cerebral vasodilation
Therapeutic Uses of β-
blockers
 Treatment of effort angina but not variant angina
 Hyperthyroidism: β-blockers control the symptoms of
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excessive sympathetic stimulation (adjuvant therapy)
Cardiac supraventricular arrhythmias to stop conversion of
atrial to ventricular arrhythmia. β1-receptor blockade results
in the following:
decreased firing rate of SA node
decreased AV conduction & prolongation of AV-nodal
refractory period
decreased ventricular response to atrial flutter
Esmolol is a cardio-selective β1-blocker that is used only
by IV route for emergency treatment of supraventricular
arrhythmias arising during surgery
Side Effects of β-blockers
 Hypoglycemia that is much pronounced in
patients with diabetes especially after insulin
injection or oral hypoglycemic
 Severe cardiac slowing & lowered cardiac
contractility make the use of β-blockers cautious
in cases of sinus bradycardia, partial heart block
& severe congestive heart failure
Side Effects of β-blockers
 Dysrhythmias or anginal attacks may develop
after withdrawal of β-blockers from long term
patients
o This may be due to adrenergic receptor
super-sensitivity mediated by receptor upregulation or re-enhancement of sympathetic
cardiac drive
o Dosage of β-blockers should be tapered off
gradually over 1-2 weeks
Side Effects of β-blockers
 Bronchoconstriction: β2-receptor blockade can
produce an increase airway resistance in patients
with asthma; selective β1-blockers should be
used in asthmatics
 Peripheral vascular disease vasoconstriction
is aggravated in presence of β-blockers because
of uncovering the α1-adrenoceptor-mediated
vasoconstriction in response to endogenous
catecholamines
 Sexual dysfunction via undetermined
mechanism, apparently β-adrenoceptorsindependent
Combined α- & β-adrenoceptor
Antagonists
 Labetalol and carvedilol are competitive antagonists for
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catecholamines at α1-, β1- and β2-adrenergic receptors
They don’t cause peripheral vasoconstriction
Carvedilol, has additive antioxidant activity and protect
against vascular thickening (remodeling)
These two extra properties made it of value in treatment
of some cases of heart failure
Labetalol is preferable in treatment of hypertension of
elderly & black patients to avoid peripheral
vasoconstriction
Black hypertensive patients are usually resistant to βblockers
IV labetalol is used in hypertensive emergencies &
preoperative pheochromocytma management
Indirectly Acting Adrenergic
Blockers
Reserpine
Mechanism of Action:
 Potent inhibition of transporters responsible for
neuronal vesicular NE uptake from neuronal
cytoplasm (as well as other biogenic amines)
 Inhibition of vesicular storage capacity
 Hence, NE leaks into cytoplasm to mitochondria
where it is catabolizstores are depleteded by
MAO
 Ultimately peripheral & central NE (together with
DA & 5-HT)
Reserpine
 Actions & Uses:
 Reduction of vascular tone at small arteries & veins
as a result of peripheral adrenergic
neurotransmitter depletion
 Bradycardia & reduced cardiac output a s a result
of decreased 1-mediated actions
 It mayy be used in hypertension resistant to other
agents
 Centrally, it may cause depression, nightmares and
parkinsonism
 It increases tone & motility of GIT as well as gastric
HCl secretion
Guanethidine
 It inhibits neuronal release of NE
 It is actively taken by adrenergic nerve terminals
competing with NE for the same transporter
proteins
 Therefore, intra-neuronal NE concentration
decreases and its release is diminished
 It is rarely used in hypertension
Effects of -Adrenergic
Receptor Antagonists
1-Adrenergic Receptor:
Bradycardia
Decreased AV nodal conduction velocity
Decreased pacemaker cells activity
Decreased forve of contraction (reduced stroke volume,
increased end-systolic volume & decreased cardiac
output)
 Decreased O2 consumption
 Reduced renin release (decreased ang II)
 Edema formation (decrased cardiac output
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2 -Adrenergic Receptor
 Peripheral vasoconstriction in some areas
 Decreased glcogenolysis & insulin release
 Decreased adrenergic mediated tremors