Download 07 Adrenoceptor-antagonist

Adrenoceptor blockers
Overview
• The adrenergic blockers (also called sympathlytic
agents) bind to adrenoceptors but do not trigger the
usual receptor-mediated intracellular effect
• These drugs act by either reversibly or irreversibly
blocking the receptor, thus preventing its activation
by endogenous catecholamines
• The adrenergic antagonists are classified according
to the their relative affinities for α or β receptors
α-adrenoceptor blocking drugs
α-adrenoceptor antagonist drugs
Introduction
• The main groups of α-adrenoceptor antagonists
are:
1) Non-selective
α-receptor
antagonists:
phentolamine
2) α1-selective
antagonists:
prazosin,
doxazosin, terazosin
3) α2-selective
antagonists:
yohimbine,
idazoxan
α-adrenoceptor antagonist drugs
Pharmacologic effects
A. Cardiovascular effects
I. α1 Receptor Antagonists:
• Blockade of α1 receptors inhibits vasoconstriction
induced by endogenous catecholamines
• Vasodilation may occur in both arteriolar resistance
vessels and veins. The result is a fall in blood
pressure due to decreased peripheral resistance
(epinephrine reversal)
•
The fall in blood pressure is opposed by
baroreceptor reflexes that cause increases in heart
rate and cardiac output, as well as fluid retention
α-adrenoceptor antagonist drugs
Pharmacologic effects
A. Cardiovascular effects
I. α1 Receptor Antagonists:
• These reflexes are exaggerated if the antagonist
also blocks α2 receptors on peripheral sympathetic
nerve endings, leading to enhanced release of
norepinephrine and increased stimulation of
postsynaptic β1 receptors in the heart and kidney
α-adrenoceptor antagonist drugs
Pharmacologic effects
A. Cardiovascular effects
II. α2 Receptor Antagonists:
• Blockade of α2 receptors in the CNS and on
sympathetic
nerve
endings
can
increase
sympathetic outflow and potentiate the release of
norepinephrine from nerve endings, leading to
activation of α1 and β1 receptors in the heart and
peripheral vasculature with a consequent rise in
blood pressure
α-adrenoceptor antagonist drugs
Pharmacologic effects
B. Other effects
• The eye: blockade of α1 -receptors in the eye elicits
miosis
•
The nasal cavity: blockade of α1 -receptors elicits
nasal stuffiness
•
The genitourinary tract: blockade of α1 -receptors
in the base of the bladder and the prostate
decreases resistance to the flow of urine
α-adrenoceptor antagonist drugs
Specific agents
1. Phenoxybenzamine
• Irreversible α-receptor antagonist with long duration
of action (14–48 hours or longer)
• Phenoxybenzamine is somewhat selective for α1
receptors but less than prazosin
• It may inhibit the reuptake of released norepinephrine
by presynaptic adrenergic nerve terminals
• It also antagonizes the actions of histamin (H1),
acetylcholine, and 5-HT
α-adrenoceptor antagonist drugs
Specific agents
2. Phentolamine
• It is a potent competitive α receptor antagonist that
has similar affinities for α1 and α2 receptors. Its action
is short-lasting (4-hours)
• It has minor inhibitory effects at serotonin receptors
and agonist effects at muscarinic and H1 and H2
histamine receptors
α-adrenoceptor antagonist drugs
Specific agents
3. Prazosin, terazosin, and doxazosin
• Are selective competitive α1 receptor antagonists
• It decrease peripheral vascular resistance and lower
arterial blood pressure by causing the relaxation of
both arterial and venous smooth muscle., as well as
smooth muscles in the prostate
• Associated with less tachycardia than occurs with
non-selective α-receptor antagonists
α-adrenoceptor antagonist drugs
Specific agents
4. Tamsulosin
• Is a selective α1 antagonist with high affinity for
α1A (smooth muscles of the prostate) and α1D
than α1B subtype
• This selectivity accounts for its relatively minimal
effect on blood pressure and its use in BPH
α-adrenoceptor antagonist drugs
Clinical uses
A. Pheochromocytoma: Phenoxybenzamin
B. Chronic Hypertension: α1-selective antagonists
e.g. prazosin, doxazosin, and terazosin
C. Peripheral vascular disease (e.g. Raynaud's
phenomenon): prazosin or phenoxybenzamine
D. Urinary obstruction in patients with benign
prostatic hyperplasia (BPH): selective α1 receptor
antagonists (Prazosin, doxazosin, and terazosin,
tamsulosin)
Raynaud's phenomenon
α-adrenoceptor antagonist drugs
Adverse effect
1) Orthostatic hypotension: especially first dose of
selective α1 antagonist prazosin and non-selective
agents
2) Marked reflux tachycardia (non selective agents):
contraindicated in patients with decreased coronary
perfusion
3) Nasal stuffiness
4) Inhibition of ejaculation (non-selective agents)
5) CNS: fatigue, sedation, & nausea
(phenoxybenzamine)
β-adrenoceptor blocking drugs
Introduction
• They differ in their relative affinities for β1 and β2
receptors, intrinsic sympathimimetic activity, in CNS
effect, and in pharmacokinetics
• None of the clinically available β-receptor antagonists
are absolutely specific for β1 receptors: their
selectivity is dose-dependent; it tends to diminish at
higher drug concentrations
• There are no clinically useful β2 antagonists
• The names of all β-blockers end in “-olol” except for
labetalol and carvedilol
Pharmacokinetic Properties of the BetaReceptor Antagonists
• Absorption: well absorbed after oral administration
& peak concentrations occur 1–3 hours after
ingestion
• Bioavailability: on average, only about 25% of
propranolol, the prototype of β–blockers, reaches the
systemic circulation b/c it undergoes extensive
hepatic first-pass metabolism
Pharmacokinetic Properties of the BetaReceptor Antagonists
• Distribution: the β–adrenergic antagonists are
rapidly distributed and have large volumes of
distribution. Propranolol and penbutolol are quite
lipophilic and readily BBB
• Clearance: most β–adrenergic antagonists have
elemination half-lives in the range of 3–10 hours
• Esmolol has a half-life of about 10 minutes. The drug
contains an ester linkage, and it is hydrolyzed rapidly
by esterases in erythrocytes
β-adrenoceptor antagonist drugs
Pharmacologic effects
A. Cardiovascular effects
•
Blocked of β1-receptor will produce both negative
inotropic and chronotropic effects on the heart: cardiac
output, work, and oxygen consumption are decreased
•
Blockade of
vasodilation
•
Blocked of receptors in the kidney will inhibit the release
of renin caused by the sympathetic nervous system
•
This decreased blood pressure/hypotensive effect
triggers a reflex peripheral vasoconstriction that is
reflected in reduced blood flow to the periphery
β
receptors
prevents
β2-mediated
β-adrenoceptor antagonist drugs
Pharmacologic effects
b. Respiratory system: blockade of the β2 receptors
in bronchial smooth muscle may lead to an increase
in airway resistance, particularly in patients with
asthma & COPD
c. Local anesthetic action, also known as
"membrane-stabilizing" action, is a prominent effect
of several β-blockers (e.g. acebutolol, labetalol,
metoprolol, & penbutolol)
β-adrenoceptor antagonist drugs
Pharmacologic effects
d. Metabolic and endocrine effect
• β-Receptor antagonists modify the metabolism of
carbohydrates and lipids
• β–blockade lead to decreased glycogenolysis in the
human liver and decreased glucose release (β2receptor blockade)
• Therefore, β-blockers should be used with caution in
type I diabetic patients
β-adrenoceptor antagonist drugs
Pharmacologic effects
d. Metabolic and endocrine effect
• The chronic use of selective β1- and non selective βadrenoceptor antagonists has been associated with
increased plasma VLDL and decreased of HDL
cholesterol
• Such effect is less likely to occur with blockers
possessing intrinsic sympathomimetic activity (partial
agonists)
β-adrenoceptor antagonist drugs
Specific agents
I. Nonselective β-adrenergic antagonists
• Agents: propranolol (prototype), timolol,
nadolol, levobunolol , & Carteolol
• They lack selectivity and block both β1 and β2
receptors with equal affinity
β-adrenoceptor antagonist drugs
Specific agents
II. β1-adrenergic antagonists (cardioselective)
• Agents: metoprolol, acebutolol, atenolol, esmolol,
bisoprolol, & nebivolol
• Drugs that preferentially block the β1 receptors :
eliminate the unwanted bronchoconstrictor effect (β2
effect) of propranolol seen among asthmatic
patients
•
β1-selective antagonists may be preferable in
patients with diabetes or peripheral vascular
disease when therapy with a blocker is required
β-adrenoceptor antagonist drugs
Specific agents
II. β1-adrenergic antagonists (cardioselective)
• Nebivolol is the most highly selective β1-adrenergic
receptor blocker, and it has the additional quality of
eliciting vasodilation
• This may be due to an action of the drug on
endothelial nitric oxide pathway
β-adrenoceptor antagonist drugs
Specific agents
III. Partial β-adrenergic agonists
• Agents: Pindolol, acebutolol, carteolol, bopindolol,
oxprenolol, celiprolol, & penbutolol
•
They have the ability to weakly stimulate both β1
and β2 receptors and are said to have intrinsic
sympathomimetic activity (ISA)
β-adrenoceptor antagonist drugs
Specific agents
III. Partial β-adrenergic agonists
•
The result of these opposing actions is a much
diminished effect on cardiac rate and cardiac output
compared to that of β-blockers without ISA.
Therefore, these partial agonists may be less likely
to cause bradycardia
•
They minimize the disturbances of lipid and
carbohydrate metabolism that are seen with other βblockers
β-adrenoceptor antagonist drugs
Specific agents
III. Antagonists of both α- and β-adrenoceptors
• Agents: Labetalol, carvedilol, medroxalol, &
bucindolol
• These are reversible β-blockers with concurrent α1blocking
actions
that
produce
peripheral
vasodilation, thereby reducing blood pressure
•
They contrast with the other β-blockers that produce
peripheral vasoconstriction, and they are therefore
useful in treating hypertensive patients for whom
increased peripheral vascular resistance is
undesirable
Therapeutic uses of Beta-Receptor–Blocking
Drugs
I. Cardiovascular applications
a) Hypertension
b) Ischemic heart disease (IHD)
c) Heart failure
d) Cardiac arrhythmias
Therapeutic uses of Beta-Receptor–Blocking
Drugs
II. Non-cardiovascular applications
A. Glaucoma: topical administration of beta-blockers
(e.g. timolol, betaxolol, carteolol, levobunolol, and
metipranolol) reduces intraocular pressure by
decreasing the production of aqueous humor by the
ciliary body, which is physiologically activated by
cAMP
B. Hyperthyroidsim: propranolol
Therapeutic uses of Beta-Receptor–Blocking
Drugs
II. Non-cardiovascular applications
C. Migrane prophylaxis: Propranolol, metoprolol and
probably also atenolol, timolol, and nadolol. The
mechanism may depend on the blockade of
catecholamine-induced vasodilation in the brain
vasculature
D. Performance anxiety (stage fright) : propranolol
E. Tremor: propranolol due to reduced β2-alteration of
neuromuscular transmission
Choice of a β-adrenoceptor antagonist drug
• The various β-receptor antagonists that are used for
the treatment of HTN and angina appear to have
similar efficacies (i.e. interchangable).
• Selection of the most appropriate drug for an
individual patient should be based on PK and PD
differences among the drugs, cost, and whether there
are concurrent medical problems
Choice of a β-adrenoceptor antagonist drug
• For some diseases (e.g., myocardial infarction,
migraine, cirrhosis with varices, and congestive heart
failure), it should not be assumed that all members of
this class of drugs are interchangeable; the
appropriate drug should be selected from those that
have documented efficacy for the disease
• For example in heart failure clinical trials have
demonstrated that at least three antagonists—
metoprolol, bisoprolol, and carvedilol—are effective in
reducing mortality associated with chronic heart
failure
Adverse effects of β-adrenoceptor antagonist
drug
1) Bradycardia (most common): normal response to βadrenoceptor blockade
2) Bronchoconstriction: β2 receptor blockade associated
with the use of non-selective β-blockers (e.g. propranolol)
3) Hypoglycemia in type I diabetic patients who are subject
to frequent hypoglycemic episodes
4) Coolness of hands & feet in winter
5) CNS effects: include fatigue, sleep disturbances
(including insomnia and nightmares), and depression
• Hydrophilic drugs nadolol or atenolol are associated with a
lower incidence of central nervous system adverse effects
Adverse effects of β-adrenoceptor antagonist
drug
6) Cardiac arrhythmias:
• Treatment with β-blockers must never be stopped
quickly because of the risk of precipitating cardiac
arrhythmias, which may be severe especially drugs with
short half-lives, such as propranolol and metoprolol
• The β-blockers must be tapered off gradually for 1
week. Long-term treatment with a β antagonist leads to
up-regulation of the β-receptor. On suspension of
therapy, the increased receptors can worsen angina or
hypertension