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Antagonists
Adrenoceptor Antagonist Drugs
• Pharmacologic antagonist drugs
whose major effect is to occupy alpha
1, alpha 2, and beta receptors outside
the CNS and prevent their activation
by catecholamines and related
agonists.
Basic Pharmacology of Alpha Blockers
• MECHANISM OF ACTION:
- Alpha-receptor antagonists may be reversible
or irreversible
- Reversible antagonists dissociate from
receptors and the blockade can be surmounted
with sufficiently high agonist concentrations
(i.e: Phentolamine, “-zosins” for antihypertensive
effects)
- Irreversible antagonists do not dissociate
and cannot be surmounted
(i.e.: Phenoxybenzamine – forms an
ethyleneimonium intermediate which
binds covalently to alpha receptors
resulting to irreversible blockade)
Pharmacologic Effects
• Cardiovascular Effects
- Alpha receptors on vascular smooth muscle play a
great role in arteriolar and venous tone
(vasoconstriction by alpha 1 stimulation leads to BP
elevation)
- Alpha-receptor antagonist drugs cause lowering of
peripheral vascular resistance and blood pressure
- Alpha blockers often cause orthostatic hypotension
and reflex tachycardia
Pharmacologic Effects
• Other Effects
- Alpha receptor blockade in other tissues may elicit
miosis (pupil constriction)
- Alpha 1 receptors expressed in the bladder and
prostate may be blocked by alpha blockers and lead
to the decrease in resistance to the flow of urine
(alpha 1 blockers will relax prostatic smooth
muscles and relax/open the bladder sphincter)
- Treatment of urinary retention due to BPH
PHENOXYBENZAMINE
• Non-selective irreversible α-blocker
• Binds covalently to α-receptors causing
irreversible blockade
• Binds to both alpha receptors but has
somewhat greater affinity for alpha 1 than alpha
2
(its selectivity is less compared to the alpha 1
selectivity of –zosins)
Relative Selectivity of Adrenergic Antagonists
DRUGS RECEPTOR AFFINITY
ALPHA ANTAGONISTS
PRAZOSIN, TERAZOSIN, DOXAZOSIN α1 >>>> α2
PHENOXYBENZAMINE α1 > α2
PHENTOLAMINE α1 = α2
YOHIMBINE, TOLAZOLINE α2 >> α1
MIXED ANTAGONISTS
LABETALOL, CARVEDILOL β1 = β2 > α1 > α2
BETA ANTAGONISTS
BETAXOLOL, ESMOLOL, ATENOLOL, ACEBUTOLOL, β1 >>> β2
ALPRENOLOL, METOPROLOL, CELIPROLOL, NEBIVOLOL
BUTOXAMINE β2 >>> β1
• Attenuation of catecholamine-induced vasoconstriction
• Causes relatively little fall in BP in normal supine
individuals
• Great fall in BP when sympathetic tone is high (e.g. as
a result of upright posture)
• Cardiac output may be increased due to reflex effects
and also blockade of presynaptic alpha 2 receptors in
cardiac sympathetic nerves (no more inhibition of
catecholamine release, catecholamines will bind to
beta receptors instead since alpha receptors are
blocked)
• Used in the treatment
of pheochromocytoma
(a rare tumor of adrenal gland
which results in the release of
too much epinephrine and
norepinephrine that would
increase heart rate,
metabolism, and blood
pressure)
• Adverse effects:
Orthostatic hypotension
Tachycardia
Fatigue
Sedation
Nausea
Inhibition of ejaculation
PHENTOLAMINE
• Non-selective reversible alpha blocker
• Potent competitive antagonist at both alpha 1 and
alpha 2 receptors
• Reduces peripheral resistance on vascular smooth
muscles
• Cardiac stimulation is due to antagonism of
presynaptic alpha 2 receptors (leading to enhanced
release of NE from synaptic nerves) and activation of
baroreflex mechanisms.
Relative Selectivity of Adrenergic Antagonists
DRUGS RECEPTOR AFFINITY
ALPHA ANTAGONISTS
PRAZOSIN, TERAZOSIN, DOXAZOSIN α1 >>>> α2
PHENOXYBENZAMINE α1 > α2
PHENTOLAMINE α1 = α2
YOHIMBINE, TOLAZOLINE α2 >> α1
MIXED ANTAGONISTS
LABETALOL, CARVEDILOL β1 = β2 > α1 > α2
BETA ANTAGONISTS
BETAXOLOL, ESMOLOL, ATENOLOL, β1 >>> β2
ACEBUTOLOL, ALPRENOLOL, METOPROLOL,
CELIPROLOL, NEBIVOLOL
PROPRANOLOL, CARTEOLOL, NADOLOL, β1 = β2
PENBUTOLOL, PINDOLOL, TIMOLOL
BUTOXAMINE β2 >>> β1
• Has minor inhibitory effects at serotonin receptors
and agonist effects at muscarinic and histamine
receptors
• Principal adverse effects: tachycardia, arrhythmias,
myocardial ischemia
• Also used in the treatment of pheochromocytoma
• Sometimes used in the reversal of local anesthesia
(local anesthetics are often co-administered with
vasoconstrictors to slow their removal from the site,
local phentolamine permits reversal of
vasoconstriction at the end of the procedure)
SELECTIVE ALPHA 1 BLOCKERS
• ALFUZOSIN
• DOXAZOSIN
• PRAZOSIN
• TAMSULOSIN
• TERAZOSIN
• Highly selective for alpha 1 receptors and
typically 1000-fold less potent at alpha 2
receptors (relative absence of tachycardia
compared to non-selective alpha blockers)
• effective in the management of hypertension
since they relax vascular smooth muscles
• Alpha 1 blockade also relaxes prostatic
smooth muscles and used in men with
urinary retention due to Benign Prostatic
Hyperplasia.
OTHER ALPHA BLOCKING DRUGS
• Silodosin – resembles Tamsulosin; used in BPH
• Indoramin – also an alpha 1 antagonist; antihypertensive
• Urapidil - alpha 1 antagonist, weak alpha 2 and 5-HT1A
agonist, and weak beta 1 antagonist activity (Eur – for BPH
and HTN)
• Carvedilol & Labetalol – alpha 1 and beta antagonistic effects
• Chlorpromazine & haloperidol – neuroleptic drugs, potent
dopamine blockers having alpha antagonist activity
• Trazodone – antidepressant, blocks alpha 1 receptors
• Ergotamine & dihydroergotamine – cause reversible alpha
blockade (partial agonist action)
ALPHA 2 BLOCKERS
• YOHIMBINE - alpha 2 selective antagonist
- Sometimes used in the treatment of orthostatic hypotension
since it promotes NE release through the blockade of alpha
2 receptors in the CNS and periphery
- Once widely used to treat erectile dysfunction (superseded
by PDE-5 inhibitors)
- Able to reverse antihypertensive effects of alpha 2 agonists
like clonidine
- Used in veterinary medicine to reverse anesthesia produced
by xylazine (xylazine is an alpha 2 agonist used to calm
animals)
Basic Pharmacology of Beta Blockers
• MECHANISM OF ACTION:
- Antagonizing the effects of catecholamines at β
adrenoceptors by occupying β receptors and
competitively reduce occupancy by
catecholamines and other beta agonists.
- Most are pure antagonists, some are partial
agonists
- Partial agonists cause partial activation which is
less than the activation of a full agonist.
- Partial agonists inhibit beta receptor activation
in the presence of high catecholamine
concentrations
- However, they moderately activate the
receptors in the absence of endogenous
agonists
- Some are also inverse agonists (e.g. Betaxolol
and Metoprolol) which means that they reduce
the constitutive activity of beta receptors.
- Beta-receptor-blocking drugs differ in relative
affinities for β1 and β2 receptors.
Pharmacokinetic Properties
Absorption
- Most of the drugs in this class are well-absorbed after oral
administration
- Peak concentrations occur 1-3 hours after ingestion
- Some beta-blockers are in sustained-release preparations
Bioavailability
- Propranolol has low bioavailability since it undergoes extensive
hepatic or 1st pass metabolism
- 1st pass effect varies among individuals = great variability in
drug plasma concentrations
- Bioavailability is limited in varying degrees for most beta-
antagonists (EXCEPT for Betaxolol, Penbutolol, Pindolol, and
Sotalol)
Distribution and Clearance
- Beta antagonists are rapidly distributed and have
large Vd
- Half-lives range from 3-10 hours
- Esmolol (half-life of approximately 10 minutes)
- Elimination may be prolonged in the presence of
hepatic disease or hepatic enzyme inhibition
- Nadolol is excreted unchanged in the urine and has
a very long half-life (up to 24 hours; renal failure may
prolong elimination)
Pharmacodynamics of Beta-Blockers
OVERVIEW:
Most of the effects are due to
occupation and blockade of Beta
receptors
Some actions may include partial
agonist activity at Beta receptors
Some actions may include local
anesthetic effects
Effects on the Cardiovascular System
• Beta-blocking drugs lower blood pressure in
patients with HTN
B1 Blockade = B2 Blockade
• β1-SELECTIVE
-Safer in patients who experience
- Betaxolol bronchoconstriction in response
to non-selective beta blockers
- Bisoprolol
-Still use with great caution in
- Esmolol patients with a history of asthma
- Acebutolol -However, in some patients with
- Atenolol COPD the benefits may outweigh
- Metoprolol the risks especially if they
- Celiprolol experienced MI
- Nebivolol
• NEBIVOLOL
- The most highly selective Beta 1 adrenergic
blocker
- Additionally elicits vasodilation (promotes
endothelial nitric oxide production)
- May also increase insulin sensitivity and does not
affect lipid profile
- Sometimes referred to 3rd generation beta-
blocker because of activation of nitric oxide
synthase
• TIMOLOL
- Nonselective beta blocker having excellent
ocular hypotensive effects when administered
topically in the eye (no local anesthetic
action)
• NADOLOL
- Has a very long duration of action
• LEVOBUNOLOL (Nonselective)