Adrenergic

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

PROPRANOLOL, CARTEOLOL, NADOLOL, β1 = β2

PENBUTOLOL, PINDOLOL, TIMOLOL

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

- via suppression of renin release

- via slowing heart rate
• Beta-blockers are also valuable in the
treatment of angina and chronic heart failure
• Negative inotropic and chronotropic effects
• Acute rise in peripheral vascular resistance is
due to unopposed alpha-receptor mediated
sympathetic effects in response to the fall in
cardiac output
• Chronic administration lowers peripheral
resistance in patients with HTN
Effects on the Respiratory Tract
• Blockade of Beta 2 receptors in bronchial
smooth muscles may lead to an increase in
airway resistance (asthma)
• Beta 1 selective blockers have some
advantage over nonselective beta blockers

(Therapy: β1 blockade in the heart is

desirable and β2 blockade is undesirable)
 Effects on the Eye
• Beta-blocking agents reduce intraocular
pressure (glaucoma)
• Mechanism: decrease in aqueous humor
production
Metabolic and Endocrine Effects
• Beta-blockers may impair
response to hypoglycemia
- associated with partial inhibition
of glycogenolysis in the liver due to
Beta 2 receptor blockade

(used with caution in diabetic

patients with hypoglycemic
therapy)
• Beta-blockers such as propranolol inhibit
sympathetic stimulation of lipolysis
• Chronic use (selective & non-selective) has been
associated with increased VLDL and decreased
HDL (unfavorable due to increased CVD risk)
• Less CVD risk with Beta blockers having intrinsic
sympathomimetic activity (partial agonists)
Effects Not Related to Beta-Blockade
• Partial β-agonist activity has been considered to
prevent untoward effects such as precipitation of
asthma or excessive bradycardia (intrinsic
sympathomimetic)
• Pindolol, Penbutolol, Labetalol, Celiprolol,
Carteolol, Acebutolol
• Not as effective in prevention of secondary
myocardial infarction compared to pure
antagonists.
• Local anesthetic action (membrane-
stabilizing action)
• This is an effect of several beta-blockers
as a result of typical local anesthetic
blockade of sodium channels.
• Insignificant in systemic administration since
concentration in the plasma is too low for the
anesthetic effect to be evident
• Important: membrane-stabilizing β-blockers
are NOT to be used topically on the eye
(undesirable  eliminate protective reflex due
to local anesthesia of the cornea)
• SOTALOL
• Nonselective beta blocker
• Lacks local anesthetic action
• Categorized as a Class III anti-arrhythmic
agent (potassium channel blockade)
 SPECIFIC AGENTS
• PROPRANOLOL
- The prototypical beta-blocking drug
• β-NONSELECTIVE - Pindolol
- Propranolol
- Carteolol - Sotalol
- Carvedilol - Timolol
- Labetalol
- Nadolol
- Penbutolol

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)

• BETAXOLOL (Beta 1 Selective)

- Both are also used for topical ophthalmic
application in glaucoma
• PARTIAL β-AGONISTS
- Pindolol
- Acebutolol
- Carteolol
-Effective in major
- Bopindolol cardiovascular
- Oxprenolol application (HTN and
- Celiprolol angina)
- Penbutolol
• PARTIAL β-AGONISTS
- Although these agents are less likely to cause
bradycardia and plasma lipid abnormalities than
the pure antagonists, the overall clinical
significance of intrinsic sympathomimetic activity
remains uncertain
• LABETALOL
- Has affinity to alpha adrenoceptors especially
alpha 1
- Blood pressure lowering effect is less
accompanied by tachycardia compared to purely
alpha blocking agents
- Safe for gestational HTN
• CARVEDILOL, MEDROXALOL, BUCINDOLOL
- Nonselective beta blockers with some capacity to
block alpha 1 adrenergic receptors
- Drug interaction with enzyme inhibitors such as
fluoxetine and quinidine may occur especially for
carvedilol which is extensively metabolized by
the liver
• ESMOLOL
- An ultra-short acting Beta 1 selective blocker
- Rapid metabolism due to its ester linkage
- Useful in arrhythmias and myocardial ischemia
in acutely ill patients
 Ischemic Heart Disease
Cardiac Arrhythmias
Heart Failure
Other Cardiovascular Disorders
Glaucoma
Hyperthyroidism
Neurologic Diseases
Hypertension
Miscellaneous
 HYPERTENSION
- Beta blockers are proved to be effective
and well tolerated in HTN
- Often used with either a diuretic or a
vasodilator
 ISCHEMIC HEART DISEASE
- Beta blockers reduce the frequency of
anginal episodes and improve exercise
tolerance in many patients with angina
- Beta blockade → decreased cardiac work
and reduction in oxygen demand
- Beta blockers such as propranolol and
metoprolol prolong survival of patients who
have had MI
 CARDIAC ARRHYTHMIAS
- Beta blockers are often effective in the
treatment of supraventricular and ventricular
arrhythmias
- They increase the AV nodal refractory
period and therefore slow ventricular
response rates in atrial flutter and fibrillation
- Sotalol has anti-arrhythmic effects via
additional ion channel blockade
 HEART FAILURE
- Metoprolol, Bisoprolol, and Carvedilol = effective
in reducing mortality in patients with chronic heart
failure
- They appear to be beneficial on myocardial
remodeling and decreasing risk of sudden death
- Note: they may worsen acute congestive heart
failure, but cautious long-term use with gradual
dose increments in patients who tolerate them
may enhance survivability
 OTHER CARDIOVASCULAR
DISORDERS
- Beta blockers are useful in dissecting aortic
aneurysm to decrease the rate of
development of systolic pressure
 OPEN-ANGLE GLAUCOMA
- Timolol, Betaxolol, Carteolol, Levobunolol,
metipranolol
- Mechanism: decrease aqueous humor
secretion from the ciliary epithelium =
reduction in intraocular pressure
 HYPERTHYROIDISM
- Propranolol has been used extensively in
patients with thyroid storm (severe
hyperthyroidism)
- It is used cautiously in such patients to
control supraventricular tachycardia that
often lead to heart failure
 NEUROLOGIC DISEASES
- Prophylactically taken to reduce tremors and
anxiety
- Performance anxiety/Stage fright
- May contribute to the symptomatic treatment of
alcohol withdrawal in some patients
- Reduction in the frequency and intensity of
migraine headaches (especially propranolol)
 MISCELLANEOUS
- Beta blockers diminish portal vein pressure in
patients with cirrhosis
- Propranolol and Nadolol decrease the
incidence of first episode bleeding from
esophageal varices and decrease the
mortality rate associated with bleeding in
patients with cirrhosis
- Infantile hemangiomas (most common
vascular tumors of infancy)
- Propranolol has been found to reduce the
volume, color, and elevation of infantile
hemangioma in infants younger than 6
months and children up to 5 years of age
 CLINICAL TOXICITY
- Bradycardia (most common)
- Hypotension
- Mild sedation
- Vivid dreams
- Depression (rare)
- Bronchoconstriction (especially
for non-selective BBs)
- Antidote for Cardiac Beta
Blockade:
Isoproterenol/Glucagon
Interaction:
Propranolol + Verapamil
= severe hypotension, bradycardia,
HF, and cardiac conduction
abnormalities
(may occur even with
topical/ophthalmic BB and oral
verapamil)
Note: Abrupt discontinuation may
worsen ischemic heart disease