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Adrenergic antagonists adrenoreceptor blockers 2

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Adrenergic antagonists, adrenoreceptor
blockers
Dr.Jibachha Sah
M.V.Sc(Veterinary pharmacology)
College of Veterinary Science,NPI
Bhojard,Chitwan
 Adrenergic antagonists

●An adrenergic antagonist is a drug that inhibits the function of adrenergic

receptors. There are five adrenergic receptors, which are divided into two groups.

● The first group of receptors are the beta (β) adrenergic receptors. There
are β1, β2, and β3receptors.

● The second group contains the alpha (α) adrenoreceptors. There are
only α1 and α2 receptors.

● Adrenergic receptors are located near the heart, kidneys, lungs,

and gastrointestinal tract.

● There are also α-adreno receptors that are located on vascular smooth muscle.

●β3- adrenergic receptors are located in fat cells.

Antagonists reduce or block the signals of agonists. They can be drugs, which are added to the
body for therapeutic reasons, or endogenous ligands. The α-adrenergic antagonists have
different effects from the β-adrenergic antagonists.

Mechanisms of action
There are three different types of antagonists.

(i) Competitive
While only a few α-adrenergic antagonists are competitive, all β-adrenergic antagonists
are competitive antagonists. Competitive antagonists are a type of reversible antagonists. A
competitive antagonist will attach itself to the same binding site of the receptor that the
agonist will bind to.
Two examples of competitive adrenergic antagonists
are propranolol and phentolamine. Phentolamine is a competitive and nonselective
α-adrenoreceptor antagonist. Propanalol is a β-adreno receptor antagonist
Propranolol Uses

Propranolol is a adrenergic antagonist (non-selective β-blocker), used to treat

hypertension, angina, high blood pressure, irregular heartbeats, shaking (tremors), and
other conditions.

Dose: 10-160 mg (Oral), 2-5 mg ( i.v. injected over 10 min.)

Route: Oral, Intravenlous

It is used after a heart attack to improve the chance of survival. It is

also used to prevent migraine headaches and chest pain (angina).
Lowering high blood pressure helps prevent strokes, heart attacks,
and kidney problems. Preventing chest pain can help improve for
ability to exercise.
Side effects: Adverse effects of Propranolol are as follows:
●Bronchoconstriction,
● CNS effects like- depression, dizziness, lethargy, fatigue, weakness, visual disturbances,
hallucinations, short-term memory loss, emotional lability, vivid dreams (including
nightmares),and depression.
● Metabolic disturbances like Fasting hypoglycemia, decreased glycogenolysis.
● Arrhythmias,
● Sexual impairment.

Contraindications:
● Propranolol is contraindicated in patients with COPD or asthma.
Veterinary use
Propranolol is a beta blocker that is used to control the heart rate of cats and dogs with
irregular heart rhythms.

Dose indication

If the medicine is a liquid, measure the dose with

reasonable care.
Try to give this medication at about the same time(s) each
day.
DO NOT give the pet more medicine than directed.
DO NOT give the medicine more often than directed.
Try not to miss giving any doses.

Potential side effects?

The following side effects have been reported and usually occur in older pets: slow heart
rate, drowsiness, worsening heart failure, low blood pressure, low blood sugar levels,
difficulty breathing (bronchoconstriction), diarrhea, temporary loss of consciousness.
Drug interactions

The following drugs can potentially interact with propranolol: sympathomimetics,

anesthetic agents, phenothiazines, thyroid hormones, methimazole, propylthiouracil,
cimetidine, furosemide, hydralazine, tubocurarine, succinylcholine, phenobarbital,
rifampin, phenytoin, epinephrine, insulin, lidocaine, theophyllin, calcium channel blockers,
and antacids.
 Phentolamine (Regitine) is a reversible nonselective α-adrenergic antagonist.

Mechanism of action
Its primary action is vasodilation due to α1 blockade.

Non-selective α-blockers can cause a much more pronounced reflex tachycardia than the
selective α1 blockers. Like the selective α1 blockers, phentolamine causes a relaxation of
systemic vasculature, leading to hypotension. This hypotension is sensed by the baroreceptor
reflex, which results in increased sympathetic nerve firing on the heart,
releasing norepinephrine
Uses

The primary application for phentolamine is for the control of hypertensive emergencies,
most notably due to pheochromocytoma.

Pheochromocytomas (PH or PCC) are tumors arising from chromaffin cells of the adrenal
medulla that synthesize, store, metabolize and usually but not always
secrete catecholamines.
The adrenal medulla is the principal site of the conversion of the amino acid tyrosine into the
catecholamines; epinephrine, norepinephrine, and dopamine.
 Use

Phentolamine given by injection causes blood

vessels to expand, thereby increasing blood
flow.

When injected into the penis (intracavernosal), it increases

blood flow to the penis, which results in an erection.

Phenoxybenzamine and phentolamine are used in human and

veterinary medicine to treat pheochromocytoma, a tumor of
the adrenal medulla that results in a massive increase in the
levels of circulating catecholamines.
(ii)Non-competitive
While competitive antagonists bind to the agonist or ligand binding site of the receptor
reversibly, non-competitive antagonists can either bind to the ligand site or other site called
the allosteric site. A receptor's agonist does not bind to its allosteric binding site. The binding
of a non-competitive antagonist is irreversible.

An example of an adrenergic non competitive antagonists is phenoxybenzamine.

Mechanism of action of phenoxybenzamine.

Phenoxybenzamine blocks the alpha adrenergic response to circulating epinephrine and

norepinephrine.
Usage

Dogs and Cats

●Phenoxybenzamine is used in dogs and cats to reduce internal urethral sphincter tone.
● It may also be used for urethral spasm secondary to bacterial urethritis.
● Phenoxybenzamine is used to reduce blood pressure associated with pheochromocytoma.

Horses

● Phenoxybenzamine may be used to decrease urethral sphincter tone, in horses with an

atonic bladder.
● It may be used with bethanacol.

● There are earlier reports of its use in the early stages of laminitis and for diarrhea.

Bethanechol is used to treat urinary retention (difficulty urinating), which may occur after
surgery, after delivering a baby, and in other situations.
Side Effects
Common side-effects include:
•Hypotension or hypertension, tachycardia, weakness dizziness, GI
disturbances (nausea).
•Ocular side-effects include miosis and increased intraocular pressure.

Precautions
•Phenoxybenzamine causes vasodilation and should be avoided in animals
that are significantly dehydrated or azotemic. Hydration may be supported
with intravenous fluids.

•Phenoxybenzamine should be used with caution in animals with kidney

damage, congestive heart failure or other cardiac problems, and those with
coronary or cerebral arteriosclerosis. It should not be used in animals with
glaucoma or diabetes mellitus.

•Phenoxybenzamine should not be used in horses with signs of colic.

Drug Interactions
•Phenoxybenzamine will antagonize alpha adrenergic sympathomimetic drugs.
•The effects of phenoxybenzamine will be increased when used with drugs such as
epinephrine, that have both alpha and beta adrenergic properties.

Overdose
•Overdose with phenoxybenzamine may produce hypotension, tachycardia, GI
distress, lethargy, and shock.
•If the overdose is treated early, gastric-emptying may be appropriate.
(iii)Uncompetitive
There were few if any adrenergic uncompetitive antagonists. An uncompetitive antagonist is
slightly different from the other two types of antagonists. The action of an uncompetitive
antagonist is dependent on the receptor's prior activation. This means only after the agonist
binds to the receptor can the antagonist block the receptor's function.

Example
Alpha blockers
Phentolamine
phenoxybenzamine
Beta blockers
Propranolol Oxprenolol
Metoprolol
Nebivilol
Atenolol
 Dog and cat showing acute stress responses
The fight-or-flight response (also called hyperarousal, or the acute stress response) is a
physiological reaction that occurs in response to a perceived harmful event, attack, or threat
to survival.[More specifically, the adrenal medulla produces a hormonal cascade that results
in the secretion of catecholamines, especially norepinephrine and epinephrine.
Drug is classified as an adrenergic antagonist?

Drug Name Category

Adrenergic Agonist, Direct
Terbutaline
beta2-selective
Adrenergic Agonist, Direct
Epinephrine Non-selective (alpha1,
alpha2, beta1, beta2)
Adrenergic Agonist, Direct
Dobutamine
"Cardioselective" (B1)
Adrenergic Agonist, Indirect
Ephedrine
Mixed-receptor agonist
Drug Name Category Mechanism, Indications, Adverse Effects, Unique Properties

Dopamine Adrenergic Agonist, Direct Important in maintenance of renal blood flow. Dopamine receptors
are found in kidneys. Has Epi-like activity at high doses. Can be used
in cardiogenic shock. Can cause nausea and vomiting

Oxymetolazine Adrenergic Agonist, Topical nasal decongestant (via action on alpha1 receptors). In high
Directalpha1, alpha2 doses, can paradoxically produce hypotension, probably via
alpha2 receptors.

Xylometolazine Adrenergic Agonist, Topical nasal decongestant.

Directalpha1, alpha2
Norepinephrine Adrenergic Agonist, Increase b.p. ------> reflex bradycardia.. If reflexes are blocked by
Directalpha1, alpha2, beta1 Hexamethonium, then you see a direct tachycardia.

Methoxamine Adrenergic Agonist, Used to maintain blood pressure during anesthesia. Produces fewer
Directalpha1-selective arrhythmias than other drugs.

Naphazoline Adrenergic Agonist, Used to induce mydriasis before ophthalmic exam.

Directalpha1-selective
Phenylephrine Adrenergic Agonist, Used topically as a nasal decongestant (restrict blood flow to nose),
Directalpha1-selective and to induce mydriasis for ophthalmic exam.Not a catechol, and not
broken down by COMT, thus it has longer half-life (20 minutes) then
catecholamines.
alpha-Agonist ------> increase b.p. ------> reflex bradycardia.
Major effects

●Adrenergic antagonists have inhibitory or opposing effects on the receptors in the

adrenergic system.

● The adrenergic system modulates the fight-or-flight response.

● Since this response, which is mostly seen as an increase in blood pressure, is produced by
the release of the endogenous adrenergic ligands, administration of an adrenergic antagonist
results a decrease in blood pressure, which is controlled by both heart rate and vasculature
tone.

● Administration of an adrenergic antagonist that specifically targets the beta receptors,

results in this decrease in blood pressure by slowing or reducing cardiac output
Clinical uses

●Adrenergic antagonists are mostly used for cardiovascular disease. The adrenergic
antagonists are widely used for lowering blood pressure and relieving hypertension.

● These antagonists have a been proven to relieve the pain caused by myocardial
infarction, and also the infarction size, which correlates with heart rate.[

● There are few non-cardiovascular uses for adrenergic antagonists. Alpha-adrenergic

antagonists are also used for treatment of ureteric stones, pain and panic
disorders, withdrawal, and anesthesia.
 Limitations

While these adrenergic antagonists are used for treating cardiovascular disease, mainly
hypertension, they can evoke harmful cardiac events.

Side effects and toxicity

When overused, adrenergic antagonists can result

in bradycardia, hypotension, hyperglycemia and even hypodynamic shock(cold shock). This is
because adrenergic stimulation by agonists results in normal calcium channel regulation. If
these adrenergic receptors are blocked too often, there will be an excess in calcium channel
inhibition, which causes most of these problems
Adrenoreceptor blockers (adrenoceptor antagonists)

Alpha blockers are also called alpha-adrenergic blocking agents, alpha-adrenergic

antagonists, adrenergic blocking agents and alpha-blocking agents. Examples of
alpha blockers used to treat high blood pressure include: Doxazosin , Prazosin
A. Classification
Subdivisions of the α blockers are based on selective affinity for α1 versus α2 receptors or a
lack thereof.

Irreversible, long-acting—Phenoxybenzamine is the prototypical long-acting α blocker; it

differs from other adrenoceptor blockers in being irreversible in action. It is slightly α1-
selective.

Reversible, shorter-acting—Phentolamine is a competitive, reversible blocking agent that

does not distinguish between α1 and α2 receptors.

Alpha1-selective—Prazosin is a highly selective, reversible pharmacologic α1 blocker.

Doxazosin, terazosin, and tamsulosin are similar drugs.

Alpha2-selective—Yohimbine and rauwolscine are α2-selective competitive pharmacologic

antagonists.
Pharmacokinetics

Alpha-blocking drugs are all active by the oral as well as the parenteral route, although
phentolamine is rarely given orally.

Phenoxybenzamine has a short elimination half-life but a long duration of action—about 48

h—because it binds covalently to its receptor.

Phentolamine has a duration of action of 2–4 h when used orally and 20–40 min when given
parenterally.

Prazosin and the other α1-selective blockers act for 8–24 h.

Beta blockers, also known as beta-adrenergic blocking agents, are medicationsthat
reduce your blood pressure.

Beta blockers work by blocking the effects of the hormone epinephrine, also known as
adrenaline.

beta-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines
and other hormone levels.
Receptor blockade effects
Heart:
1 blockade→HR↓, heart conductivity↓, contractility↓, CO↓
2) blockade→ vasoconstriction↑
3) blockade→ bronchoconstriction
4) Renin secretion↓
BETA BLOCKERS USED?
Beta blockers are used to manage a variety of conditions. They include, but are not limited
to:
cardiac arrhythmias,

heart failure,

high coronary artery disease risk,

diabetes,

post heart attack (myocardial infarction),

angina pectoris due to coronary atherosclerosis, and

hypertension (high blood pressure). (In the management of hypertension, it may be used
alone or concomitantly with other antihypertensive agents, particularly thiazide diuretics).
Off-label uses of beta blockers include, but are not limited to:
migraine headaches,

glaucoma,

hyperthyroidism,

fibromyalgia,

generalized anxiety disorder,

parkinsonian tremor, and

atrial fibrillation.

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