c
 




÷


 O

 

‡ The adrenergic antagonists (also called blockers or

sympatholytic agents) bind to adrenoceptors but do not trigger
the usual receptor-mediated intracellular effects

‡ They are competitive antagonist at Ĵ & ǀ or both Ĵ & ǀ

adrenergic receptors and differ in important ways from
adrenergic neurone blocking agents, which act by interfering
with the release of adrenergic neurotransmitter on nerve
stimulation.
 c


c 
 
‡ These drugs inhibit adrenergic response mediated through the Ĵ
adrenergic receptor without affecting those mediated through ǀ
receptor.
‡ These drugs act by either reversibly or irreversibly attaching to
the receptor, thus preventing its activation by endogenous
catecholamines.
‡ They are classified as Ĵ1,Ĵ2-adrenoceptor antagonist drugs and
non equilibrium & equilibrium type.
 




O. Non equilibrium type

i. ǀ- Haloalkylamines- phenoxybenzamine

OO. Equilibrium type (competitive)

A. Non selective
i. Ergot alkaloids-Ergotamine, ergotoxine
ii. Hydrogenated ergot alkaloids-Dihydroergotamine (DHE),
dihydroergotoxin
iii. Omidazolines- Tolazoline, phentolamine
iv. Miscellaneous-Chlorpromazine
 V


 i 

÷. Ĵ1 selective
‡ Prazosin
‡ Terazosin
‡ Doxazosin
‡ Tamsulosin

C. Ĵh selective
‡ yohimbine
 ( 




‡ Ĵ-receptor antagonists may be reversible or irreversible in their

interaction with these receptors .

‡ Reversible antagonists can dissociate from receptors & the

block can be surmounted with sufficiently high concentration of
agonist.

‡ Whereas irreversible antagonists cannot be dissociated and

cannot be surmounted.
 ( 


 


‡ The duration of action of a reversible antagonist is largely

dependent on the half-life of the drug in the body and the rate
at which it dissociates from its receptor.

‡ The shorter the half-life of the drug in the body, the less time
it takes for the effects of the drug to dissipate .

‡ On contrast, the effects of an irreversible antagonist may

persist long after the drug has been cleared from the plasma
  


   

Ĵ-  
‡ Ĵ-receptor antagonist drugs cause a lowering of peripheral
vascular resistance and blood pressure.

‡ These drugs can prevent the pressor effects of usual doses ofĴ
agonists.

‡ Alpha-receptor antagonists often cause orthostatic hypotension

and reflex tachycardia.

‡ Non selective blockers usually cause significant tachycardia if

blood pressure is lowered below normal.

‡ Ĵ blockers can inhibit ejaculation

‡ Tachycardia may be more marked with agents that block Ĵ2-
presynaptic receptors in the heart, since the augmented release
of norepinephrine will further stimulate ǀ receptors in the
heart.

‡ ÷lockade of receptors in other tissues elicits miosis (small

pupils) and nasal stuffiness.

‡ Alpha1 receptors are expressed in the base of the bladder and

the prostate, and their blockade decreases resistance to the
flow of urine .

‡ Alpha blockers, therefore, are used therapeutically for the

treatment of urinary retention due to prostatic hyperplasia.
ë  c

 Ô  


‡ Ot is more selective to Ĵþ receptor.

‡ Ot binds covalently to receptors, causing irreversible blockade

of long duration (14²48 hours or longer).

‡ Ot inhibits the reuptake of released norepinephrine by

presynaptic adrenergic nerve terminals.

‡ blocks histamine (H1), acetylcholine, and serotonin receptors as

well as Ĵ-receptors.
pharmacologic actions:
actions
‡ The fall in ÷P caused by phenoxybenzamine is mainly postural
because venodilation is more prominent than arteriolar
dilation.
‡ Cardiac output may be increased because of reflex effects
& the blocking of some presynaptic 2 receptors in cardiac
sympathetic nerves.
‡ Ot is lipid soluble & penetrates brain and can produce CNS
stimulation ,nausea & vomiting on rapid i.v. injection.
‡ Therapeutic uses:
‡ Used in pheochromocytoma
Pharmacokinetics:
‡ Oral absorption is erratic & incomplete
‡ i.m. & s.c. injections are very painful
‡ Most of the administered dose is excreted in urine in 24hrs.
‡ Chronic administration of phenoxybenzamine leads to
accumulation of in adipose tissue.
Dose:
‡ 20-60 mg/day oral
‡ 1 mg/kg by slow i.v. infusion over 1 hour
Adverse effects:
‡ Postural hypotension ,palpitation, nasal blocking, miosis,
inhibition of ejaculation
 Ô



‡ Ot equally blocks Ĵ1 & Ĵ2 adrenergic receptor.

‡ Rapidly acting with short duration of action.

‡ Ot reduces peripheral resistance through blockade of Ĵ1

receptors and possibly Ĵ2 receptors on vascular smooth muscle.

‡ Ot has minor inhibitory effects at serotonin receptors .

‡ Phentolamine has agonist effects at muscarinic and H1 and H2

histamine receptors

‡ Release of histamine.
‡ Ot stimulates the GOT smooth muscles

‡ Use: treatment of pheochromocytoma

² control of hypertension due to clonidine withdrawal
‡ Adverse effects: severe tachycardia, arrhythmias, and
myocardial ischemia.

‡ Dose: 5 mg i.v.
 


‡ Highly selective Ĵ1 blocker.

‡ Ot blocks sympathetically mediated vasoconstriction & produces
fall in ÷P which is attended only in mild tachycardia.
‡ Prazosin relaxes both arterial and venous vascular smooth
muscle
‡ Pharmacokinetics:
‡ Ot is extensively metabolized in humans
‡ Highly bound to plasma proteins
‡ Excreted in bile
‡ Plasma half life is about 3 hours
‡ ÷ioavailability is between 50-60%
‡ Uses
Uses: antihypertensive, Raynaud·s disease, prostatic
hypertrophy
 á 


‡ reversible Ĵ1-selective antagonist.

‡ Terazosin has high bioavailability[90%]

‡ Ot is extensively metabolized in the liver.

‡ The half-life of terazosin is 9²12 hours.

‡ Ot is used in benign prostatic hyperplasia (÷PH).

 


‡ Long acting, plasma half life is about 22 hours

‡ Extensively metabolized in the liver.

‡ Used in hypertension & ÷HP.

‡ Dose: 1 mg OD initially ,increases up to 8 mg ÷D

 á
 

‡ Ot is a competitive Ĵ1 antagonist.
‡ Tamsulosin has higher affinity for Ĵ1A and Ĵ1D receptors than for
the Ĵ1÷ subtype .
‡ Ot has a high bioavailability & is extensively metabolized in the
liver .
‡ Tamsulosin has greater potency in inhibiting contraction in
prostate smooth muscle.
‡ Tamsulosin has less effect on standing blood pressure .
‡ Alfuzosin : it is Ĵ1 selective quinazoline derivative that is used in
the treatment of ÷HP
‡ Ot has a bioavailability of about 60% & has an elimination half-
life of about 5 hours.
Ondoramin it is another Ĵ1-selective antagonist that also has
‡ Ondoramin:
efficacy as an antihypertensive.
‡ Yohimbine
Yohimbine: Ot is an indole alkaloid, is an Ĵ2-selective antagonist.
‡ Ot is in the treatment of orthostatic hypotension.
‡ Yohimbine can reverse the antihypertensive effects of an 2-
adrenoceptor agonist such as clonidine .
 V  
 

  
Ô     


‡ Pheochromocytoma is a tumor of the adrenal medulla or

sympathetic ganglion cells.

‡ The tumor secretes catecholamines, especially norepinephrine

and epinephrine.

‡ There is elevated plasma and urinary norepinephrine,

epinephrine, and their metabolites, normetanephrine and
metanephrine.

‡ Alpha-receptor antagonists are most useful in the preoperative

management of patients with pheochromocytoma.
‡ Administration of phenoxybenzamine will help control
hypertension and will tend to reverse chronic changes resulting
from excessive catecholamine secretion in the preoperative
period.

‡ Of the effect of phenoxybenzamine is not as expected ,it will be

able to simplify the operative course.

‡ Phenoxybenzamine can be very useful in the chronic treatment

of inoperable or metastatic pheochromocytoma
K 
   
‡ Alpha blockers have limited application in the management of
hypertensive emergencies
‡ labetalol used in the management of hypertension

Ô  
 
‡ prazosin & phenoxybenzamine are used in the treatment of
peripheral vascular occlusive disease like Raynaud's disease.

  


 
‡ Prazosin, doxazosin, and terazosin are all efficacious in patients
with ÷PH
‡ These drugs are useful in patients who also have hypertension.
‡ The mechanism of action is by partial reversal of smooth muscle
contraction in the enlarged prostate and in the bladder base.

 

 

‡ A combination of phentolamine with the nonspecific smooth

muscle relaxant papaverine, when injected directly into the
penis, may cause erections in men with sexual dysfunction .

‡ Systemic absorption may lead to orthostatic hypotension .

‡ Long term administration may result in fibrotic reaction.

 c 


‡ Orthostatic hypotension

‡ Reflex tachycardia

‡ Hypotension

‡ Nasal stuffiness

‡ Diarrhoea ²increased intestinal mobility

‡ Reduced renal blood flow

c 

 c 
c

 


‡ Ĵ2 antagonists have relatively little clinical usefulness

‡ They have limited benefit in male erectile dysfunction
á