1. Alpha-Adrenergic
Blockers
Dr. Hiwa K. Saaed
Ph.D. Pharmacology
& Toxicology

2. Receptor
Tissues Response
α1
Eye-radial (dilatory)
muscle
Contacts (mydriasis)
Most vascular
smooth muscle
-Arterioles (skin,
viscera)
-veins
Contraction
↑TPR→↑ diastolic
pressure ↑afterload
↑ venous return→↑ preload
Bladder trigone and
sphincter
Contraction→urinary
retention
Male sex organs Vas deferens→ ejaculation
Liver (in some
species, rat )
Stimulate glycogenolysis
Kidney ↓ rennin release
Pilomotor smooth
muscle
Contraction (erect hair)

3. Receptor tissue Response
α 2
Adrenergic & cholinergic
Prejunctional nerve terminals
↓ transmitter release
and NE synthesis
Platelets Stimulate Aggregation
Pancreas (β cells) Inhibit insulin release
Some vascular smooth muscle Contracts
Fat cells Inhibits lipolysis
Medullary vasomotor center ↓sympathetic outflow
→ CO &
vasodilation→↓ BP

4. Localization of 1-Adrenergic Receptors

5.  Like the agonists, the adrenergic antagonists are classified
according to their relative affinities for α1 or α2 receptors .
 Drugs that block α-adrenoceptors profoundly affect blood
pressure, resulting in decreased peripheral vascular resistance.
 Because normal sympathetic control of the vasculature occurs
in large part through agonist actions on α-adrenergic receptors
 This induces a reflex tachycardia resulting from the lowered
blood pressure.
Alpha-Adrenergic Blockers

6. Alpha-Adrenergic Blockers Classification
I. Type of blockade
1. Irreversible (non-competitive) :
Phenoxybenzamine; slow onset and long duration.
2. Reversible (competitive): All the rest
II. Selectivity: α1 or α2 receptors .
-Nonselective: Phenoxybenzamine and phentolamine
-Selective:
1. alpha-1 selective: Prazosin, terazosin, others
2. alpha-2 selective: Yohimbine
3. alpha/beta blockers: Labetalol
-Others: phenothiazines, haloperidol, tricyclic antidepressants
trazodone

7. α Antagonists Receptor Affinity
Prazosin, terazosin, doxazosin α1>>>>α2
Phenoxybenzamine α1>α2
Phentolamine α1=α2
Rauwolscine, yohimbine, tolazoline α2>α1
Mixed antagonists
Labetalol, carvedilol β1=β2≥α1>α2

8. Alpha-Adrenergic Blockers
Nonselective
– Phenoxybenzamine (3-4 days)
Selective
• Short-acting selective 1-blocker
– Prazosin t1/2 3 hrs, Alfuzosin t1/2 5 hrs
• Long-acting selective 1-blockers
– Terazosin t1/2 9-12 hrs
– Doxazosin t1/2 22 hrs
• Long-acting selective 1A-subtype
– Tamsulosin t1/2 9-15 hrs

9. Pharmacological Effects - Phenoxybenzamine
1. Cardiovascular system
• ↓PR: ↓ Blood pressure: reflex tachycardia:
• Furthermore, the ability to block presynaptic
inhibitory α2-receptors in the heart will
result in more norepinephrine release,
which stimulates β- receptors on the heart
to increase cardiac output.
• It reduces BP when sympathetic tone is
high upright posture, reduced blood volume

10. Adrenergic System - Antagonists

11. Epinephrine reversal:
• All α-adrenergic blockers reverse the α-agonist
actions of epinephrine. the vasoconstrictive action of
epinephrine is interrupted, but vasodilation of other
vascular beds caused by stimulation of β2 receptors
is not blocked.
• Therefore, the systemic blood pressure decreases in
response to epinephrine given in the presence of
phenoxybenzamine. ….Why?
• The actions of norepinephrine are not reversed but
are diminished, …why?

12. Pharmacological Effects –
Phenoxybenzamine
2. Eye – miosis
3. Nasal stuffiness
4. GI tract – Increased motility
5. Urinary bladder – decreased tone in sphincter
6. Metabolic effects – increased insulin secretion
7. It also blocks histamine, serotonin and cholinergic
receptors

13. Clinical uses -
Phenoxybenzamine
1. Pheochromocytoma: a catecholamine-
secreting tumor of cells derived from the adrenal
medulla
2. Raynaud; peripheral vascular disease
3. Autonomic hyperreflexia which predisposes
paraplegics to strokes
4. BPH

14. Adverse effects
Phenoxybenzamine
• Postural hypotension
• Tachycardia it is contraindicated in patients with
decreased coronary perfusion.
• Sedation, fatigue
• Nasal stuffiness
• Miosis
• Impotence (inhibits ejaculation)
• Exercise care in hypovolemic patients.

15. Imidazoline derivatives – phentolamine (5-7hr)
produces a competitive block of α1 and α2-
receptors.
1. Block serotonin receptors
2. Stimulate H1 & H2
3. Stimulate M1; Parasympathomimetic
• Increased gastric motility & acid secretion
• Increased secretion from exocrine glands, such as
salivary, sweat, lacrimal, pancreatic
• Cardiac stimulation reflex and direct!!
• it can be injected intracavernosally to produce
vasodilation of penile arteries (rarely used)

16. Alpha-1 selective blockers
Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin
• the first three drugs are useful in the treatment of
hypertension.
• Alfuzosin & Tamsulosin are indicated for the treatment
of benign prostatic hypertrophy
• Prazosin (t1/2 3hrs): No significant tachycardia
Used in CHF and in hypertension but tolerance develops
with time, may be due to fluid retention.
• Adverse effects: First dose phenomenon.
• Favorable effect on plasma lipids: increase HDL/LDL
ratio
• Terazosin (t1/2 9-12 hrs)

18. Other α -adrenoceptor antagonists
• Indoramin: antihypertensive.
• Urapidil is an α1 antagonist (its primary effect) that
also has weak α2-agonist and 5-HT1A-agonist actions
and weak antagonist action at β1 receptors. It is used
in Europe as an antihypertensive agent and for BPH.
• Labetalol has both α1-selective and β-antagonistic
effects.
• Neuroleptic drugs such as chlorpromazine and
haloperidol are potent dopamine receptor antagonists
but are also antagonists at α-receptors.
• Antidepressant: trazodone block α1 receptors.

19. 2 - selective antagonists Yohimbine
Chief active compound in Pausinystalia yohimbine
(bark), Effects opposite of Clonidine
Enters CNS => increased sympathetic output =>
increased HR, BP, can cause severe tremors
Ingredient in many weight loss products
Enhances sexual activity – aphrodisiac
Blocks other receptors: serotonin, dopamine, Increases
ADH release
Experimental uses in Treatment of :
1. Raynaud's phenomenon to inhibit smooth muscle
contraction,
2. type 2 diabetes (α2 receptors inhibit insulin
secretion),
3. depression.

20. Therapeutic Uses of
Alpha-Adrenergic Blockers
• Hypertension - alpha-1 selective
• Pheochromocytoma
• Peripheral vascular disease – Raynaud’s
• Local Vasoconstrictor Excess
• Benign prostatic hyperplasia
• Erectile Dysfunction: Yohimbine or
intracavernous phentolamine + papaverine