Alpha Adrenergic Blockers (Alpha Antagonists)

The sympathetic system starts from the central nervous system and reaches the ganglia and then the adrenergic neurons, where neurotransmitters are released (nor-adrenaline). They act on the adrenergic receptors (alpha and beta). Two main types of alpha receptors are found; alpha 1 and alpha 2.

Alpha 1 receptors are mainly present in most of the smooth muscles, piloerector, papillodilator muscles and the heart. Alpha 2 receptors presynaptically regulate the release of neurotransmitters. They are also present in the platelets; in the fat cells they cause lipolysis.

Classification:

Alpha adrenergic blockers are the agents which block or antagonize the effects of alpha agonists. They are classified according to the receptor sensitivity.

They are:

1.      Selective Alpha Blockers

Quinazolines

Prazosin

Terazosin

Doxazosin

Alfuzosin

Benzensulfonamides

Tamsulosin (Alpha 1a)

2. Selective Alpha 2 blockers

Indole

Yohimbine

3. Non-selective (both alpha 1 and alpha 2) blockers

Imidazolines

Phentolamine

Tolazoline

Haloalkylamines(alpha 1 with some alpha 2 activity)

Phenoxybenzamine

Dibenamine

4. Mixed alpha and beta adrenoceptor blocking drugs

Labetalol

Carvedilol

Classification based on Mechanism of Action

Reversible Alpha Blockers

Phentolamine

Prazosin

Irreversible Alpha Blockers

Phenoxybenzamine (makes covalent bond with alpha receptors, thus dissociation is slow).

Phenoxybenzamine forms ethylene ammonium which binds alpha receptors, forming strong bonds.

Pharmacological Actions

1. CVS

a. Blood Pressure

Tone of smooth muscles of both arteriolar and venous blood vessels is maintained by alpha receptors. The blockers act to cause vasodilatation, producing decreased TPR and decreased blood pressure.

b. Vasoreversal phenomenon

This was first discovered by Dale in 1913, thus is also called Dale vasomotor reversal phenomenon. When adrenaline is administered it acts on both alpha and beta receptors, causing increased TPR and increased blood pressure (both systolic and diastolic). When alpha blockers are given, they antagonize the effects of alpha receptors, causing decrease in systolic blood pressure. Adrenaline effect is reversed by administration of alpha blockers. This has no therapeutic importance.

c. Postural Hypotension

Sympathetic activity is maintained by alpha 1. When blocked, a standing person has pooling of blood in the periphery. Due to the fact that alpha 1 receptors are blocked, vasodilatation occurs and blood flow to periphery is increased, while venous return is decreased. The constriction of arterioles further causes peripheral filling of blood and peripheral hypotension.

d. Reflex tachycardia

Alpha 2 blockers (non-selective alpha blockers) are seen more to cause reflex tachycardia. The negative feedback mechanism in NE release by alpha 2 receptors (presynaptic) causes decreased noradrenaline. When less is released, an increase in release is observed. When alpha 2 receptors are blocked, this negative feedback is inhibited. Uninhibited release of NE has effects on beta receptors (beta 1), causing tachycardia and arrhythmias.

2. Eye –Misois

Alpha 1 receptors are found in the papillary dilator muscles while constrictors are acted upon by M3. Due to alpha blockers, the constrictors are unopposed and cause miosis. This has beneficial role in glaucoma, but alpha blockers have no role in treatment of glaucoma.

3. Nasal Stuffiness

Vasodilatation within mucous membrane of nasopharynx occurs, causing nasal stuffiness.

4. Bladder

Alpha 1 receptors are also found in the base of bladder and neck of prostate. A decrease in pressure is observed leading to decreased mechanical resistance to flow of urine. This is important in the treatment of benign prostatic hyperplasia.

Useful clinically in urinary retention due to BPH.

5. GIT

When alpha 1 receptors are blocked, sphincters are opened, leading to increased motility, which may cause diarrhea and vomiting.

6. Vas Deferens

Decrease contraction of vas deferens smooth muscles leading to difficulty in ejaculation.

Therapeutic Uses

1. Antihypertensive

Due to blockage of alpha 1 receptors, there is decreased vasoconstriction, leading to decreased HTN.

In mild to moderate hypertension, Prazosin (short acting) is used. Others include Doxazosin, terazosin which are longer acting. Effective hypertensive emergency must be coped with. (Labetolol is more efficient as is more selective, Urapidil may be used as well) Alpha blockers are not the first line of defense.

Indication is also seen in sudden withdrawal of Clonidine. Alpha 2 selective drugs are used as sudden hypertension might be observed.

 

2. Benign Prostatic Hypertrophy

 

This occurs in elderly male. An obstruction to the flow of urine occurs resulting in decreased smooth muscle mass. Alpha 1 stimulation leads to further vasoconstriction and decrease in flow of urine. This results in nocrurine and dribbling of urine.

Surgical operation is recommended. In some cased drug therapy may prove to be beneficial. Prazosin and Terazosin (selective alpha 1 antagonists) like drugs are given which may cause tone reversal.

Newer agents like Tamsulosin (alpha 1 a) are highly effective, especially in non-hypertensive patients. Finasteride may be given in combination with dexazosin to cause the reversal of smooth muscle mass in prostate. Buy (Finasteride) Propecia Online.

3. Local Vasoconstrictor Excess

To enhance the absorbance at site of application, vasoconstrictors (adrenaline) are added to local anesthetic. If given in excess, to reverse the effects, alpha blockers are given to block the vasoconstrictor effects.

4. Pheochromocytoma

Tumor of adrenal medulla in which chromaffin cells are involved, causing increase in adrenaline and noradrenaline. This results in tachycardia, palpitations, headache, excessive sweating and increased sympathetic activity. The condition can be diagnosed by 3 hydroxy 4 methoxymandelic acid or by the presence of metabolites in urine or by using radio-isotopes, CT scan or MRI.

Alpha blockers are effective. Phentolamine is used intraoperatively (best treatment surgery) to reverse the increased blood pressure and tachycardia by drug therapy. Phenoxybenzamine is given preoperatively in 10-20 mg/day dose a few days before starting surgery.

More advanced techniques are available now to counter the rise in blood pressure.

Beta blockers are always administered before alpha receptor blockers have been instituted to reverse cardiac effects of excessive catecholamines. Due to blockage of negative feedback mechanism because of blockage of alpha 2 receptors, noradrenaline may affect heart to produce tachycardia. Beta blockers prevent NE effects on heart and tachycardia. This is to counter effects of alpha blockers.

Labetolol (non-selective alpha beta blocker) is also effective in pheocytochroma.

Metyrosine decreases the synthesis of adrenaline and noradrenaline. It is effective in metastatic and refractory cases. We give metyrosine with phenoxy benzamine. This is not considered appropriate for operation and refractory cases.

5. Congestive Cardiac Failure

Prazosin and congeners are used. They decrease the after load and preload.

6. Erectile Dysfunction

Alpha blockers have no role in erectile dysfunction.

7. Peripheral Vascular Spastic Disease

a. As sympathetic response increases, spasm of vessels occurs as in Reynaud’s phenomenon affecting fingers and toes.

b. Intermittent claudication due to spasm of muscles.

Phentolamine can cause vasodilatation.

8. Migraine

Stress induced vasoconstriction leads to hypoxia, causing the smooth muscles of vessels to relax resulting in vasodilatation. Thus blood pressure is not maintained and stretch of vessels in region of trigeminal nerve supply lead to migraine.

Nowadays, ergotamine is given.

9. Shock

If fluid replacement fails, alpha blockers are given, thus decreased vasoconstriction leads to increased cardiac output and blood moves from pulmonary to systemic circulation and from extra vascular to vascular compartment.

10. Autonomic Hyper-reflexia

During spinal cord transaction, there is increased vasoconstriction, so alpha blockers are given.

Specific Uses of Alpha 2 antagonists:

1. Reynaud’s Phenomenon

2. Diabetes Mellitus type II (block alpha 2 receptors which decrease insulin release, to increase it)
3. Psychiatric Depression (to cope neurotransmitter depletion)

Adverse Effects

1. Postural hypotension-as normally due to change in posture, an increase in sympathetic activity occurs, stimulating alpha 1 receptors, causing vasoconstriction and diverting blood upwards.

2. Reflex tachycardia (non selective alpha blockers, selective alpha 1 blockers are less prominent having little or no effect on alpha 2 receptors)
3. Nasal stuffiness
4. Sedation (esp. in phenoxy benzamine which is highly lipid soluble)
5. Diarrhea (increased stimulation of GIT)
6. Failure of ejaculation (alpha 2 blockage)
7. Peptic Ulcer aggravation –phentolamine
8. First dose phenomenon

Continue Reading

Phentolamine

Phenoxy benzamine

Prazosin

Terazosin, Tamsulosin and Yohimbine

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