α-adrenoceptor Antagonists

Non-selective α-adrenoceptor Antagonists

Irreversible Non-Competitive
Phenoxybenzamine (Dibenzyline®)
- Phenoxybenzamine is a non-selective irreversible non-competitive α- adrenoceptor antagonist. - It is binds covalently to both α1 and α2 receptors and the only way the body can overcome the   block; is to synthesize new a-adrenoceptors, which requires a day or longer. - Covalent binding with the receptors due to presence of N-chloro-ethyl. - Half-life: about 24 hours. (long acting) - Duration of action: 3 to 4 days. - Routes of administration:  Orally.
Reversible Competitive
Tolazoline (Priscoline®)	Phentolamine (Rogitine®)
- Tolazoline and Phentolamine are non-selective reversible competitive a-adrenoceptor antagonist. - They are      a competitive block of α1 and α2 receptors. - Phentolamine more potent than Tolazoline. - Duration of action: approximately 4 hours after a single injection. (short acting) - Route of administration: Parenterally.

 

Pharmacological  action	-  α1 receptor blocker effect:   Prevents vasoconstriction of peripheral blood vessels by endogenous   catecholamines à decrease peripheral resistance à reflex tachycardia. - α2 receptor blocker effect:   Block presynaptic inhibitory α2 receptors in the heart à increase NE release   àstimulates β1 receptors on the heart à increase CO .
Therapeutic uses	A) Hypertension in patients with pheochromocytoma. B) Non-specific uses of non-selective a blockers:      1) Symptomatic benign (non-cancerous) prostatic hyperplasia (BPH):         - Urinary retention associated with BPH treated by a-blockers which cause             àrelaxation of smooth muscle in the bladder neck, prostate, and prostate            capsule à Improve urine outflow.      2) Raynaud's  phenomenon:        - Is a recurrent vasospasm of the fingers and toes and usually occurs in          response to stress or cold exposure.     3) Impotence (Erectile Dysfunction; ED):        - Side effects of intrapenile injections of non-selective a-blockers à priapism         (painful prolonged erection lasting 4 hours or more), fibrotic reaction in penis         tissues and failure of ejaculation. C) Phentolamine used in prevention or treatment of dermal necrosis (caused by      following IV extravasation of NE). D) Phentolamine used in diagnosis of pheochromocytoma (Phentolamine blocking      test). E) OraVerse (Phentolamine) injection; is the only local anesthetic reversal agent.      In 2008 FDA has approved OraVerse for the reversal of soft-tissue anesthesia      and the associated functional deficits resulting from a local dental anesthetic         (about 55 min. vs. 155 min.).
Side effects	- Postural hypotension. - Reflex tachycardia. - Failure (difficulty) of ejaculation or retrograde ejaculation à due to blocking a   receptor in smooth muscles of vas deferens and ejaculatory ducts à failure of   contraction.

Selective α1-adrenoceptor Antagonists

Prazosin (Minipress®)
About The DRUG	- Prazosin is a selective competitive α1 receptors blocker. - In contrast to non-selective α1-adrenoceptor blockers, produce less reflex   tachycardia. - It acts by blocking postsynaptic α1-adrenoceptors on vascular smooth muscle     àvasodilatation à decrease total peripheral resistance à decrease BP. - Routes of administration: Orally.
Therapeutic uses	- Treatment of hypertension. - Symptomatic benign prostatic hyperplasia (BPH). - Congestive heart failure (CHF): -        Used as an adjunct to digoxin and diuretics for the treatment of CHF.        Due to decrease systemic resistanceà decrease preload and        afterload à  increaseCO. - Pheochromocytoma:        Used alone or in combination with B-blockers. - Peripheral vasospasm caused by ergot alkaloid toxicity. - Raynaud's phenomenon.
Side Effects	- First-dose orthostatic hypotension (initial syncope attack or first-dose   phenomenon) to overcome; the first dose must be minimized and giving at bed   time. - Headache, dizziness, drowsiness and nausea. - Edema (sodium and water  retention). - Priapism and failure of ejaculation (rare).
Doxazosin (Cardura®)		Terazosin (Hytrin®)
- Doxazosin and Terazosin are selective competitive α1 receptors blockers used Orally for:    symptoms of BPH and treatment of hypertension. - Side effects: same as Prazosin.
Alfuzosin (Xatral®)
- Alfuzosin is a selective a1 blocker used for symptoms of benign prostatic hyperplasia (BPH).   Not used for the treatment of hypertension. - Alfuzosin have better cardiovascular tolerability than Prazosin, Terazosin or Doxazosin. - Most common side effects: dizziness, upper respiratory tract infection, headache and fatigue. - Contraindication: patients with renal insufficiency and patients with history of QT prolongation.
Tamsulosin (Omnic Ocas®)
Tamsulosin is a selective α1 blocker that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels. - Tamsulosin is the most drug prescribed (more selective) in symptoms of benign prostatic hyperplasia (BPH). - It has some benefit in allowing kidney stones to pass through the ureter. - Dosage form:         Tamsulosin MR (Modified Release) capsule.         Tamsulosin OCAS (Oral-Controlled Absorption System) capsule.   Tamsulosin OCAS appeared to have the most favourable efficacy/tolerability ratio. - Dose: Initial Dose: 0.4 mg orally once a day - Maximum Dose: 0.8 mg orally once a day. - Most common side effect: Failure of ejaculation or retrograde ejaculation.
Silodosin (Rapaflo®)
- Silodosin is a selective a1 blocker (selective a1A receptor) in the prostate. - It is used in symptoms of benign prostatic hyperplasia (BPH). - same uses of Tamsulosin but Silodosin acts more rapidly.
Other Drugs Used in BPH (Not Act on α1 Receptors)
Dutasteride (Avodart®)		Finasteride (Proscar®)
- Finasteride and Dutasteride are a 5α-reductase inhibitors. - They are inhibits 5α-reductase enzyme which convert testosterone into the more potent androgen   dihydrotestosterone this lead to reduction in prostate size with improve in urinary flow. - Used primarily in the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia. - Side effects: ↑ risk of impotence (5%), dercease sexual desire (3%) and failure of ejaculation (1%). - Duodart (Dutasteride 0.5 mg + Tamsulosin 0.4 mg) is a combination used once daily in BPH.
Tadalafil (Cialis®)
- Approved for treatment of erectile dysfunction, symptoms of benign prostatic hyperplasia (BPH)  or combined erectile dysfunction and symptoms of BPH. (discussed in next topic)

Selective α2-adrenoceptor Antagonists

Yohimbine (Yohimbex®)

- Yohimbine is a selective competitive α2-blocker. - It is a natural alkaloid derived from the bark of the yohimbe tree in Central Africa. - Uses: mydriatic and erectile dysfunction. - Mechanism of action: The exact mechanism for its use in impotence has not been fully                                            elucidated.                                            Yohimbine blocks central pre-synaptic a2-adrenergic receptors                                             leads to ↑ release of neurotransmitters in CNS and in corpora                                            cavernosum penis such as nitric oxide (NO), noradrenaline, and                                            dopamine. - Common side effects: Tachycardia, hypertension increased motor activity, tremor, and dizziness.

                                                        

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