Postsynaptic Alpha Adrenergic Antagonist

Aka: Postsynaptic Alpha Adrenergic Antagonist, Alpha Adrenergic Antagonist, Peripheral Alpha-1 Adrenergic Antagonist, Alpha Adrenergic Receptor Blocker

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II. Indications

  1. Non-selective agents
    1. Hypertension (non-selective agents)
      1. Not first-line Antihypertensives, and avoid using as monotherapy (higher risk of CVA and CHF)
    2. Pheochromocytoma Hypertensive Crisis (Phentolamine, Phenoxybenzamine)
  2. Selective Alpha-1a Antagonists (e.g. Tamsulosin)
    1. Benign Prostatic Hypertrophy (Selective )
    2. Medical Expulsive Therapy for Ureteral Stone

III. Mechanism: General and Antihypertensive Effects

  1. See Alpha Adrenergic Receptor
  2. Peripheral Alpha-1 Adrenergic Antagonists
    1. These agents are post-synaptic adrenergic alpha blockers, resulting in arterial and Venous Vasodilation
    2. Nonselective post-synaptic Alpha Antagonists (Terazosin, Doxazosin, Prazosin) result in general peripheral vasodilation
    3. Selective Alpha-1a Antagonist (Tamsulosin, Alfuzosin, Silodosin) primarily result in Urethral region relaxation
  3. Contrast with Presynaptic Adrenergic Release Inhibitors that also lower Blood Pressure
    1. Central Acting Adrenergic Agonists (e.g. Clonidine) activate central alpha-2 receptors that inhibit CNS sympathetic signals
    2. Presynaptic Peripheral Acting Adrenergic Antagonists (e.g. Reserpine) block peripheral Norepinephrine release

IV. Mechanism: Benign Prostatic Hypertrophy

  1. Preparations used in Benign Prostatic Hypertrophy
    1. See Selective Alpha-1a Antagonist (Tamsulosin, Alfuzosin, Silodosin)
    2. Terazosin (Hytrin)
    3. Doxazosin (Cardura)
    4. Prazosin (Minipress)
  2. Rapid relaxation of Smooth Muscle tone
    1. Bladder neck
    2. Prostate Capsule
    3. Prostatic Urethra
  3. Relieves symptoms of urinary obstruction
    1. May see full effect within 2 weeks
  4. Does not effect size of Prostate (unlike Proscar)

V. Pharmacokinetics

  1. Agents are highly Protein bound (>90%)
  2. Bioavailability is roughly 50% for the non-selective Alpha Adrenergic Receptor Blockers (Prazosin, Terazosin, Doxazosin)

VI. Medications: Non-Selective Alpha Antagonists

  1. Terazosin (Hytrin)
    1. Hypertension
      1. Start 1 mg orally at bedtime
      2. Titrate to effective dose 1 to 5 mg daily or in divided doses (Maximum 20 mg/day)
    2. Benign Prostatic Hypertrophy (replaced by Selective Alpha-1a Antagonists)
      1. Start 1 mg orally at bedtime
      2. Titrate to effect by doubling dose every 1-2 weeks (to 2, 5 and 10 mg, maximum of 20 mg/day)
      3. Observe for effects after 4 to 6 weeks on optimal dose (typically 10 mg)
  2. Doxazosin (Cardura)
    1. Hypertension
      1. Start: 1 mg orally at bedtime and titrate dose (Maximum 16 mg/day)
    2. Benign Prostatic Hypertrophy (replaced by Selective Alpha-1a Antagonists)
      1. Start: 1 mg orally at bedtime and titrate every 1-2 weeks doubling dose, to a maximum of 8 mg at bedtime
      2. Extended release formulation (e.g. Cardura XL) 4 mg in am daily (may increase to 8 mg daily after 3-4 weeks)
    3. Medical Expulsive Therapy for Ureteral Stone (replaced by Selective Alpha-1a Antagonists)
      1. Extended release formulation (e.g. Cardura XL) 4 mg orally daily (not FDA approved)
  3. Prazosin (Minipress)
    1. Terazosin and Doxazosin are preferred instead (once daily dosing at similar cost)
    2. Hypertension
      1. Start 1 mg orally twice daily to three times daily
      2. Titrate to usual daily total dose 20 mg divided two to three times daily
      3. Maximum total daily dose: 40 mg/day (but doses above 20 mg/day offer little additional benefit)

VII. Medications: Unique Non-Selective Alpha Antagonists Indicated in Pheochromocytoma Hypertensive Crisis

  1. Pharm: Htn Alpha Postsynaptic Antagonist
  2. Phenoxybenzamine (Dibenzyline)
    1. Indicated in the Hypertensive Crisis of Pheochromocytoma
      1. Terazosin and Doxazosin are preferred as routine Antihypertensive agents (once daily dosing at similar cost)
    2. Irreversible alkylation of the Alpha Adrenergic Receptor
    3. Start 10 mg orally twice daily
      1. Titrate to typical dose 20 to 40 mg orally twice daily
      2. Maximum daily dose: 120 mg/day
  3. Phentolamine (Rogatine)
    1. Hypertensive Crisis in Pheochromocytoma
      1. Dose: 5 mg IV/IM for one dose (results in profound drop in BP, e.g. 60/25 mmHg decrease in BP)
    2. IV Extravasation of Catecholamines (e.g. Norepinephrine)
      1. Prepare 5-10 mg in 10 ml Normal Saline, and inject 1 ml around extravasation site
      2. In adults may repeat dose up to a total of 5 ml injected around extravasation site

VIII. Medications: Selective Alpha-1a Antagonists (Prostate specific agents)

  1. See Selective Alpha-1a Antagonists
  2. Alfuzosin (Uroxatral, generic)
  3. Silodosin (Rapaflo)
  4. Tamsulosin (Flomax, generic)

IX. Medications: Combination Alpha-Beta Antagonists

  1. Labetalol (Trandate)
  2. Carvedilol (Coreg)

X. Adverse Effects (Incidence: 7 to 9%)

  1. Dose at bedtime
    1. Slowly titrate to reduce side effects (esp. Orthostatic Hypotension, Dizziness, drowsiness)
  2. Cardiovascular adverse effects (also occurs with selective agents, albeit less often)
    1. Postural or Orthostatic Hypotension
      1. Common with first dose (may be severe)
      2. Exacerbated by Hyponatremia, and when combined with PDE5 Inhibitors (e.g. Sildenafil)
    2. Dizziness or Light Headedness
    3. Syncope (with initial dosing, esp. Prazosin)
    4. Associated with Fall Risk and secondary Fracture risk
  3. Other adverse effects
    1. Intraoperative Floppy Iris Syndrome (Cataract Extraction complication)
    2. Drowsiness
    3. Fatigue
    4. Asthenia
    5. Xerostomia
    6. Headache
    7. Nightmares
    8. Sexual Dysfunction

XI. Precautions

  1. Pregnancy Category C with most Peripheral Alpha-1 Adrenergic Antagonists
    1. Unknown safety with Doxazosin
  2. Avoid using as monotherapy for Hypertension
    1. Higher risk of CVA and CHF compared with other agents
    2. (2000) JAMA 283:1967-75 [PubMed]

XII. References

  1. Aldridge (1996) Lancet 348:602
    1. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)64801-5/abstract
  2. Hamilton (2010) Tarascon Pocket Pharmacopeia, p. 76-7
  3. (1994) Med Lett Drugs Ther 36: 15 [PubMed]
  4. (1997) Med Lett Drugs Ther 39: 1011 [PubMed]
  5. Grimm (2011) J Clin Hypertens 13(9):654-7 +PMID: 21896145 [PubMed]
  6. Lee (2000) Ann Pharmacother 34:188-99 [PubMed]

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