Nursing Pharmacology:  Autonomic Pharmacology Adrenergic Drugs

α-Adrenergic Antagonists (Blockers)

  Introduction

• α-adrenergic receptor activation is responsible for many actions of both endogenous catecholamine and drugs.

• α₁-adrenergic receptor activation results in contraction of arterial and venular smooth muscle.

• α-adrenergic receptor activation causes:

  • Decreased sympathetic outflow.

  • Increased vagal tone.

  • Increased platelet aggregation.

  • Decreased release of the transmitters acetylcholine and norepinephrine (presynptic inhibitory effect).

  • Metabolic regulation effects, e.g.:

    •  Decreased insulin release

    •  Decreased lipolysis

  α-adrenergic receptor antagonists:

  • Phentolamine (Regitine) exhibits comparable potency at  α₁ and α₂-adrenergic receptors

  • Prazosin (Minipress) is more potent at α₁ compared to α₂-adrenergic receptors

  • Yohimbine (Yocon) is more potent at α₂ compared to α₁-adrenergic receptors

α₁-adrenergic receptor antagonists- Cardiovascular Effects

• α₁-adrenergic receptor blockade inhibits vasoconstriction caused by endogenous catecholamines.

• α₁-adrenergic receptor blockers cause an arteriolar and venular vasodilation (a reduction in peripheral resistance) that decreases blood pressure. (BP = Cardiac Output x Total Peripheral Resistance)

• Hypotensive responses trigger baroreceptor reflexes that act to increase

  •   Heart rate

  •   Cardac output

  •   Fluid retention

• If the drug blocks both α₁ and α₂ adrenergic receptors, then the α₂ presynaptic effect serves to increase norepinephrine release further increasing heart rate through ß₁ cardiac stimulation.

• α₁-adrenergic antagonists block effects of sympathomimetic amines. For example:

  • pure α-adrenergic agonist effects (phenylephrine (Neo-Synephrine)) are nearly completely blocked

  • norepinephrine α-receptor mediated effects are blocked but ß₁ effects remain.

  • "Epinephrine reversal": epinephrine blood pressure increases (pressor effects) are converted to vasodepressor effects due to a receptor blockade in the presence of continued ß₂ receptor activation.

    • Recall that ß₂ receptor activation causes vasodilation by meanse of ß₂ receptor activation that leads to relaxation of vascular smooth muscle.

α₂-adrenergic receptor antagonists

• α₂-adrenergic antagonists increase norepinephrine release from nerve endings.

  • Activation of central nervous system (CNS) α₂-adrenergic receptors cause a decrease in sympathetic outflow and consequently a decrease in blood pressure.

  • α₂-adrenergic antagonists such as yohimbine (Yocon) increase sympathetic outflow and increase blood pressure.

  • Activation of a₂-adrenergic receptors can result in smooth muscle contraction or relaxation, depending on vascular beds.

Phenoxybenzamine (Dibenzyline)

• Phenoxybenzamine blocks both α₁ and α₂ adrenergic receptors.

• Phenoxybenzamine reacts with a adrenergic receptors to form a covalent bond.

  • Receptor blockade is "irreversible" (covalent) and reactivation of receptor function requires de novo receptor synthesis

  • Pharmacological effects are secondary to α adrenergic blockade.  Such effects include:

    • A decrease in peripheral resistance

    • Reflex cardiac stimulation

    • Impaired response to hypovolemia and anesthetic-induced vasodilation

    • Impaired response to exogenous pressors

    • Orthostatic hypotension

 Therapeutic Uses for α-adrenergic blocking drugs

• Treatment of elevated and fluctuating blood pressure due to pheochromocytoma.

  • Pheochromocytomas are adrenal medullary tumors secreting into the circulation large amounts of catecholamines.

  • High blood catecholamine levels cause severe hypertension.

  • Phenoxybenzamine (Dibenzyline) or phentolamine (Regitine) are used to control blood pressure prior to definitive surgical treatment.

• Drugs in this category are useful in controlling autonomic hyperreflexia in patients with spinal injury.

• Some α adrenergic antagonists (blockers) are effective in treating benign prostatic hypertrophy by relaxing smooth muscle that otherwise would impede urine flow.

• Major adverse effects of α-adrenergic blockade:

  • Hypotension

  • Orthostatic hypotension

  • Reflex tachycardia

  • Inhibition of ejaculation

Phentolamine  (Regitine) and Tolazoline (Priscoline)

• Competitive antagonist at both α₁ and  α₂ adrenergic receptor

• Phentolamine also blocks 5-HT (serotonin) receptors.

• Phentolamine causes mast cell histamine release.

• Tolazoline is less potent, but otherwise similar to phentolamine.

• Some clinical uses for phentolamine:

  • Short-term management of pheochromocytoma

  • Counteracts dermal necrosis following extravasation of vasoconstrictive, α-adrenergic receptor agonists

•   Major adverse effects

Prazosin (Minipress) and Terazosin (Hytrin)

• Prazosin and terazosin are selective α₁ adrenergic receptor blockers.

  • Both cause a significant reduction in peripheral vascular resistance and venous return, a combination which reduces reflex tachycardia.

  • Prazosin and trazosin decrease preload: no significant increase cardiac output or heart rate.

  • Possible CNS effect: suppression of sympathetic outflow.

• Significant orthostatic hypotension following first-dose.

• Some therapeutic uses for prazosin/terazosin:

  • Essential hypertension.

  • Congestive heart failure (arteriolar and venular dilatation)

    • Reduction in preload and afterload improves cardiac output

    • Reduction in pulmonary congestion

    • Prazosin has not been shown to improve longevity (by contrast to treatment with an angiotensin converting enzyme (ACE) inhibitor or by a combination of the vasodilator hydralazine and an organic nitrate.

  • Benign prostatic hypertrophy

    • Mechanism is: α₁-adrenergic receptor blockade reduces bladder and urethral trigone muscle tone.

Other α-adrenergic receptor blockers

• Yohimbine (Yocon) α₂ adrenergic receptor blocker

• Labetalol (Trandate, Normodyne) (α and ß receptor blocker)

• Ketanserin (5-HT [serotonin] and alpha-adrenergic receptor blocker)

• Some antipsychotic drugs (e.g. haloperidol (Haldol), chlorpromazine (Thorazine))

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.225-232.