Medical Pharmacology: The Pharmacology of Alpha-2-Receptor Antagonists

Medical Pharmacology Chapter 5: Autonomic Pharmacology: Adrenergic Drugs

α₂-Adrenergic Receptor Antagonists

Overview¹⁵²

**"The Adrenergic Receptors"**

Attribution: Joel The Adrenergic Receptors https://www.youtube.com/watch?v=Ip1o57qIoZw Med Immersion Youtube Channel: https://www.youtube.com/channel/UC5MpSzULJdwGOkGqmkHMC8A

α₂-adrenergic receptor antagonists (blockers) have both peripheral and central (CNS) actions.

Peripheral α₂-adrenergic receptors are localized presynaptically and upon activation, inhibit norepinephrine along with cotransmitter release from sympathetic nerve terminals.

Blockade of these receptors increase synaptic norepinephrine.

**Adrenergic Receptor Signal Transduction (α₂-receptor system is outlined)**²³⁵

The mechanism of adrenergic receptors.^{236 (text slightly modified)} Epinephrine and norepinephrine are receptor ligands to either α₁, α₂ or β-adrenergic receptors. α₁ couples to G_q, which results in increased intracellular Ca²⁺ which results in smooth muscle contraction. α₂, on the other hand, couples to G_i, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle relaxation. β receptors coupled to G_s, and increases intracellular cAMP activity, resulting in for example heart muscle contraction, smooth muscle relaxation and glycogenolysis.²³⁶

Central α₂-receptors localized in the pontomedullary brain region regulate sympathetic outflow.¹⁵²
- Activation of these receptors reduce sympathetic activity which results in a decrease in blood pressure.
- By contrast, inhibition of these receptors by α₂-adrenergic antagonists, such as yohimbine, has the effect of increasing sympathetic outflow as well as promoting norepinephrine release peripherally.
- Increased norepinephrine activates of both α₁-and β₁-adrenergic receptors; such activation causes an increase in blood pressure.¹⁵²

Yohimbine (Yocon):¹⁵²
- Yohimbine (Yocon) is classified as a α₂-adrenergic receptor antagonist.
- Yohimbine competes competitively with agonists for receptor binding sites.

Non-Selective Adrenergic Receptor Antagonists

Nonselective α-adrenergic receptor antagonists:¹⁵²

Nonselective α-adrenergic receptor blockers are represented by phentolamine (Regitine) and phenoxybenzamine (Dibenzyline).

Phentolamine is a competitive antagonist; whereas, phenoxybenzamine produces very long-term, "irreversible" covalent receptor blockade.
- These agents are viewed as historically "classical" α-adrenergic receptor blockers, preceding more current agents, such as prazosin.
With respect to cardiovascular activity, nonselective α-blockers reduce peripheral resistance due to antagonism at α-adrenergic vascular receptors.
- As a result of decreased peripheral resistance in blood pressure, an autonomic compensatory reflex, tachycardia, is observed.
  - Cardiac stimulation probably occurs not only due to increased reflex sympathetic activity but also by increased norepinephrine release from cardiac sympathetic nerve terminals due to blockade of presynaptic α₂-adrenergic receptors.
    - Activation of these presynaptic α₂ receptors inhibit norepinephrine release (hence blockade of these receptors enhance release).
- Nonselective α-adrenergic receptor antagonism can cause postural (orthostatic) hypotension and resulting tachycardia predisposes to arrhythmias in some circumstances.

Clinical uses of these "classical" nonselective blockers, phentolamine and phenoxybenzamine include management of vascular effects associated with pheochromocytoma.

Pheochromocytoma
Gross pathology illustrating pheochromocytoma, an adrenal gland tumor (ref. 12)

Phentolamine (Oraverse) has been FDA approved for reversal or decreasing soft-tissue anesthesia duration.

Local anesthetic preparations may include a sympathomimetic, which causes localized vasoconstriction thus prolonging local anesthesia and reducing local anesthetic systemic effects.

Reversal of this vasoconstriction at the end of the case may be accomplished by blocking local sympathomimetic activity caused by e.g. epinephrine administered in the local anesthetic solution.¹⁵²

Vasocontrictors added to local anesthetic solutions

Purpose of adding epinephrine to a local anesthetic solution: Increased duration: addition of epinephrine (1:2000,000 or 5 ug/ml) to cause vasoconstriction

Reduced systemic absorption

Higher anesthetic concentration near nerve fibers

Prolongation of conduction blockade (about 50% longer)

Reduced systemic absorption (by about 33%)

Factors influencing the effectiveness of epinephrine on local anesthesia: Dependencies:

Which anesthetic is used:

Reduced effect of epinephrine on duration of conduction blockade and systemic absorption comparing mepivacaine (Carbocaine) and etidocaine (Duranest) [these are more lipophilic] with lidocaine (Xylocaine), which is less lipophilic

More lipophilic local anesthetics will tend on their own to associate strongly with tissues

Level of sensory blockade needed for spinal or epidural anesthesia

Duration of lower extremity sensory anesthesia extended by epinephrine or phenylephrine (Neo-Synephrine); this effect is not observed for abdominal region anesthesia

Conditions: epinephrine (0.2 mg) or phenylephrine (Neo-Synephrine) (2 mg) added to mepivacaine (Carbocaine) or lidocaine (Xylocaine) -- placed in subarachnoid spaces

Spinal anesthesia -- tetracaine (pontocaine): duration of action extended by vasoconstrictors

Condition 1: epinephrine plus tetracaine (pontocaine) (6 mg, low-dose)- result: increase in spinal anesthesia success rate

Condition 2: epinephrine plus tetracaine (pontocaine) (10 mg, higher dose)- result: no increase in spinal anesthesia success rate

Prolongation of local anesthetic action (no effect by epinephrine on time-to-onset): Mechanisms --

Decreased systemic absorption

Increased local anesthetic concentration in the vicinity of sensory nerves

Increased uptake of the local anesthetic

Advantages of reduced local anesthetic systemic absorption:

Local anesthetic absorption rate more likely to match metabolic rate resulting in less local anesthetic systemic toxicity

Toxicities associated with systemic epinephrine absorption:

Local anesthetic + epinephrine: increased cardiac irritability which may cause an increased risk of cardiac arrhythmias

Increased possibility of hypertensive response in susceptible patients

Other agents which may be added to local anesthetics that affect duration of action

Dextran (low-molecular-weight) when added to local anesthetic solutions result in increased peripheral nerve block anesthesia duration (probably due to a reduction in local anesthetic systemic absorption)

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.

Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.

Other Adrenergic Receptor Antagonists

Examples of other α-adrenergic receptor blockers¹⁵²
- Ergot alkaloids: these alkaloids exhibit complex affinities for receptors and can act as partial agonists or antagonists at α-receptors, dopamine receptors and 5-HT (serotonin) receptors.
- Indoramin (Baratol) is categorized as a selective, α₁-receptor antagonist, acting by competitive inhibition.
  - This agent,not available in the United States, may be used for management of hypertension, BPH, and migraine prophylaxis. Indoramin also competitively blocks histamine H₁ and 5-HT receptors.
- Urapidil, also not currently available in the United States, is a selective α₁ receptor blocker.
  - Antihypertensive actions of urapidil may involve CNS activity in addition to well-established peripheral antagonism at α₁-adrenergic sites.
- Neuroleptic drugs: certain well-known antipsychotic agents such as chlorpromazine and haloperidol (and other neuroleptic drugs belonging to the phenothiazine and butyrphenone groups) antagonize at α-adrenergic receptor sites.
  - In addition to blockade at α-receptor sites, these agents exhibit dopamine (D₂) receptor antagonism, which is the likely basis for their antipsychotic activity.¹⁵²

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