Autonomic pharmacology

α₂-Adrenergic Receptor Agonists

Overview:¹⁵²
- The principle clinical use for α₂-adrenergic receptor agonists is in hypertension management.¹⁵²
  - In pharmacological classification, the α₂-adrenergic receptor agonist prototypical agent is clonidine (Catapres).
    - Clonidine (Catapres)
    - The mechanism of antihypertensive action of clonidine describes activation of central (CNS) α₂-adrenergic receptors likely located in brainstem neurons regulated by the hypothalamus.¹⁸⁰
      - A consequence of this neuronal activation is a reduction in sympathetic outflow from the brain.
  - α₂-adrenergic agonists when applied topically to the eye decrease intraocular pressure by reducing aqueous humor production.¹⁵²
    - Clonidine appears unsuitable for this application because ocular administration still results in systemic hypotensive effects
      - However, apraclonidine (lopidine) and brimonidine (Alphagan), both derivatives of clonidine, when administered both reduce intraocular pressure and have either no or very limited effects on blood pressure.
      - Apraclonidine (Lopidine)
      - Brimonidine (Alphagan)

As described in the introduction, clonidine (Catapres) has major cardiovascular actions, particularly on blood pressure and heart rate.
- IV clonidine infusion causes a transient increase in blood pressure due to activation of postsynaptic α₂-adrenergic receptors associated with vascular smooth muscle.
  - Illustration of vascular smooth muscle cell location¹⁸²
  - The coupling between α₂-adrenergic receptor activation and vascular contractile effects is likely mediated by calcium influx.¹⁸¹
    - This α₂-receptor associated calcium channel appears distinct from the membrane potential-dependent calcium channel.
  - Affinity for clonidine at postsynaptic α₂ vascular smooth muscle receptor sites appears high; although, its partial agonist character reduces pharmacological efficacy.¹⁵²
    - This hypertensive reaction is not observed following oral administration.
    - Transient hypertension following IV administration, however leads to prolonged hypotension as a result of reduced CNS sympathetic outflow, possibly due to some extent by activation of α₂ adrenergic receptors localized in the brainstem.
  - Clonidine-mediated hypotension occurs due to reduced cardiac output (secondary to decreased rate), reduced capacitance vessel tone (vasorelaxation), and decreased peripheral vascular resistance.¹⁸³
    - Reduction in arterial blood pressure following clonidine administration is also associated with diminished renal vascular resistance with maintenance of renal blood flow.
- Clonidine is a imadazoline compound and two relatively new antihypertensive drugs also are imadazolines.
  - Clonidine Imadazoline
  - These agents are rilmenidine (Hyperium, Tenaxum) and moxonidine (Physiotens).
    - Rilmenidine (Hyperium)
    - Moxonidine (Physiotens)
  - These latter two imadazoline-antihypertensive drugs suggest a possible antihhypertensive role for imadazoline receptors which are described by three classes:.^152,184
    - I₁ which appear responsible for antihypertensive actions of imadazolines¹⁸⁴
    - I₂ which describes an allosteric binding site associated with monoamine oxidase¹⁸⁴
    - I₃ which is involved in insulin secretion regulation from pancreatic beta cells. ¹⁸⁴
    - Furthermore, I₁-imadazolines receptor activation induces phosphatidylcholine hydrolysis, forming diacylglycerol (DAG).¹⁸⁵
      - Elevation of DAG promotes synthesis of second messengers arachidonate acid and eicosanoids.
      - Another effect of I₁-imadazolines receptor activation is the inhibition of the sodium-hydrogen antiporter transport as well as induction of catecholamine synthetic enzymes.

In order to investigate the relative roles of α₂-adrenergic receptors and imadazoline receptors in mediation of hypotensive responses to agent such as clonidine, rilmenidine, and moxonidine several experimental approaches have been used.

One method examined antihypertensive effects of these agents in "wild-type" mice and transgenic mice (D79N), which lacked functional α_2a-adrenergic receptors.

This model had been previously used to investigate whether or not the imadazoline α₂-adrenergic agonists, brimonidine and dexmedetomidine acted through α₂-adrenergic receptors and/or I₁-imadazoline receptors.
- In that study no evidence was found for I₁-imadazoline receptor mediated hypotension¹⁸⁷ , although these agents, brimonidine and dexmedetomidine exhibit selectivity for α₂ over I₁-imadazoline receptors.¹⁸⁸
In the present study, clonidine-mediated hypotension was either eliminated or substantially reduced in those mice lacking functional α₂-adrenergic receptors (D79N mutant transgenic mice) and substantially attenuated in rilmenidine and moxonidine groups.¹⁸⁶

Effects of Clonidine on Changes in Mean Blood Pressure (mmHg)¹⁸⁶

Conscious wild-type and D79N mutant α_2A-adrenoceptor mice: Effects of clonidine (30, 100 and300 mg kg; i.v.) on changes in mean blood pressure (mmHg) are shown. Each bar represents the mean value with S.E. mean for data collected at 5 min intervals over 30 min time periods. The mean values are obtained from four mice. (Figure and legend adapted from ref (186 ).

Effects of Rilmenidine on Changes in Mean Blood Pressure (mmHg)¹⁸⁶

Conscious wild-type and D79N mutant α_2A-adrenoceptor mice: Effects of rilmenidine (100, 300 and 1000 μg/kg; i.v.) on changes in mean blood pressure (mmHg) are shown. Each bar represents the mean value with S.E. mean for data collected at 5 min intervals over 30 min time periods. The mean values are obtained from four mice. (Figure and legend adapted from ref (186).

Based on findings using D79N transgenic mice, the authors concluded that not only was expression of α_2a-adrenergic receptors a prerequisite for cardiovascular effects of rilmenidine and moxonidine in conscious mice but also that results did not indicate I₁-imidazoline receptor-mediated activity.

Other studies, however, utilizing many biochemical and pharmacological methods, argue for involvement of imidazoline receptors both for vasomotor tone regulation and mechanism of at least some centrally acting antihypertensive agents.¹⁸⁹
- For example, functional studies using selective antagonists indicated that hypotensive effects of clonidine-related agents are mediated by imidazoline-specific receptors; by contrast, their sedative action involved α₂-adrenergic receptors located in the locus ceruleus.
- When compared with clonidine, agents such as a rilmenidine were found more selective for imadazoline receptors than for α₂-adrenergic receptors.
  - This relative selectivity was suggested to explain reduced side effects associated with rilmenidine and similar agents at doses which produce hypotensive responses.
- Newer imidazoline-like compounds, which exhibit selectivity for both I₁ and I₂ imidazoline binding sites, have been synthesized.¹⁸⁹
  - Some of these agents, when injected centrally in animals, were sufficient alone to reduced blood pressure.
  - Furthermore, imidazoline receptors and α₂-adrenergic receptors might both be involved in hypotensive activity of centrally acting agents.
- These authors concluded that exclusive stimulation of imadazoline receptors with a highly selective agent (S23515) or exclusive stimulation of α₂-adrenergic receptors (using α-methylnorepinephrine) acting within the CNS is sufficient to cause hypotension.¹⁸⁹
  - They also concluded that a hypotensive effect requires the "integrity" of the α₂-adrenergic receptors (at a minimum for the case of "pure"α₂-adrenergic agonists and hybrid drugs).^189.152

Clonidine reduces sympathetic preganglionic fiber activity in the splanchnic nerve and also reduces firing frequency and postganglionic cardiac nerve fibers.¹⁵²

These effects are blocked by administration of the α₂-adrenergic antagonist, yohimbine.
Clonidine administration reduces heart rate both by increasing parasympathetic outflow (a vagal, cholinergic action) and by decreasing sympathetic activity.

An additional mechanism for clonidine antihypertensive activity is activation of presynaptic α₂ receptors that, when activated, attenuate postganglionic sympathetic neuronal release of norepinephrine (NE), ATP, and NPY (neuropeptide Y).

NMR Solution structure of Neuropeptide Y^191,191a

Neuropeptide Y (NPY) has been shown to potentiate vasoconstriction induced by neurostimulation and by norepinephrine in, for example, human saphenous vein preparations.¹⁹⁰

NPY also induces release of a cycloxygenase metabolite (thromboxane A₂), which may act synergistically with respect to norepinephrine-related vasoconstriction.

The influence of NPY on vascular smooth muscle contraction, as a function of neurostimulation frequency and norepinephrine concentrations is illustrated below:

Effects of Neuropeptide Y (NPY) on smooth muscle contraction induced by nerve stimulation or by application of norepinephrine (noradrenaline)¹⁹⁰

"Comparison of the first series (Control) of vasoconstrictor responses to 1 min transmural nerve stimulation (left) and 1 min noradrenaline infusion (right) with the second series of vasoconstrictor responses to the same stimuli obtained 30 min after the addition of 50 nM NPY in superfused human saphenous vein rings with intact endothelium (n=10).
Contractions are expressed as the percentage of the maximal contraction to transmural nerve stimulation (16 Hz) and noradrenaline (norepinephrine) (NA, 10 mM) at the beginning of the experiments.
The contractile effects of this first series of transmural nerve stimulation and noradrenaline are significantly different from those of the second series in the presence of NPY; P<0.001 and P<0.005 vs control period for transmural nerve stimulation and noradrenaline, respectively.
Data points represent means and vertical lines show S. E. .mean."¹⁹⁰

Clonidine adverse effects:¹⁵²
- Two major clonidine adverse effects are dry mouth and sedation.
  - The likelihood of these reactions is at least 50% and may be a sufficient significance to recommend cessation of clonidine administration.
    - These effects may be less prominent after several weeks of dosing.
  - Sexual dysfunction has also been reported following clonidine administration.
  - Some patients may also experience profound bradycardia which might be expected based on clonidine stimulation of parasympathetic (cholinergic, vagal) outflow.
  - Clonidine may be administered by oral administration and is also available by transdermal patch.
    - With transdermal patch, contact dermatitis may occur in about 15%-20% of patients.
  - Sudden discontinuation of long-term clonidine treatment may cause withdrawal reactions.
Clonidine overdosage (poisoning):¹⁹²
- With overdosage, clonidine may present with a variety of symptoms.
- Most of these effects are secondary to generalized sympathetic depression.
  - Such effects include:
    - pupillary constriction
    - lethargy
    - bradycardia
    - apnea
    - coma
    - hypotension, and
    - hypothermia.
  - Clonidine may also induce hypertension due to direct activation of α₁-adrenergic receptors, an effect which is usually transient and may also be observed with oxymetazoline and tetrahydrazoline.
    - Complete recovery following clonidine overdosage usually occurs within a day.
  - With respect overdosage diagnosis, patients may present with pinpoint pupils, respiratory depression, hypotension and bradycardia, effects which could mimic opioid intoxication; however, clonidine overdose does not usually respond to the opioid antagonist naloxone (Narcan).
  - Treatment of clonidine toxicity is primarily supportive (24 hours).
    - Such supportive efforts involve airway protection and ventilation, if needed.
    - Other consequences such as coma, hypotension, bradycardia, sometimes with AV block may require management including fluids, atropine, and dopamine.
    - Decontamination, if appropriate, involves oral administration of activated charcoal; whereas, gastric lavage is typically not required after small to moderate ingestions, provided activated charcoal has been given promptly.
    - Lastly, whole-bowel irrigation could be considered after ingestion of clonidine skin patches.
Clonidine therapeutic applications:^152,173
- The principal therapeutic use for clonidine (Catapres) is in the management of hypertension.¹⁵²
  - Mechanisms for clonidine antihypertensive effects have been previously described.
  - Clonidine may also be helpful in decreasing diarrhea in a subset of diabetic patients with autonomic neuropathy.
    - The mechanism here appears based both on an increase of sodium chloride and fluid absorption with inhibition of bicarbonate secretion secondary to G.I. tract α₂-adrenergic receptors.
    - Narcotic-, alcohol-and tobacco-withdrawal may benefit from clonidine administration.
      - In those settings, clonidine may decrease adverse sympathetic activity and attenuate drug craving.
  - Additionally, there are apparent applications for clonidine in management of some child and adolescent psychiatric disorders.¹⁹³
    - Clonidine appears clinically helpful in reducing states of hyperarousal seen in children and adolescents with PTSD (posttraumatic stress disorder) and ADHD (attention deficit hyperactivity disorder).
    - Drug side effects in this setting are similar to those described earlier; however, some reports have suggested possible cardiac toxicity associated with clonidine when combined with methyphenidate (Ritalin).
      - During the period of clonidine administration, blood pressure and pulse rate should be monitored; furthermore, clonidine discontinuation should be gradual in order to avoid rebound hypertension.
      - Blood pressure should be evaluated during the withdrawal period.¹⁵²
- Clonidine appears useful in the anesthesia setting as well.¹⁷³
  - Clonidine administration decreases MAC (minimum alveolar concentration; an anesthetic concentration at which 50% of patients do not respond to noxious stimuli)-thus reducing anesthetic and analgesic requirement.
  - Clonidine also provides sedation and reduces anxiety.
  - During regional anesthesia including peripheral nerve block, clonidine increases block duration.
    - This effect might be due to direct spinal cord action, mediated by α₂-dorsal horn neuronal postsynaptic receptors.
  - Additional possible benefits from clonidine administration in the anesthesia setting may include:
    - decreased postoperative shivering
    - inhibition of opioid-induced muscle rigidity
    - reduced opioid withdrawal symptoms as well as
    - management of certain chronic pain syndromes.¹⁷³
- A related agent, dexmedetomidine (Precedex) appears also useful in the anesthesia setting due to its sedative, analgesic and sympatholytic (anti-sympathetic nervous system) effects.¹⁷³
  - These actions reduce cardiovascular reactions occurring during the perioperative time frame.
  - Following dexmedetomidine (Precedex) administrations, patients exhibit sedation from which they are readily aroused.
  - Dexmedetomidine appears useful in sedating ventilated patients postoperatively both in the postanesthesia care facility as well as in intensive care, due to a combination of both its anti-anxiety and analgesic activities.
  - Long-term administration of clonidine or dexmedetomidine can increase the number of adrenergic receptors and also induces a supersensitive state.
    - Therefore, sudden discontinuation of either agent may predispose to hypertensive reaction.
    - After only two days of dexmedetomidine administration, sudden discontinuation may induce this hypertensive state, a reaction which might be expected following a more extended clonidine treatment period.
      - One possible explanation for this effect is a higher α₂-receptor affinity observed with dexmedetomidine compared to clonidine.¹⁷³

Other uses for clonidine:¹⁵²

In hypertensive patients with suspected pheochromocytoma, clonidine administration has been used in the differential diagnosis.

Plasma norepinephrine in patients with primary hypertension will notably decrease following clonidine administration, an effect not typically observed in patients with pheochromocytoma.

Clonidine: Suppression Testing in Pheochromocytoma¹⁹⁶
In this setting clonidine would be part of "suppression and stimulation" testing. Suppression of plasma catecholamines by clonidine has occasionally been used in cases in which pheochromocytoma diagnosis appears uncertain. This use may be problematic in that clonidine may cause severe hypotension and may be unreliable in this application. The clonidine suppression test requires proper patient preparation. For example, interfering foods and medications (numerous) should be discontinued for week. Certain agents in particular including beta-adrenergic receptor blockers, tricyclic antidepressants and thiazide diuretics may interfere with clonidine suppression and must be discontinued for at least two days prior to the test. Overnight fasting along with smoking abstention are also required. A normal clonidine suppression test is considered as either a minimum plasma norepinephrine level of 500ng/L or less or plasma norepinephrine suppression to <70% of baseline levels. Elevated baseline catecholamine levels in some "stressed" patients may not drop following clonidine. Misleading clonidine suppression testing has resulted in unnecessary exploratory laparotomies; as a consequence, clonidine testing should not be the basis of pheochromocytoma diagnosis.

Pheochromocytoma is a neuroendocrine tumor of the adrenal medulla which secretes high concentrations of epinephrine and epinephrine.

Pheochromocytoma

Adrenal Gland: Bilateral Pheochromocytoma: Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides."¹⁹⁴	"A symptomatic patient with pheochromocytoma and islet cell tumor of the pancreas. A small right pheochromocytoma with a necrotic center (P) is seen. In addition, an intensely enhancing mass is present in the neck of the pancreas (I). Two small pancreatic cysts are also seen but the bulk of the pancreas is spared. Pancreatic islet cell tumors are associated with pheochromocytomas and are generally not accompanied by cystic pancreatic disease."¹⁹⁵

There are numerous "off label" clonidine uses.¹⁵²

Off-Label Clonidine Uses¹⁵²
atrial fibrillation	attention-deficit/hyperactivity disorder (see above	growth delay in children	cyclosporine-related nephrotoxicity
Tourette's syndrome	mania	hyperhydrosis	posthepatic neuralgia
psychosis	restless leg syndrome	ulcerative colitis	allergy-induced inflammatory reactions in asthmatic patients

Apraclonidine (Iopidine):¹⁵²
- Apraclonidine (Iopidine) is classified as a relatively selective α₂-adrenergic receptor agonist.
- Topical application of apraclonidine reduces intraocular pressure.
- Lack of systemic cardiovascular effects makes apraclonidine probably more useful than clonidine in the ophthalmic setting.
  - Furthermore, this agent likely does not cross the blood brain barrier; apraclonidine interferes with α₂-adrenergic receptor-mediated aqueous humor formation.
  - The clinical use of apraclonidine focuses on short-term adjuvant therapy in glaucoma patients whose intraocular pressure is not adequately managed by other pharmacological agents such as β-adrenergic receptor antagonists, parasympathomimetics or carbonic and hydrase inhibitors.
  - Apraclondine may be employed as well in the control of or prevention of increases in intraocular pressure following laser trabeculoplasty or iridotomy.
    - Use of laser (typically argon) burns to the trabecular meshwork increases aqueous outflow due to effects on trabecular meshwork and Schlemm's canal.¹⁹⁷
      - This method may be used in many forms of open-angle glaucoma.
      - Resultant pressure reduction often allows a reduction in medical therapy and postponement of glaucoma surgery.
      - Laser trabeculoplasty can be used in initial treatment of primary open-angle glaucoma; however, intraocular pressures slowly increase, returning to pretreatment levels in about 2-5 years.
        
        However, this initial intervention may adversely affect outcome of subsequent glaucoma drainage surgeries.
Brimonidine (Alphagan):¹⁵²
- Brimonidine (Alphagan) is, like apraclonidine, related to clonidine.
  - Brimonidine, following ocular administration, reduces intraocular pressure in patients with open-angle glaucoma or with ocular hypertension.
- Classified as a selective α₂-adrenergic receptor agonist, brimonidine administration reduces intraocular pressure by two mechanisms.
  - Reduced aqueous humor production.
  - Increased outflow.
- Brimonidine efficacy in decreasing intraocular pressure compares favorably to timolol (Timoptic® and others), a β-adrenergic receptor antagonist.
  - Unlike apraclonidine, brimonidine crosses the blood brain barrier and may cause CNS-mediated sedation and hypotention.
    - Brimonidine-induced hypotensive and sedative responses are much less prominent to those associated with clonidine (Catapres).
Guanfacine (Tenex, Intuniv):¹⁵²
- Guanfacine (Tenex) is classified as a selective α₂-adrenergic receptor agonist, somewhat more selective for α₂-adrenergic receptors when compared to clonidine.
  - Hypotensive effects after guanfacine administration are due to reduced sympathetic outflow.
  - Guanfacine in a sustained-release preparation (Intuniv) is FDA-approved for treatment of ADHD (attention deficit hyperactivity disorder) in children (6-17 years old).
Guanabenz (Wytensin):¹⁵²
- Guanabenz (Wytensin) is another centrally acting α₂-adrenergic receptor agonist, reducing blood pressure by decreasing sympathetic outflow.
  - The adverse effect profile for guanabenz is comparable to that described earlier for clonidine.
    - Extensive hepatic metabolism requires consideration of dosage adjustment in patients with liver disease.
Methyldopa (Aldomet):¹⁵²
- Methydopa: α-methyl-3,4-dihydroxyphenylalanine conversion to α-methylnorepinephrine
  →
- Methyldopa (Aldomet) also acts centrally, producing hypotensive responses.
  - Methyldopa is metabolized to α-methylnorepinephrine which stimulates central α₂adrenergic receptors (like clonidine) and reduces blood pressure.
Tizanidine (Zanaflex):¹⁵²
- Tizanidine (Zanaflex)
- Tizanidine (Zanaflex) is primarily classified as a muscle relaxant helpful in management of spasticity presenting as a result of spinal or cerebral disorders.
  - Moreover, tizanidine also possesses α₂-adrenergic receptor agonist properties somewhat similar to those exhibited by clonidine.

Methydopa: α-methyl-3,4-dihydroxyphenylalanine conversion to α-methylnorepinephrine
	→

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Clonidine	Imadazoline