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Understanding Alpha-2 Agonists: mascots and ballicules for NE, clonidine, dexmedetomidine, etc.

Norepinephrine – endogenous neurotransmitter, α1 > α2 > β receptor agonist

Clonidine – imidazoline > α2 receptor agonist

Guanfacine – selective α2A receptor agonist


Dexmedetomidine – α2 > imidazoline receptor agonist

  • PRECEDEX – IV dexmedetomidine for ICU sedation

  • IGALMI – sublingual film for acute agitation in schizophrenia/bipolar

Tizanidine (Zanaflex) – spasmolytic, imidazoline >> α2 receptor agonist

Lofexidine – expensive alternative to clonidine for opioid withdrawal, with fewer side effects

Xylazine – α2 agonist, animal tranquilizer used as a cutting agent for illicit opioids

Methyldopa – α2 agonist and DOPA decarboxylase inhibitor, antihypertensive

 

Centrally Acting Alpha-2 Agonists


Here are some ballicules showing binding affinities of centrally acting alpha-2 agonists.

ballicule stahl balls for norepinephrine, guanfacine, lofexidine, xylazine, dexmedetomidine, clonidine, tizanidine, i.e., alpha-2 agonist mechanisms of action
Ballicules of alpha-2 agonists, including norepinephrine

Yes, the endogenous neurotransmitter norepinephrine (NE) is a (nonselective) centrally acting alpha-2 agonist. The prescription alpha-2 agonists mimic the sympatholytic aspect of NE, which is otherwise a sympathomimetic neurotransmitter. The alpha-2 agonsits incorporate the negative feedback component of NE while largely excluding the "fight or flight" components of NE.


comparing centrally acting alpha-2 adrenergic agonists
Ballicules representing the alpha-2 agonist component

Adrenergic receptors (alpha and beta) are G protein-coupled receptors for epinephrine (EPI) and norepinephrine (NE). EPI and NE are neurotransmitters of the sympathetic ("fight or flight") nervous system. They also serve as hormones secreted by the adrenal glands, which is why they are also referred to as adrenaline and noradrenaline.


Let's start with the endogenous ligand for alpha-2 receptors, norepinephrine (noradrenaline). Norepinephrine binds alpha-1 adrenergic receptors with the greatest affinity. Alpha-1 binding elevates blood pressure. Peripheral alpha-2 binding (in vascular smooth muscle) elevates blood pressure, but central (in the CNS) alpha-2 receptor binding lowers blood pressure by feedback inhibition. In the CNS, alpha-2 agonists act on presynaptic α2 adrenergic receptors. Activation of these receptors results in negative feedback, decreasing release of NE from the presynaptic neuron and lowering blood pressure.


If there existed an alpha-2 agonist that could not cross the blood-brain barrier, central (in CNS) negative feed would not occur, and the effect would be peripheral vasoconstriction and elevation of blood pressure. When an existing alpha-2 agonist is injected intravenously, there is a brief elevation in blood pressure for ~ 2 minutes, followed by decreased BP after the drug reaches the brain, as seen with IV dexmedetomidine (Precedex).


Several alpha-2 agonist medications also bind I1 imidazoline receptors, which are discussed below in context of tizanidine.


You may be unaware that norepinephrine binds dopamine receptors, with ~10% of the affinity of dopamine. If you wondered, norepinephrine does not bind to serotonin receptors at all.

Norepinephrine (NE) mechanism of action includes binding dopamine receptors
Binding affinities of norepinephrine

Stimulation of alpha-1 receptors by norepinephrine elevates blood pressure. In the CNS, alpha-2 receptor binding by NE lowers blood pressure by feedback inhibition. Norepinephrine's net effect is BP increase, as its binding affinity for alpha-1 receptors (Ki ~50) is much stronger than its binding affinity to alpha-2 receptors (Ki ~300 to ~600).

norepinephrine mechanism of action
Acting on alpha-2 receptors, norepinephrine elevates BP in peripheral vessels, and decreases BP in the CNS by feedback inhibition.

Centrally acting alpha-2 agonists are sympatholytics, mimicking NE in binding to presynaptic autoreceptors in the CNS, which leads to feedback inhibition of NE release.


There are three α2 receptor subtypes. The α2A and α2C receptors predominate throughout the brain, and the α2B-subtype is present in the thalamus. Activation of α2-adrenergic receptors mediate a wide variety of responses including sedation and analgesia. The primary site of α2-adrenergic receptor-mediated anti-nociception is the spinal cord.


What's the opposite of an alpha-2 agonist?


That would be an alpha-2 adrenergic receptor ANTAGONIST (BLOCKER). α2 BLOCKERS increase release of adrenergic, dopaminergic and serotonergic neurotransmitters.


Phentolamine (OraVerse) is an alpha-2 ANTAGONIST that is peripherally-acting, i.e., does not cross the blood-brain barrier. It dilates blood vessels and can be administered intravenously to treat hypertensive crises. Contrast the alpha-2 agonist clonidine which has the oppose mechanism at the receptor but can be used to treat hypertensive crisis because it permeates the blood-brain barrier to exert its hypotensive effect from within the brain, by feedback inhibition.


Although α2-adrenoceptor ANTAGONISTS are not in widespread clinical use, some psychiatric drugs have built-in α2 BLOCKING activity.


Mirtazapine (Remeron) and yohimbine are alpha-2 ANTAGONISTS that can entirely block the antihypertensive effect of alpha-2 agonists like clonidine. Addition of mirtazapine to an established clonidine regimen has resulted in hypertensive crisis (Reem et al, 2012).

interaction between mirtazapine and clonidine
the interaction between mirtazapine (alpha-2 blocker) and clonidine (alpha-2 agonist)

interaction between mirtazapine and clonidine with norepinephrine
Binding affinity for alpha-2c receptors: mirtazapine (antagonist) > clonidine (agonist) > norepinephrine (agonist)

Stimulation of α2 receptors (e.g., by clonidine) can impair sexual functioning. Mirtazapine and yohimbine can enhance sexual functioning by BLOCKING α2 receptors centrally.


Alpha-2 antagonism is a principal antidepressant mechanism of mirtazapine. BLOCKING alpha-2 receptors in the CNS results in release of norepinephrine, and serotonin in downstream brain circuits.


Most second-generation antipsychotics have α2 ANTAGONIST effects. Specifically, BLOCKING the adrenergic receptor subtype α2C in the brain has been suggested to be beneficial for antipsychotic action (Proudman et al, 2022).The potent α2C-BLOCKING action of clozapine (Clozaril) may be important for its unique efficacy in schizophrenia through downstream cortical dopamine release and NMDA receptor-mediated responses (Marcus et al, 2010). Risperidone, paliperidone, olanzapine, and brexpiprazole also potently BLOCK α2C receptors.


Now back to the topic of the day, alpha-2 adrenergic receptor agonists (activators)...

 

Clonidine (Catapres, Kapvay)


Clonidine

❖ Sympatholytic

❖ Centrally acting alpha-2 adrenergic receptor agonist

❖ Imidazoline I1 receptor agonist


FDA-approved for:

❖ Hypertension

❖ ADHD in children (extended-release KAPVAY)


The best-known alpha-2 agonist is clonidine. Clonidine's psychiatric uses are mostly related to its effect on alpha-2a receptors. Activity of clonidine at other receptors causes additional sedation and hypotensive effect. Compare to guanfacine which is more selective for alpha-2a.

Clonidine (Catapres, Kapvay) mechanism of action alpha-2 Stahl  ball molecule, ballicule
Receptor binding affinities of clonidine

MASCOT FOR CLONIDINE (CATAPRES): “Clown dines (while) Cat oppresses”

Clonidine (Catapres, Kapvay) visual mnemonic
In Cafer's Psychopharmacology, antihypertensives and meds with the same mechanisms as antihypertensives are depicted as being soaked with a high-pressure spray.

Clonidine is rarely used as a first-line maintenance medication for hypertension, but it is a drug of choice for the treatment of hypertensive urgencies.


Clonidine is a reasonable first-line antihypertensive for those with one of the following comorbid conditions, to kill two birds with one stone (although guanfacine may be a better choice, unless a sedative component is needed).


Psychiatrists have found many off-label therapeutic uses of clonidine:


ADHD

Clonidine is considered safe and effective for childhood ADHD. It may be used as an alternative to or in combination with a stimulant. Clonidine is more effective for treatment of hyperactivity than for inattention. It is typically dosed BID for this indication. Onset of effect may be delayed by 2–4 weeks and effect size is less than seen with stimulants. In 2018 an extended-release formulation of clonidine (KAPVAY) was released for treatment of ADHD in children.


Intermittent explosive disorder / Oppositional defiant disorder

Clonidine is useful in management of aggressive individuals who are highly irritable and impulsive. For violent children, consider trying clonidine before turning to an antipsychotic.


Opioid withdrawal

Clonidine is a second-line treatment for opioid withdrawal (behind buprenorphine). A clonidine transdermal patch can be applied with additional PO doses throughout the day as tolerated.


Tics/Tourette’s disorder

Alpha-2 agonists are the first-line treatment for tic disorders. For Tourette’s disorder, guidelines recommend trying clonidine prior to FDA-approved medications (antipsychotics).


Hot flashes

Clonidine can alleviate hot flashes/flushes, including those caused by SSRIs.


Sialorrhea (hypersalivation)

A side effect of clonidine is dry mouth, making clonidine an option to counteract clozapine-induced hypersalivation. This should be done cautiously because clozapine and clonidine both decrease blood pressure. As mentioned above, Marcus et al (2010) postulated that clozapine's potent α2-agonist action may be important for its unique efficacy in schizophrenia, but I could not find any mentions in the literature of clonidine potentially attenuating the therapeutic effect of clozapine.


Anxiety

Clonidine can relieve physical "fight or flight" symptoms associated with anxiety such as tremor, sweating, and tachycardia (although the beta blocker propranolol is usually better tolerated).


Pain (combination with opioid)

Clonidine may be useful for severe pain in cancer patients not adequately relieved by opioid analgesics alone.


Insomnia

Some individuals are sensitive to the possible sedating effects of clonidine. For those individuals, clonidine may be useful as a sleep aid.


Akathisia

Akathisia is a sense of inner restlessness caused by antipsychotics. Clonidine may help alleviate akathisia, but propranolol (Inderal) or benzodiazepines are more commonly used.


Smoking cessation

Clonidine is possibly helpful for long-term maintenance of smoking cessation.


Clonidine is notorious for rebound hypertension upon discontinuation due to overactivity of the sympathetic nervous system. After sudden cessation of clonidine (0.9 mg/day) almost all subjects showed an excessive increase of heart rate and blood pressure. Seven of the fourteen patients had subjective symptoms, in three severe enough to require interruption of observation by therapeutic intervention 12 to 60 hours after the last dose of clonidine (Geyskes et al, 1979).


Adding a beta blocker does not prevent rebound hypertension caused by clonidine discontinuation, and the phenomenon of beta blocker-induced unopposed alpha stimulation (if it's real) may be of concern.


PHARMACODYNAMIC INTERACTIONS:

❖ Hypotensive effects

❖ Sedation/CNS depression

❖Do not add mirtazapine (Remeron), a central alpha-2 blocker, to clonidine because it will block the action of clonidine, potentially leading to a hypertensive crisis. Do not add clonidine to mirtazapine, because clonidine may be of no benefit. Here is the "Interaction of the week" blog post on mirtazapine+clonidine.

Interaction between clonidine and mirtazapine (Remeron)
Due to opposing actions at alpha-2 receptors, mirtazapine renders clonidine ineffective.

PHARMAKINETIC INTERACTIONS:

Kinetic interactions:

❖ None significant— “in a bubble”

clonidine cyp450 metabolism (not applicable)
Clonidine is not involved in clinically significant pharmacokinetic interactions.

Clonidine IR dosing: For adults, the starting dose for most uses is 0.1 mg BID, to increase 0.1 mg/day in weekly intervals as tolerated. If baseline BP is in the low to normal range, start 0.05 mg BID instead. May be dosed more aggressively for inpatient management of opioid withdrawal. Max is 2.4 mg total daily dose. Taper slowly to stop to avoid rebound hypertension.


Clonidine ER (Kapvay) dosing: For ADHD (ages 6–17) the dose range is 0.1–0.4 mg/day divided QD–BID; Start Kapvay at 0.1 mg HS, may increase by 0.1 mg/day in weekly intervals; Divide doses > 0.2 mg/day; AM and HS doses may be unequal with HS > AM dose; Taper no faster than 0.1 mg/day in 3–7 day intervals, to avoid rebound hypertension.


Clonidine therapeutic transdermal system (CATAPRES-TTS)


In comparison with oral clonidine, transdermal clonidine reduces side effects such as dry mouth, drowsiness, and sexual dysfunction. Minor skin reactions occur at the site of application with moderate frequency. Adherence to transdermal clonidine is high, and patients commonly prefer it to oral therapy (J.F. Burris, 1993). For opioid withdrawal, it can be used in combination with oral clonidine:


Example opioid-withdrawal order set:

Clonidine 0.2 mg/24h transdermal patch x1, remove in 1 week

Clonidine 0.2 mg PO q 4 hours while awake if systolic blood pressure (SBP) > 120

Clonidine 0.1 mg PO q 4 hours while awake if SBP 100–120

Hold PO Clonidine if pulse < 50 or SBP < 100

Also lorazepam (PRN anxiety), dicyclomine (PRN abdominal cramping), ondansetron (PRN nausea), loperamide (PRN diarrhea), ibuprofen (PRN body aches), and phenylephrine nasal spray (PRN rhinorrhea).

 

Guanfacine (Tenex, Intuniv)


Guanfacine

❖ Sympatholytic

❖ Centrally acting alpha-2A adrenergic receptor agonist


Guanfacine has fewer side effects than clonidine because it is select for alpha-2a adrenergic receptors. Unless sedative effect is needed, it does not make much sense to choose clonidine over guanfacine for psychiatric purposes.

guanfacine mechanism of action
Guanfacine is distinguished from other alpha-2 agonists as being selective for activating only alpha-2a receptors.
Guanfacine (TENEX)

Pronunciation: GWAHN fa seen / TEN ex

Mascot: “Gun facing Ten X’s”

guanfacine tenex is an alpha-2 agonist, visual mnemonic
Mascot for guanfacine

FDA-approved for:

❖ Hypertension

❖ Childhood ADHD (ER formulation INTUNIV)


Used off-label for:

❖ Opioid withdrawal

❖ Migraine prophylaxis

❖ Tourette's disorder

❖ Adult ADHD

❖ Conduct disorder


Guanfacine is much more selective for alpha-2A receptors than clonidine, making it less sedating than clonidine. Unlike clonidine, guanfacine does not activate imidazoline receptors.


If guanfacine is abruptly discontinued, rebound hypertension is less prominent than with clonidine. Although blood pressure and heart rate rose significantly, the changes after clonidine withdrawal were greater and occurred earlier (day 2) than those after guanfacine withdrawal (day 4) (Adesh et al, 1985).


Guanfacine IR dosing: For ADHD, start 1 mg q PM, increase to 1 mg BID at one week; maximum 4 mg total daily dose. For hypertension, it is dosed once daily at HS with maximum of 3 mg. Taper dose over 4–7 days to discontinue.


Guanfacine (INTUNIV)


Pronunciation: GWAHN fa seen / TEN ex

Mascot: “Gun facing (the) In-tune tuna”

guanfacine (Intuniv) mnemonic
Mascot for the ER formulation (Intuniv) of guanfacine

The advantage of Intuniv over generic guanfacine (Tenex) is once-daily dosing. Generic guanfacine IR is given in divided doses, BID–TID. Contrast the QD dosing of guanfacine ER to clonidine ER (Kapvay), which is given BID above when dosed above 0.2 mg/day.


Guanfacine ER (INTUNIV) dosing: Recommended dose is 1–4 mg once daily in the morning or evening, depending on the child’s weight. Start 1 mg once daily and adjust in increments of no more than 1 mg/week. Do not administer with high-fat meals, because it will increase absorption. Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles. When discontinuing, taper the dose in intervals of no more than 1 mg every 3–7 days. Maximum dose of 7 mg/day for those over 58.5 kg (129 pounds), less for smaller kids.


PHARMACODYNAMIC INTERACTIONS:

❖ Hypotensive effects

❖ Sedation/CNS depression

❖ Do not add mirtazapine (Remeron) to guanfacine because, as an alpha-2 ANTAGONIST, it may block the therapeutic (alpha-2A agonist) effect of guanfacine.

Interaction between guanfacine and mirtazapine
Due to opposing action at alpha-2a receptors, mirtazapine renders guanfacine ineffective.

PHARMACOKINETIC INTERACTIONS

❖ 3A4 substrate, major (fish)


guanfacine is a CYP3A4 substrate
fish = sensitive CYP3A4 substrate

Here is the explanation of the fishy CYP3A4 interaction mnemonic system.


Guanfacine Dosing: For ADHD, start 1 mg q PM, increase to 1 mg BID at one week; maximum 4 mg total daily dose. For hypertension, it is dosed once daily at HS with maximum of 3 mg. Taper dose over 4–7 days to discontinue.

 

Dexmedetomidine (Precedex, Igalmi)


dexmedetomidine (Precedex, Igalmi) mechanism of action Stahl ballicule by Jason Cafer MD
Receptor binding profile of dexmedetomidine is similar to clonidine.

Dexmedetomidine (PRECEDEX)


Pronunciation: DEX med e TOE mi deen / PRESS e dex

MASCOT: “Death metal toe meeting”

Precedex
Mascot for dexmedetomidine - "death metal toe meeting"

❖ Sympatholytic

❖ Central alpha-2 agonist

❖ Imidazoline I1 receptor agonist

❖ Intravenous sedative


FDA-approved for:

❖ ICU sedation/procedural sedation


Dexmedetomidine (Precedex) is a sympatholytic used as a sedative. It activates presynaptic α2 adrenergic receptors and imidazoline receptors. It is commonly used intravenously in the ICU to manage agitation and to facilitate mechanical ventilation.


The unique and highly sought-after sedative response of dexmedetomidine is “arousable sedation” or "cooperative sedation" produced at low doses. Dexmedetomidine provides an easy transition from sleep to wakefulness, thus allowing a patient to be cooperative and communicative when stimulated.


With increasing dose dexmedetomidine produces sedation indistinguishable from stage N2 sleep. If a large enough dose is administered, dexmedetomidine produces deep sedation or even general anesthesia.


Unlike most sedatives, dexmedetomidine's mechanism does not involve GABA. Memory and cognitive functions are not severely impaired by dexmedetomidine. It is much less likely to cause delirium or agitation than alternatives such as propofol (Diprivan) or benzodiazepines.


Onset of action is delayed (15–30 minutes) compared to alternatives such as midazolam or propofol. Effects persist for about 3 hours after the infusion is stopped (in critically ill patients coming off a high dose infusion at steady state).


Noradrenergic activity in the locus coeruleus maintains arousal and consciousness. Much of the sedative effect of dexmedetomidine is through decreased release of norepinephrine by negative feedback created when dexmedetomidine stimulates presynaptic α2 adrenergic receptors. This is why it is called a “centrally acting” α2 agonist.


When dexmedetomidine is infused intravenously it produces initial vasoconstriction by activating α2B receptors in vascular smooth muscle, increasing blood pressure for ~2 minutes. The transient BP-elevating effect is not observed with non-intravenous routes of administration. As dexmedetomidine crosses the blood-brain barrier, it begins to exert its “centrally acting” effect resulting in decreased BP and HR, with up to an 80% decrease in circulating catecholamine (epinephrine and norepinephrine) levels.


Dexmedetomidine has no effect on airway reflexes and does not depress respiratory drive, even at high doses. It can provide profound sedation without the need for complex airway management.


Dexmedetomidine's analgesic mechanism, in addition to alpha-2 agonism, may involve inhibition of spinal ERK1/ 2 signaling.


Oral bioavailability of dexmedetomidine is only ~15% with extensive first-pass metabolism. It is highly lipophilic and distributes rapidly and widely into tissues. When in circulation, it is 96% protein-bound (to albumin and α1-glycoprotein). Compare clonidine which is only 50% protein bound. All the metabolites of dexmedetomidine are inactive and excreted renally, which can give the urine a green tinge.


Dexmedetomidine has protective effects on many organs, including the brain, by decreasing inflammatory cytokines and inhibiting cell apoptosis. Contrast its neuroprotective effects with other anaesthetics, which tend to be neurotoxic. It may become a promising multi-organ protection drug in the future (Bao & Tang, 2020).


Similar medications with simpler names are available to veterinarians—medetomidine and detomidine. Another similar veterinary anaesthetic, xylazine— street name is “tranq”—was found in about 20% of fentanyl seized by the DEA.


Dosing of Precedex

The IV dose (mcg/kg/hr) for intubated ICU patients > non-intubated patients > those awake for fiberoptic intubation. Do not bolus. The 1.0 ng/ml concentration is generally associated with being heavily sedated, and 0.10 ng/ml would be a barely perceptible change in the level of alertness.


Dexmedetomidine (IGALMI)


Pronunciation: DEX med e TOE mi deen / ee GAHL mee

Mascot: “It calm me” (Death metal toe meeting)

Igalmi film 90 mg 280 mg mnemonic
Igalmi mascot

❖ Sympatholytic

❖ Central alpha-2 agonist

❖ Imidazoline I1 receptor agonist

❖ Sublingual film


FDA-approved for:

❖ Acute agitation (in bipolar or schizophrenia)


A new formulation of dexmedetomidine was approved in 2022 as a sublingual film (Igalmi) for treatment of acute agitation in adults associated with schizophrenia or bipolar I or II disorder. Igalmi should be administered under the supervision of a healthcare provider, i.e., not for at-home use.


Oral bioavailability of dexmedetomidine is only ~15% but the drug is ~80% absorbed through the oral (or nasal) mucosa.


Based on our experience with intravenous dexmedetomidine (Precedex), we know that dexmedetomidine does not depress respiratory drive and can induce a state of "cooperative sedation" without delirium.


The label states that “safety and effectiveness has not been established beyond 24 hours from the first dose”. Withdrawal and tachyphylaxis (rapidly diminishing response) may occur with prolonged use.


Each Igalmi film has 2 microdeposits of dexmedetomidine, each containing half of the full 120 mcg or 180 mcg dose. The film can be cut between the two darker blue dots to obtain half doses of 60 mcg or 90 mcg.


The film dissolves in about 7 minutes sublingually and about 18 minutes with buccal (between gum and cheek) administration. Maximal plasma concentration of dexmedetomidine is achieved at approximately 2 hours.


Cautions and side effects of Igalmi

The Igalmi label states there are no contraindications to its use, but includes warnings to to avoid use of IGALMI in patients with hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope.


There are precautions regarding orthostatic hypotension, bradycardia, somnolence, and QT prolongation. With repeated doses, QT prolongation with Igalmi is slightly less than seen with repeated doses of IM haloperidol (Haldol) or IM ziprasidone (Geodon).


At 2 hours, incidence of orthostatic hypotension was 16% at the 120 mcg dose, and 18% at the 180 mcg dose (versus 9% with placebo). Orthostatic hypotension was defined as SBP decrease ≥ 20 mmHg or DBP decrease ≥ 10 mmHg after 1, 3, or 5 minutes of standing. However, patients were excluded if they had treatment with alpha-1 noradrenergic blockers (prazosin, terazosin, doxazosin, tamsulosin, alfuzosin), benzodiazepines, other hypnotics or antipsychotic drugs four hours prior to study drug administration; had a history of syncope or syncopal attacks; or SBP < 110 mmHg; DBP < 70 mmHg; HR < 55.


Because IGALMI decreases sympathetic nervous system activity, hypotension and/or bradycardia may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in geriatric patients.


Dosing and administration instructions for Igalmi

Assessment of blood pressure and pulse is not required for the initial dose but is required prior to giving a repeat dose.


May administer sublingually (preferred) or buccally. Initial dose is 120 mcg for mild/mod agitation. For severe agitation, give 180 mcg (120 mcg if mild/moderate liver impairment or age 65+). Use 90 mcg in severe liver impairment. Total max is 360 mcg / 24 hr.


Two additional doses may be administered at least two hours apart unless SBP < 90 mmHg, DBP < 60 mmHg, HR < 60, or postural decrease in SBP ≥ 20 mmHg or in DBP ≥ 10 mmHg.


Do not eat or drink for 15 minutes after sublingual administration (1 hr after buccal administration).


After IGALMI administration, patients should be adequately hydrated and should sit or lie down until vital signs are within normal range. If a patient is unable to remain seated or lying down, precautions should be taken to reduce the risk of falls. Ensure that the patient is alert and not experiencing orthostatic hypotension or symptomatic hypotension prior to allowing them to resume ambulation.


Pharmacodynamic interactions of dexmedetomidine:

❖ Sedation/CNS depression

❖ Hypotensive effects

❖ Bradycardia

❖ QT prolongation (moderate)

❖ Alpha-2 agonist (effect may be blocked by mirtazapine)


Pharmacokinetic interactions of dexmedetomidine:

❖ Minimal clinically significant kinetic interactions (in a bubble)

Igalmi drug-drug interactions
Dexmedetomidine is not involved in clinically relevant pharmacokinetic interactions.

 

Tizanidine (Zanaflex)

tizanidine mechanism of action
Principal mechanism of tizanidine is activation of imidazoline receptors.

Pronunciation: tye ZAN i deen / ZAN a flex

Mascot: "Zany flex (in a) Tizzy”

tizanidine
Mascot for tizanidine (Zanaflex): Mascot: "Zany flex (in a) Tizzy”

❖ Antispasmodic (muscle relaxant)

❖ Imidazoline I1 receptor agonist

❖ Central alpha-2 agonist


FDA-approved for:

❖ Spasticity


Tizanidine (Zanaflex) has about 10% of the antihypertensive potency of clonidine. Compared to clonidine, tizanidine is more selective for imidazoline receptors over alpha adrenergic receptors. The relation between α2/imidazoline receptor agonism and spasmolytic action is not fully understood.


Imidazoline receptors are so-named because imidazoline-type drugs bind to them. An endogenous ligand for these receptors is poorly characterized (possible agmatine), although none of the endogenous candidates have an imidazoline ring structure. Don’t confuse the drugs with imidazoline rings (dexmedetomidine, clonidine, tizanidine, lofexidine) with imidazole derivatives (ketoconazole, miconazole, clotrimazole).


imidazoline imidazole rings
Imidazoline or imidazole (dexmedetomidine) ring structures of four α2 receptor agonists

Interestingly, all known ligands for imidazoline receptors also bind to α2 receptors. Activation of imidazoline receptors lowers blood pressure and causes CNS depression without depressing respiration. Hypotensive action of this class of medication is more strongly correlated with imidazoline receptors, while sedative effects are more strongly correlated with α2 receptors.

norepinephrine, guanfacine, lofexidine, xylazine, dexmedetomidine, clonidine, tizanidine mechanisms
The alpha-2 agonists that contain an imidazoline or imidazole ring bind imidazoline receptors.

Here are some other facts about the mysterious imidazoline receptors. There are 3 subtypes of imidazoline receptors, I1 (hypotensive effects), I2 (located on mitochondria), and I3 (involved in insulin secretion). Ligands for I1 receptors (e.g., agmatine) were originally called “clonidine-displacing substances” and were theorized to work as “the brain’s own clonidine”. I1 receptors are upregulated in patients with endogenous depression and can be downregulated with desipramine. MAOIs downregulate I2 receptors.


Tizanidine is intended for PRN dosing.


Dosing: Start: 2 mg q 6–8 hours PRN; Maximum 36 mg total daily dose; May increase 2–4 mg/dose every 1–4 days; Give consistently with food or on empty stomach; Taper dose by 2–4 mg/day to stop.


Pharmacodynamic interactions of tizanidine:

❖ Hypotensive effects

❖ Sedation/CNS depression


Pharmacokinetic interactions of tizanidine:

❖ 1A2 substrate, major (tree) – contraindicated with strong 1A2 inHibitors fluvoxamine (Luvox), viloxazine (Qelbree), and ciprofloxacin (Cipro)

Tizanidine (Zanaflex) is a CYP1A2 substrate interaction mnemonic
Tizanidine is a CYP1A2 substrate (represented as a tree in Cafer's Psychopharmacology)

 

Lofexidine (LUCEMYRA)


lofexidine mechanism
Although lofexidine binds the same receptors as other alpha-2 agonists (plus 5-HT1A receptors) affinity for alpha-2A is by far the strongest, which makes the other effects irrelevant at therapeutic dose. It is essentially a selective alpha-2A agonist like guanfacine.

Pronunciation: lo FEX i deen / LOO sem eer uh

Mascot: “Lose my Loaf”

lofexidine
Lofexidine is not used as an antihypertensive, but is depicted with high pressure spray because it shares alpha-2 agonist mechanism with antihypertensives.

❖ Central alpha-2 agonist

❖ Sympatholytic


FDA-approved for:

❖ Opioid withdrawal


Lofexidine (Lucemyra) was approved in 2018 for treatment of opioid withdrawal symptoms. It has been available in the UK since 1992. It is still under patent and expensive in the U.S., costing $2,000 a week.


Clonidine, a generic alpha-2 agonist, has long been used off-label in the US opioid withdrawal. Prescribers haven’t been clamoring for another alpha-blocking sympatholytic, even one with an FDA indication for opioid withdrawal.


Subjects treated with lofexidine (compared to clonidine) for opioid withdrawal showed significantly fewer withdrawal symptoms, less sedation, and less hypotension (Gerra et al, 2001). Cravings and drop-out rates were no different.


Lofexidine prolongs QT interval whereas clonidine does not.


With acute opioid exposure, norepinephrine release from the locus coeruleus is reduced. With chronic opioid use, the brain compensates by releasing more norepinephrine. When opioids are stopped there is a massive surge of norepinephrine release from the locus coeruleus, leading to opioid withdrawal symptoms. Lofexidine works by calming symptoms of noradrenergic overload such as sweating, anxiety, and irritability.


The lofexidine molecule includes an imidazoline ring, but I could find no mentions of it binding imidazoline receptors. That information is not in the Ki database, so possibly the binding affinity of lofexidine to I1 receptors has not been tested.


Note that buprenorphine (opioid partial agonist) is the drug of choice for opioid withdrawal. Buprenorphine may be continued as maintenance therapy, whereas lofexidine use is approved for up to 14 days.


Dosing of lofexidine: The only tablet strength is 0.18 mg. Start 3 tabs PO q 5–6 hours during peak withdrawal; Max: 4 tabs/dose up to 16 tabs/day. Consider lower doses for individuals 65 and older. Taper dose gradually over 2–4 days to stop.


PHARMACODYNAMIC INTERACTIONS:

❖ Hypotensive effects (less than clonidine)

❖ Sedation/CNS depression

❖ Bradycardia

❖ QT prolongation


PHARMACOKINETIC INTERACTIONS:

❖ 2D6 substrate, minor


Coadministration of lofexidine and paroxetine (strong CYP2D6 inHibitor) resulted in 28% increase in lofexidine levels. This is unlikely to be clinically significant, so lofexidine could be memorized "in a box" which signifies "minimal clinically significant pharmacokinetic interactions". There is a hole in the top of the box, meaning that, in some situations, a 2D6 inHibitor could reach lofexidine to cause a clinically relevant increase in serum lofexidine concentration. If interactions between CYP2D6 inHibitors and lofexidine were of greater magnitude, I would memorize lofexidine as a beach ball. I haven't decided.


lofexidine interactions
"In a box" - Lofexidine is metabolized by CYP2D6 but is not a sensitive substrate.
 

Xylazine

xylazine mechanism of action
Not approved for humans, xylazine is an alpha-2 agonist used as a cutting agent for illicit opioids.

❖ Central alpha-2 agonist

❖ Sympatholytic

❖ Animal tranquilizer (not approved for humans)


MASCOT: This horse named Xyla

xylazine
Mascot for xylazine: A horse named Xyla with a xylophone

Xylazine was approved by the FDA only for veterinary use as a sedative, analgesic, and muscle relaxant in dogs, cats, horses, elk, and specific species of deer.


Xylazine is being diverted from stocks used by equine veterinarians for use as a cheap cutting agent for heroin and fentanyl.


In 2023 the DEA issued a warning about xylazine— street name “tranq”—noting that xylazine was detected in about 23% of fentanyl powder and 7% of fentanyl pill seizures. U.S. lawmakers were calling xylazine a "zombie drug" in March 2023 and proposed regulating it as a Schedule III drug.


Xylazine can cause skin necrosis localized to sites of opioid injection, likely due to local vasoconstriction secondary to alpha-2-agonist effects (peripherally, not centrally).


Xylazine does not activate imidazoline receptors.


It is unclear whether xylazine is more dangerous than other alpha-2 agonists if co-injected with street opioids.


PHARMACODYNAMIC INTERACTIONS:

Opioids cut with xylazine may be more dangerous than opioids alone because, as a sympatholytic, xylazine may attenuate the brain’s compensatory mechanisms to counteract brain hypoxia.


PHARMACOKINETIC INTERACTIONS: Xylazine is metabolized, probably by CYP3A4, to about a dozen metabolites (Daphnée Veilleux-Lemieux, 2013).

 

Methyldopa (ALDOMET)


Mascot: "Metal DOPA"

methyldopa

❖ Central alpha-2 agonist

❖ Sympatholytic

FDA-approved for:

❖ Hypertension


Methyldopa (Aldomet) is a central alpha-2 agonist introduced in 1960 as an antihypertensive. It has been largely replaced by newer medications with fewer side effects. Methyldopa is available in oral and IV formulations.


Methyldopa is a prodrug. Alpha-methylnorepinephrine (corbadrine, levonordefrin) is the active metabolite. Although the principal mechanism is alpha-2 agonism. It also inhibits aromatic L-amino acid decarboxylase enzyme, which plays a minimal role in the blood-pressure‐lowering effect of methyldopa.


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