Dexmedetomidine

Pharmacology

Trade name- Precedex

Physiochemical Characteristics¹

• Dexmedetomidine ((S)-4-[1-(2,2-Dimethylphenylethyl]-3-H-imidazole) is available as a water-soluble salt that is typically diluted to 4 mcg/mL.

Mechanism of Action²

• Dexmedetomidine is a highly selective α₂-adrenergic agonist (α₂:α1 = 1620:1), similar in nature to clonidine (α₂:α1 = 220:1).
• The agonism occurs in the central nervous system; specifically, the α2 receptors on neurons from the locus ceruleus are inhibited, which prevents norepinephrine release in the ventrolateral preoptic nucleus. This activates sleep centers in the brain.
• The disinhibited nucleus reduces arousal in the midbrain, hypothalamic, and pontine nuclei, resulting in a sedated yet easily arousable patient.

Pharmacokinetics^2,3

• The pharmacokinetics of dexmedetomidine are listed in Table 1.

• Absorption
  • Only approved for intravenous (IV) use but well absorbed intranasally and via buccal mucosa.
  • Oral bioavailability is ~16% due to extensive first-pass effect.
• Redistribution
  • Short initial distribution half-life (~6 minutes)
  • Readily crosses blood-brain and placental barriers
  • Exhibits linear pharmacokinetics in the range of 0.2-0.7 mcg/kg/hr (for up to 24 hours)
• Metabolism
  • Undergoes almost complete biotransformation, involving both direct glucuronidation and the cytochrome P450 system with resultant inactive metabolites
  • Hepatic extraction ratio = 0.7
  • Clearance values are affected by varying levels of hepatic impairment.
• Excretion
  • Dexmedetomidine and its metabolites are primarily (95%) eliminated through the renal route via urine.
  • Not significantly different in patients with severe renal impairment
• Protein binding
  • Exhibits high-protein binding, with approximately 94% bound to plasma proteins

Systemic Effects^2,3

The systemic effects of dexmedetomidine administration are listed in Table 2.

Clinical Uses

Component of General Anesthesia¹

• Dexmedetomidine may be used as a component of a multimodal anesthetic. It has been demonstrated to decrease the need for other anesthetics, including sevoflurane and propofol.
• It demonstrates both an intra- and postoperative opioid-sparing effect.

Sedation in ICU¹

• Although initially approved for only 24 hours of ICU sedation, multiple studies have demonstrated sufficient safety profile through 30 days.
• Its use reduces the duration of mechanical ventilation and the ICU length of stay without a difference in mortality compared to traditional sedatives.⁴

Sedation for Medical Procedures

• Dexmedetomidine is FDA-approved for therapeutic procedures, diagnostic procedures, and awake fiberoptic intubations.
• Studies demonstrated a significantly reduced incidence of rescue midazolam required to complete the aforementioned procedures relative to placebo.⁵

Emergence Delirium Prophylaxis in Pediatric Anesthesia

• An IV bolus dose of 0.5 mcg/kg immediately following induction demonstrated a significant reduction in the incidence of emergence delirium, minimal side effects, no delay in emergence, and a reduction in volatile and analgesic requirements.⁶

Preoperative Anxiolysis

• Intranasal dexmedetomidine 1-2 mcg/kg is an effective anxiolytic premedication, particularly in the pediatric population; however, the clinical effect may not be observed for up to 30-45 minutes.⁷

Adjunct to Local Anesthetics in Regional Anesthesia

• Perineural dexmedetomidine as an adjutant to local anesthetic nerve blocks increases the duration of the block.⁸
• Administration of dexmedetomidine via the IV route has a similar efficacy to that of the perineural route.⁹

Adverse Effects

• Antimuscarinic effects may occur due to α2 adrenal receptor-mediated inhibition of acetylcholine release.
• Dexmedetomidine causes dose-dependent hypotension and bradycardia due to stimulation of presynaptic alpha receptors, leading to a decreased norepinephrine release and a decrease of central sympathetic flow.
• Hypertension can occur with fast administration or with a loading dose due to stimulation of alpha subtype receptors on the vascular smooth muscles. It is usually self-limiting and does not require treatment.
• No effective antagonist is available for human use.

Cautions

• In patients with baseline bradycardia, dexmedetomidine can worsen bradycardia.
• In patients with hypotension, dexmedetomidine can worsen hypotension.
• Consider avoiding a bolus in frail, critically ill, and elderly patients.
• In patients with heart failure, there is evidence of possible exacerbation of myocardial dysfunction.¹⁰