Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead 191
A 2.9 Other Analgesics
Pharmacotherapeutic group: Other hypnotics and sedatives
ATC code: N05CM18
Dexmedetomidine is an alpha-2 adrenoreceptor agonist. The sedative actions of dexmedetomidine are believed to be mediated primarily by post-synaptic alpha-2 adrenoreceptors, which in turn act on inhibitory pertussis-toxin-sensitive G protein, thereby increasing conductance through potassium channels. The site of the sedative effects of dexmedetomidine has been attributed to the locus ceruleus. The analgesic actions are believed to be mediated by a similar mechanism of action at the brain and spinal cord level. Alpha-2 selectivity is demonstrated following low and medium doses given slowly. Alpha-2 and alpha-1 activity is seen following rapid administration. Dexmedetomidine has no affinity for beta adrenergic, muscarinic, dopaminergic, or serotonin receptors.
Following administration, dexmedetomidine exhibits the following pharmacokinetic characteristics: rapid distribution phase with a distribution half-life (t½α) of about six minutes; terminal elimination half-life (t½) of approximately two hours; steady-state volume of distribution (Vss) of approximately 118 litres. Clearance has an estimated value of about 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.
Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female human patients: the average binding was 94% and constant across the different concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was statistically significantly decreased in patients with hepatic impairment compared with healthy patients. Dexmedetomidine is unlikely to cause clinically significant changes in the plasma protein binding of fentanyl, ketorolac, theophylline, digoxin, lidocaine, phenytoin, warfarin, ibuprofen and propranolol.
There are three types of initial metabolic reactions; direct N-glucuronidation, direct N-methylation and cytochrome P450 catalysed oxidation. The most abundant circulating dexmedetomidine metabolites are two isomeric N-glucuronides. Available data suggest that the formation of the oxidised metabolites is mediated by several CYP forms (CYP2A6, CYP1A2,CYP2E1, CYP2D6 and CYP2C19). These metabolites have negligible pharmacological activity.
Dexmedetomidine is eliminated almost exclusively by metabolism with 95% of a radio-labelled dose being excreted in the urine and 4% in the faeces. Approximately 34% of the excreted metabolites are products of N-glucuronidation.
In patients with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values were lower than in healthy patients. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% respectively, of those observed in the normal healthy patients. Mean clearances for free medicine were 59%, 51%, and 32% respectively, of those observed in the normal healthy patients. Although dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction depending on the degree of hepatic impairment (see sections 4.2 and 4.4).
Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t½, CL and Vss) were not different in patients with severe renal impairment (CrCI: <30 mL/min) compared with healthy patients.
No difference in dexmedetomidine pharmacokinetics due to gender was observed.
The pharmacokinetic profile of dexmedetomidine was not altered by age. The elderly are more sensitive to the effects of dexmedetomidine. In clinical trials, there was a higher incidence of bradycardia and hypotension in elderly patients (>65 years of age) (see section 4.2).
The pharmacokinetic data of dexmedetomidine in patients less than 18 years of age is limited (see section 4.2).
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