Hydex Mechanism of Action

Pharmacology: Pharmacodynamics: HYDEX is a relatively selective alpha₂-adrenoceptor agonist with sedative properties. Alpha₂ selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha₁ and alpha₂ activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration.
It has a sympatholytic effect through decrease of the release of noradrenaline (norepinephrine) in sympathetic nerve endings. The sedative effects are mediated through decreased firing of locus coeruleus, the predominant noradrenergic nucleus, situated in the brainstem. Dexmedetomidine has analgesic and anaesthetic/analgesic-sparing effects. The cardiovascular effects depend on the dose; with lower infusion rates the central effects dominate leading to decrease in heart rate and blood pressure. With higher doses, peripheral vasoconstricting effects prevail leading to an increase in systemic vascular resistance and blood pressure, while the bradycardic effect is further emphasised. Dexmedetomidine is relatively free from respiratory depressive effects when given as monotherapy to healthy subjects.
Sedation of adult ICU (Intensive Care Unit) patients: In placebo controlled trials in a post-operative ICU population previously intubated and sedated with midazolam or propofol, Dexmedetomidine significantly reduced the requirement for both rescue sedative (midazolam or propofol) and opioids during sedation for up to 24 hours. Most Dexmedetomidine patients required no additional sedative treatment. Patients could be successfully extubated without stopping the Dexmedetomidine infusion. Studies from outside the ICU have confirmed that Dexmedetomidine can be administered safely to patients without endotracheal intubation provided adequate monitoring is in place.
Dexmedetomidine was similar to midazolam (Ratio 1.07; 95% CI 0.971, 1.176) and propofol (Ratio 1.00; 95% CI 0.922, 1.075) on the time in target sedation range in a predominently medical population requiring prolonged light to moderate sedation (RASS 0 to -3) in the ICU for up to 14 days, reduced the duration of mechanical ventilation compared to midazolam and reduced the time to extubation compared to midazolam and propofol. Compared to both propofol and midazolam, patients were more easily roused, more cooperative and better able to communicate whether or not they had pain. Dexmedetomidine treated patients had more frequent hypotension and bradycardia but less tachycardia than those receiving midazolam and more frequent tachycardia but similar hypotension to propofol treated patients. Delirium measured by the CAM-ICU scale was reduced in a study compared to midazolam and delirium-related adverse events were lower on dexmedetomidine compared to propofol. Those patients who withdrew due to insufficient sedation were switched to either propofol or midazolam. The risk of insufficient sedation was increased in patients who were difficult to sedate with standard care immediately prior to switching.
Evidence of paediatric efficacy was seen in a dose-controlled ICU study in a largely post-operative population aged 1 month to ≤17 years. Approximately 50% of patients treated with Dexmedetomidine did not require rescue addition of midazolam during a median treatment period of 20.3 hours, not exceeding 24 hours. Data on treatment for >24 hours is not available. Data in new-born infants (28-44 weeks gestation) is very limited and restricted to low doses (≤0.2 mcg/kg/h) (see Pharmacokinetics as follows and Precautions). New-born infants may be particularly sensitive to the bradycardic effects of Dexmedetomidine in the presence of hypothermia and in conditions of heart rate-dependent cardiac output.
In double blind comparator controlled ICU studies the incidence of cortisol suppression in patients treated with dexmedetomidine (n=778) was 0.5% compared with 0% in patients treated with either midazolam (n=338) or propofol (n=275). The event was reported as mild in 1 and moderate in 3 cases.
Pharmacokinetics: Dexmedetomidine exhibits a rapid distribution phase with a distribution half-life (T½) of approximately 6 minutes; a terminal elimination half-life (T½) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 L. Clearance is estimated to be approximately 39 L/hr. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by IV infusion for up to 24 hours. Target concentrations are usually in the range of 0.3 to 0.6 ng/mL. Protein binding to both albumin and α₁ acid glycoprotein is 94%. Dexmedetomidine undergoes almost complete biotransformation with very little unchanged in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. There are no active metabolites. Similar kinetic data was noted in pediatric patients. Onset of action with loading infusion is 10 to 20 minutes, and the duration of action after the infusion is stopped is 10 to 30 minutes.