Dexmedetomidine

Dexmedetomidine is a concentrated preparation for the manufacture of an infusion solution used for intravenous anesthesia. Dexmedetomidine is classified as a sedative for medical use.

[ 1 ]

Indications Dexmedetomidine

Dexmedetomidine is used as a sedative in people over 18 years of age who are being treated in intensive care units.

The recommended depth of sedation should not exceed arousal to verbal stimulation, which is typically defined as a range of zero to -3 on the Richmond Agitation and Sedation Scale (RASS).

[ 2 ]

Release form

Dexmedetomidine is a concentrated substance for the preparation of an infusion solution, with the active ingredient dexmedetomidine hydrochloride.

Dexmedetomidine can only be prescribed and used by a doctor in a hospital setting, so the drug can only be purchased at a pharmacy if you have a prescription.

[ 3 ], [ 4 ], [ 5 ]

Pharmacodynamics

The active ingredient Dexmedetomidine is a selective alpha2-adrenergic receptor agonist with a wide range of pharmaceutical effects.

Dexmedetomidine has a sympatholytic property, which is manifested by decreasing the release of norepinephrine from the sympathetic endings of neurons.

The sedative property is explained by a decrease in excitability in the locus coeruleus, with the dominance of noradrenergic nerve cells located in the brainstem.

In addition, Dexmedetomidine has an analgesic effect and can affect the reduction of the dosage of anesthetics and analgesics. The properties associated with the cardiovascular system depend on the administered dose of the drug:

• with a small dose, a predominantly central effect can be observed, which leads to bradycardia and hypotension;
• At higher doses of the drug, a predominantly vasoconstrictor effect is observed, which provokes the development of general vascular resistance and an increase in blood pressure (while bradycardia only intensifies).

There is no depression of respiratory function when Dexmedetomidine is administered.

[ 6 ]

Pharmacokinetics

The kinetic properties of Dexmedetomidine were studied by single short-term infusion in healthy subjects and by long-term infusion in patients in the intensive care unit.

The drug is distributed in a two-chamber manner. In the first group of people, the distribution stage was rapid: the half-distribution period was 6 minutes.

The mean terminal half-life was approximately 1.35-3.68 h. The mean steady-state distribution was approximately 90 to 151 L/kg. Plasma clearance ranged from 35.7 to 51.1 L/h.

The average weight of patients with the above indications was equal to 69 kg.

Calculated parametric kinetic range:

• half-life is one and a half hours;
• equilibrium distribution ~ 93 l;
• clearance rates ~ 43 l per kilogram.

No accumulation is observed with infusion administration over a period of up to 2 weeks.

Binding of the active ingredient to plasma proteins is approximately 94%.

The quality of protein binding is considered constant in the concentration range of 0.85-85 ng/ml.

The active ingredient Dexmedetomidine can bind to serum albumin and alpha1-acid glycoprotein.

The metabolism of the drug occurs in the liver and consists of direct n-glucuronidation, n-methylation and cytochrome P450-mediated oxidation.

The main metabolic products are considered to be a pair of isomeric n-glucuronides.

Following intravenous infusion of the labeled drug, after 9 days, approximately 95% of the label was found in urine and approximately 4% in feces.

The major metabolic products in the urinary fluid are isomeric n-glucuronides (34%) and o-glucuronide (14.5%). Minor metabolic products may account for 1.11 to 7.66% of the dose.

Up to 1% of the unchanged active ingredient Dexmedetomidine was detected in urine fluid. Approximately 28% of the metabolic products in urine fluid were considered minor: their nature was unknown.

There is relatively little information on the kinetic properties of Dexmedetomidine used in children. The half-life is presumably similar to adult values. Plasma clearance in children under 2 months of age may presumably be underestimated.

Dosing and administration

Dexmedetomidine may only be used by qualified professionals with adequate knowledge in the relevant area.

Intubated patients are transferred to Dexmedetomidine with an initial infusion rate of 0.7 mcg/kg/hour, with subsequent dosage adjustments in the range of 0.2-1.4 mcg/kg/hour, taking into account the patient's response. For initially exhausted weak patients, the initial rate is often reduced.

It is considered a strong drug - its administration is carried out not over minutes, but over hours. Usually, one hour of infusion is not enough to achieve the required quality of sedation.

Do not use more than the maximum dosage of 1.4 mcg/kg/hour. If the desired sedation is not achieved, the patient should be transferred to another sedative.

There is no information regarding long-term use – more than 2 weeks.

For elderly people, there is no need to change the dosage.

Use in children has been little studied.

[ 11 ], [ 12 ]

Use Dexmedetomidine during pregnancy

There is no reliable information about the use of Dexmedetomidine during pregnancy.

Reproductive toxicity has been found in animal testing, but the degree of toxicity to humans has not been determined. For this reason, medical professionals advise avoiding the use of Dexmedetomidine during pregnancy, unless it is vitally necessary.

Studies have shown that Dexmedetomidine and its active ingredient penetrate into the breast milk of animals. Therefore, a certain degree of risk for children who are breastfed cannot be excluded. If there is a need to use Dexmedetomidine in a breastfeeding woman, it is recommended to stop breastfeeding.

Contraindications

Dexmedetomidine is not used in patients:

• with the possibility of developing hypersensitivity reactions;
• with existing atrioventricular block of the second or third degree (if there is no IVR);
• with uncontrolled hypotension;
• with acute cerebrovascular disorders;
• under 18 years of age;
• during pregnancy and breastfeeding.

[ 7 ], [ 8 ], [ 9 ], [ 10 ]

Side effects Dexmedetomidine

The most common side effects of Dexmedetomidine are blood pressure fluctuations and bradycardia. However, other, less frequent, adverse effects have been reported in some cases:

• hypo- and hyperglycemia;
• signs of metabolic acidosis;
• strong emotional arousal (agitation);
• hallucinations;
• increased heart rate;
• myocardial damage;
• decreased cardiac output;
• difficulty breathing;
• attacks of nausea and vomiting, thirst;
• flatulence;
• delirium;
• increase in body temperature.

Overdose

Several cases of overdose with Dexmedetomidine have been reported by specialists. According to available information, the infusion rate in patients was 60 mcg per kg of body weight per hour for 36 minutes, or 30 mcg per kg of body weight per hour for 15 minutes (in a 20-month-old infant and an adult patient, respectively).

In most cases, signs of overdose included bradycardia, hypotension, profound sedation, excessive drowsiness, and cardiac arrest.

If there is a suspicion of overdose of Dexmedetomidine, the infusion should be reduced or stopped. If necessary, provide resuscitation assistance.

It is worth noting that at the moment there has not been a single case of patient death from an overdose of Dexmedetomidine registered.

[ 13 ], [ 14 ], [ 15 ]

Interactions with other drugs

Interactions of Dexmedetomidine with other drugs have been studied in adult patients.

Combination with anesthetics, sedatives, barbiturates and narcotics may cause an increase in their effect. A similar study was conducted with infusion of isoflurane, midazolam, propofol, alfentanil. Taking into account the data obtained, it is possible to adjust the dosages.

Liver microsomal studies were performed to investigate the ability of the active component Dexmedetomidine to inhibit cytochrome P450, including the CYP2B6 isoenzyme. In vitro studies indicated the possibility of drug interactions with substrates in vivo.

The possibility of induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A4 isoenzymes by the active ingredient of the drug cannot be excluded.

In individuals undergoing treatment with drugs that lower blood pressure or provoke bradycardia (eg, beta-blockers), attention should be paid to the possible increase in these effects.

[ 16 ], [ 17 ], [ 18 ]

Storage conditions

Store at temperatures ranging from +8°C to +25°C, in a room with limited access for children.

The diluted infusion solution is stored only in a refrigerator with a temperature of +2°C to +8°C.

[ 19 ]

Shelf life

Ampoules and vials with the drug Dexmedetomidine can be stored for up to 3 years.

The diluted preparation is stored for no more than 24 hours, subject to the storage conditions described above.

[ 20 ], [ 21 ]