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102

Chapter 8

Table 1.

Pharmacology of dexmedetomidine and clonidine

Dexmedetomidine

Clonidine

α

2

1

1620:1

α

2

1

220:1

α

2

A-receptor

Imidazole-receptor

T

1/2

= 2 h

T

1/2

= 8 h

Intravenous, intramuscular

Intravenous, intrathecal, oral

No rebound effect

Rebound effect

Pharmacokinetics

Dexmedetomidine has a distribution half-life of 6 minutes and an elimination half-life

of approximately 2 hours. Even with prolonged treatment, no accumulation is seen.

Dexmedetomidine is for 94% bound to plasma proteins and is almost completely

degraded by the liver. The various metabolites have negligible pharmacological activity

and are excreted by the kidneys for 95% and for 4% via faeces. Less than 1% is eliminated

unmetabolised in the urine. It should be considered to reduce the starting dose for

patients with hepatic impairment. Patients with renal impairment do not show altered

pharmacokinetics compared to healthy subjects. No significant pharmacokinetic differences

are observed based on age or gender.

Receptors

Α

2

-receptors are located pre-, extra-, and postsynaptic (Figure 1). They are found in the

peripheral and central nervous system, on platelets and various organs such as the liver,

pancreas, kidneys, and eyes. The presynaptic α

2

-receptors appear clinically more relevant.

They regulate the release of norepinephrine and ATP via a negative feedback mechanism.

Α

2

-receptors are G-protein coupled: stimulation of the receptor leads to activation of various

G-proteins. These proteins initiate an enzyme cascade that finally leads to the inhibition of

the calcium-entry into the nerve endings with a reduced release of norepinephrine. Aside,

G-proteins adapt via a second-messenger system ion channels, thereby inducing an efflux

of potassium ions. This allows for a hyperpolarisation of the cell membrane. In summary,

activation of α

2

-receptors diminishes the release of noradrenaline and inhibits neuronal

activity.

5

Mechanism of action

The desired effects of α

2

-agonists are sedation, anxiolysis, and analgesia. These effects are

mediated via different receptors. There are also (unwanted) central and peripheral side

effects. The receptors are divided into α

2

A-, α

2

B- and α

2

C-receptors triggering analgesic,

vasoconstrictive, and anxiolytic effects mainly due to the location of the different receptors

in the body.