Pharmacodynamics
Clonidine produces most of its pharmacodynamic effects by acting as a non-selective partial agonist at α2 adrenoceptors (α2A, α2B, and α2C), where it can mimic the actions of endogenous norepinephrine at these receptors in the central nervous system and the sympathetic nervous system. Clonidine can also bind imidazoline I1 receptors in brainstem regions involved in cardiovascular responses. Through these actions clonidine lowers arterial blood pressure, heart rate, and total peripheral resistance. α2 adrenoceptor activation decreases noradrenergic arousal signaling in the ascending reticular activating system, can modify prefrontal cortical network activity relevant to attention, and suppresses nociceptive signaling in the dorsal horn of the spinal cord.
α2 adrenoceptors are Gi/Go-coupled G protein-coupled receptors that signal through heterotrimeric G proteins made up of a Gαi/o subunit protein and a paired Gβγ subunit complex (i.e., the β and γ subunits). After receptor activation, Gαi/o and Gβγ can separate, and both components contribute to inhibition of neuronal activity and neurotransmitter release. Gαi/o inhibits adenylyl cyclase, which decreases the expression of cyclic adenosine monophosphate (cAMP) and ceases protein kinase A (PKA)-dependent phosphorylation of amino acid residues involved in neuronal excitability and synaptic signaling. In parallel, Gβγ can increase K conductance through G protein-coupled inwardly rectifying potassium channels (GIRKs), an effect that reduces neuronal firing through membrane hyperpolarization.
In noradrenergic presynaptic neurons in the sympathetic nervous system, α2 adrenoceptors act as inhibitory autoreceptors that inhibit action potential-evoked neurotransmitter release. After presynaptic α2 adrenoceptor activation by clonidine, the released Gβγ dimer can inhibit voltage-gated Ca channels (including P/Q-type and N-type channels), which reduces Ca entry during presynaptic depolarization and lowers vesicular neurotransmitter release. Gβγ signaling can also increase K conductance (including via GIRKs) to oppose presynaptic depolarization and further limit voltage-gated Ca channel activation. In addition, Gβγ can bind proteins within the SNARE complex (e.g., SNAP-25), which can suppress synaptic vesicle fusion downstream of Ca entry. These mechanisms reduce the release of norepinephrine and other neurotransmitters from affected nerve terminals.
Clonidine lowers arterial blood pressure primarily by reducing sympathetic nervous system activity and increasing vagus nerve activity to the heart. In the medulla oblongata, activation of α2 adrenoceptors reduces the firing of neurons that are responsible for sympathetic nerve signaling to the heart, kidneys, and peripheral vasculature and can slow heart rate by increasing vagal tone. At postganglionic nerve fibers, presynaptic α2 adrenoceptors function as inhibitory autoreceptors that suppress nerve-evoked release of norepinephrine and other signaling compounds (including adenosine triphosphate and neuropeptide Y). These central and peripheral actions are associated with decreased plasma norepinephrine and reduced urinary catecholamine excretion, and with reductions in plasma renin and urinary aldosterone reported alongside decreases in total peripheral resistance and heart rate. With intravenous administration, clonidine may cause a short-lived increase in blood pressure attributed to α2 adrenoceptor-mediated vasoconstriction in vascular smooth muscle, followed by a more sustained hypotensive response once clonidine crosses the blood brain barrier and binds to its receptor sites in the medulla oblongata; this biphasic pattern is generally less evident with oral or transdermal routes of administration due to dilution of the drug before reaching circulation.
In the prefrontal cortex, α2A is the predominant α2 adrenoceptor subtype, and clonidine's attention- and working memory-related effects are attributed to postsynaptic α2A activation. Across the brain more generally, α2A and α2C adrenoceptors are widely distributed, while α2B is primarily expressed in the thalamus. α2A adrenoceptors on dendritic spines of prefrontal pyramidal neurons can close hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) to promote attentional control and working memory. The mechanism behind this behavioral effect has been described as the consequence of improved signal-to-noise ratio in the prefrontal cortex, which can facilitate focused attention on relevant stimuli and improved cognitive control of behavior.
Sedation is attributed to clonidine's activity on noradrenergic neurons of the locus coeruleus and thalamus. Somatodendritic α2 adrenoceptors reduce locus coeruleus firing, and presynaptic α2 adrenoceptors reduce norepinephrine release along noradrenergic pathways, in turn lowering noradrenergic modulation of arousal in the ascending reticular activating system. α2 adrenoceptors are also expressed on axon terminals that release several other neurotransmitters (i.e., serotonin, dopamine, acetylcholine, GABA, and glutamate), and their activation can suppress release at these synapses as well.
Clonidine produces analgesic effects in part through α2 adrenoceptors in the dorsal horn of the spinal cord. In primary nociceptive neurons, α2A and α2C adrenoceptors are present on axon terminals and can be co-localized with neuropeptides involved in nociceptive signaling (e.g., substance P and calcitonin gene-related peptide), and clonidine inhibits their release in preclinical models. Activation of α2 adrenoceptors in the spinal cord reduces excitatory input to dorsal horn neurons and decreases dorsal horn neuron firing, thereby inhibiting nociceptive signaling. In addition to the synergistic effect clonidine has with opioids, naloxone, an opioid antagonist, can reverse clonidine overdose.
The discovery of imidazoline receptors has prompted investigation of I1 receptor contributions to Clonidine's cardiovascular effects. I1 receptors are widely distributed, including in the central nervous system, and I1 activation has been implicated in clonidine's sympatholytic effect. One proposed model is that I1 receptor activation in the brainstem facilitates endogenous catecholamine signaling that then activates α2 adrenoceptors to reduce sympathetic activity and blood pressure, but the magnitude of I1 receptors in clonidine's hypotensive effects remains unsettled.
Growth hormone test
Clonidine stimulates release of GHRH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone. This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.
Pharmacokinetics
After being ingested, clonidine is absorbed into the blood stream rapidly with an overall bioavailability around 70–80%. Peak concentrations in human plasma occur within 60–90 minutes for the "immediate release" (IR) version of the drug, which is shorter than the "extended release" (ER/XR) version. Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6; to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0. Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys. About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces. Work with liver microsomes shows in the liver clonidine is primarily metabolized by CYP2D6 (66%), CYP1A2 (10–20%), and CYP3A (0–20%) with negligible contributions from the less abundant enzymes CYP3A5, CYP1A1, and CYP3A4. 4-hydroxyclonidine, the main metabolite of clonidine, is also an α2A agonist but is non lipophilic and is not believed to contribute to the effects of clonidine since it does not cross the blood–brain barrier.
Measurements of the half-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting of poor kidney function. Variations in half-life may be partially attributable to CYP2D6 genetics. Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing, while other work contradicts this. Following a 0.3mg oral dose, a small study of five patients by Dollery et al. (1976) found half-lives ranging between 6.3 and 23.4 hours (mean 12.7). A similar N=5 study by Davies et al. (1977) found a narrower range of half-lives, between 6.7 and 13 hours (mean 8.6), while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter mean half-life of 7.5 hours.
Clonidine can be administered via oral. The route of administration can influence both the onset and intensity of cognitive fatigue.
