Clonidine

Clonidine does not intoxicate so much as it quiets. Within thirty to sixty minutes, the first effect most people notice is a slowing of the heart rate -- not in a frightening way but as a gentle deceleration, as though the internal metronome that sets the body's tempo had been adjusted downward by a few beats per minute. Blood pressure drops, and with it comes a sensation of the vascular system relaxing, the blood vessels widening like roads after rush hour. There is a subtle lightheadedness upon standing, a reminder that gravity is making different demands on a circulatory system that has been told to ease off.

The come-up brings a sedation that is distinctly physical in character. The eyelids grow heavy, the limbs feel weighted, and there is a pervasive drowsiness that settles over the body like a lead blanket. The mind does not fog exactly, but it slows, thoughts arriving with less frequency and less urgency. Anxiety, particularly the physical kind -- the racing heart, the sweaty palms, the chest tightness -- is dramatically reduced. There is no euphoria to speak of; the pleasure, such as it is, comes entirely from the relief of sympathetic nervous system overdrive. For those in states of agitation or withdrawal, this relief can feel profound.

At peak effects, the dominant sensation is one of deep, almost narcotic drowsiness. The body feels impossibly heavy, and the desire to lie down becomes a quiet imperative. The mouth dries noticeably, and there is often a slight stuffiness in the nose. The world seems to recede to a comfortable distance, sounds becoming softer and less demanding of attention. There is a coolness to the skin, particularly in the extremities, as blood pressure settles into its lowered state. Mental activity does not cease but it simplifies, the usual cascade of overlapping thoughts reducing to a single, slow stream. Some people describe a sensation of floating in a still, dark pool -- not unpleasant, but deeply unexciting.

The offset is a gradual reawakening of the sympathetic nervous system over several hours. Heart rate and blood pressure creep back up to baseline, and the drowsiness lifts slowly. There may be a mild rebound effect -- a slight increase in heart rate and a return of the anxiety that had been suppressed -- but for most, the transition back to normal is smooth and unremarkable. The overall impression is one of pharmacological calm: efficient, clinical, and utterly devoid of glamour.

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.

In the early 1960s, the medicinal chemist Helmut Stähle was tasked by Boehringer Ingelheim with synthesizing a peripherally active a-adrenergic compound that would be useful for nasal decongestion as simple nose drops. A locally acting a-adrenergic vasoconstrictor agent was expected to provide relief from the symptoms of the common cold by shrinking the swollen nasal membranes and producing an unobstructed air passage.

Clonidine, or 2-[(2,6-Dichlorophenyl)imino]imidazoline, is a compound of the imidazoline chemical class. Imidazolines are substituted amidines in which the amidine function is incorporated into an imidazoline ring. This portion is connected to an aromatic nucleus by way of a methylene bridge.

Additionally, two chlorine atoms are substituted in the 2- and 6-positions of the phenyl ring. This addition has the critical effect of making the molecule sufficiently lipophilic to penetrate the blood-brain barrier.

Other compounds of this class include the a-adrenergic agents tolazoline, naphazoline, and phentolamine. The a-adrenergic effects of clonidine and other imidazolidine compounds may be explained on the basis of a structural overlap between clonidine and norepinephrine.

• Pharmacodynamics

Clonidine is an agonist for the α2 adrenergic receptor. When α2 receptors in the brain are stimulated, peripheral vascular resistance decreases, resulting in lowered blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels and inhibits the release of norepinephrine (NE). The net effect is a decrease in sympathetic nervous system tone.

Three G-protein coupled α2-receptor subtypes have been identified: α2A, α2B, and α2C. Each subtype has a unique pattern of tissue distribution in the central nervous system and peripheral tissues. The α2A-receptor is widely distributed throughout the central nervous system; it is found in the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. α2A receptors are also expressed in the kidneys, spleen, thymus, lung and salivary glands. The α2C-receptor is primarily expressed in the central nervous system, including the striatum, olfactory tubercle, hippocampus and cerebral cortex. The α2B receptor is located primarily in the periphery (kidney, liver, lung and heart).

The α2A- and α2C receptors are located presynaptically and inhibit the released of noradrenaline from sympathetic nerves. Stimulation of these receptors decreases sympathetic tone, resulting in decreases in blood pressure and heart rate. Sedation and analgesia is mediated by centrally located α2A receptors, while peripheral α2B receptors mediate constriction of vascular smooth muscle. α2A receptors also mediate essential components of the analgesic effect of nitrous oxide in the spinal cord. Clonidine stimulates all three α2 receptor subtypes with similar potency.

Clonidine also has peripheral α1 agonist activity.

Clonidine is also an agonist for the imidazoline I1 receptor. This has been proposed to be responsible for the antihypertensive effects.

• Pharmacokinetics

Clonidine is rapidly absorbed from the gastrointestinal tract and has excellent CNS penetration because of lipid solubility. Peak plasma concentrations are reached 3-5 hours after a single oral dose. No known pharmacologically active metabolites exist. Plasma half-life is 12-16 hours, with the antihypertensive effects occurring within 30-60 minutes of ingestion. Clonidine is excreted unchanged in the urine and is metabolized by the liver.

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There are currently anecdotal reports which describe the effects of this compound within our experience index.

At therapeutic doses (0.2-0.9 mg/d), clonidine is commonly associated with adverse effects such as dry mouth, sedation, dizziness, and constipation. While generally safe, at toxic doses clonidine can cause serious cardiopulmonary instability and central nervous system (CNS) depression in children and adults. Caution should be used when clonidine is taken with other depressants.

It is strongly recommended that one use harm reduction practices when using this substance.

The oral LD50 for clonidine in mice is 206 mg/kg and for rats, 465 mg/kg. In humans, lethality is rare with a small number of reported deaths. Morbidity, in terms of cardiorespiratory and CNS dysfunction, generally tends to be more severe in young persons than in adults.

• Overdose

Symptoms of clonidine overdose include constriction of pupils of the eye, drowsiness, high blood pressure followed by a drop in pressure, irritability, low body temperature, slowed breathing, slowed heartbeat, slowed reflexes, and weakness.

There are case reports that show naloxone may be a useful antidote in treating clonidine overdoses. However, this is not in widespread clinical use. -not addictive and has a low potential for abuse. The chronic use of clonidine can produce physical dependence and withdrawal symptoms if one suddenly stops their usage. Clonidine therapy should generally be gradually tapered when discontinuing therapy to avoid rebound hypertension from occurring.

Although clonidine is not considered to be addictive, cases of misuse have been documented among certain groups with pre-existing substance use disorders. It is sometimes used in combination with opiates to extend and potentiate their effects. This practice may increase the risk of oversedation and respiratory depression associated with opioid use.

• Germany: Clonidine is prescription medicine, according to Anlage 1 AMVV.

• Switzerland:** Clonidine is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.

• **United States:''' Clonidine is only available with a prescription.

• Responsible use

• Depressant

• Adrenaline (Epinephrine)

• Noradrenaline (Norpinephrine)

• Clonidine (Wikipedia)

• Clonidine (Erowid Vault)

• Clonidine (Isomer Design)

• Clonidine (Drugs-Forum)

• Stähle, H. (2000). A historical perspective: development of clonidine. Best Practice & Research Clinical Anaesthesiology, 14(2), 237-246. https://doi.org/10.1053/bean.2000.007