Clonidine
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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as Catapres, Catapres-TTS, Kapvay, Nexiclon XR, duraclonPW
Is a medication that is used to treat high blood pressure, anxiety, withdrawal (Typically from Alcohol, Opioids, Smoking) and many other uses.TS
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 25 μg | 50–75 μg | 75–100 μg | 100–300 μg | 300 μg+ |
| Onset | 15–45 minutes |
|---|---|
| Peak | 60–90 minutes |
| Offset | 6–8 hours |
| Total | 6–8 hours |
Dangerous interactionsPW
Caution / uncertainPW
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Alpha-2A adrenergic receptor | — | Ki 20.89 nM | CHEMBL | TargetAlpha-2A adrenergic receptor Action— AffinityKi 20.89 nM SourceCHEMBL |
| Alpha-2B adrenergic receptor | — | Ki 94.09 nM | CHEMBL | TargetAlpha-2B adrenergic receptor Action— AffinityKi 94.09 nM SourceCHEMBL |
| Alpha-2C adrenergic receptor | — | Ki 431.96 nM | CHEMBL | TargetAlpha-2C adrenergic receptor Action— AffinityKi 431.96 nM SourceCHEMBL |
| Alpha-1A adrenergic receptor | — | Ki 575.64 nM | CHEMBL | TargetAlpha-1A adrenergic receptor Action— AffinityKi 575.64 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 7 | — | Ki 878.51 nM | CHEMBL | Target5-hydroxytryptamine receptor 7 Action— AffinityKi 878.51 nM SourceCHEMBL |
| Alpha-1D adrenergic receptor | — | Ki 1979.25 nM | CHEMBL | TargetAlpha-1D adrenergic receptor Action— AffinityKi 1979.25 nM SourceCHEMBL |
| Alpha-1B adrenergic receptor | — | Ki 2627.54 nM | CHEMBL | TargetAlpha-1B adrenergic receptor Action— AffinityKi 2627.54 nM SourceCHEMBL |
| Sigma intracellular receptor 2 | — | Ki 2775.87 nM | CHEMBL | TargetSigma intracellular receptor 2 Action— AffinityKi 2775.87 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2C | — | Ki 6953.44 nM | CHEMBL | Target5-hydroxytryptamine receptor 2C Action— AffinityKi 6953.44 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2A | — | Ki 9141.13 nM | CHEMBL | Target5-hydroxytryptamine receptor 2A Action— AffinityKi 9141.13 nM SourceCHEMBL |
| Alpha-1D adrenergic receptor (Adra1d) | Agonist | 6.9 Ki | DRUGCENTRAL | TargetAlpha-1D adrenergic receptor (Adra1d) ActionAgonist Affinity6.9 Ki SourceDRUGCENTRAL |
| Alpha-2A adrenergic receptor (ADRA2A) | Agonist | 8.42 Ki | DRUGCENTRAL | TargetAlpha-2A adrenergic receptor (ADRA2A) ActionAgonist Affinity8.42 Ki SourceDRUGCENTRAL |
| Alpha-2B adrenergic receptor (ADRA2B) | Agonist | 7.5 Ki | DRUGCENTRAL | TargetAlpha-2B adrenergic receptor (ADRA2B) ActionAgonist Affinity7.5 Ki SourceDRUGCENTRAL |
| Alpha-2C adrenergic receptor (ADRA2C) | Agonist | 6.7 EC50 | DRUGCENTRAL | TargetAlpha-2C adrenergic receptor (ADRA2C) ActionAgonist Affinity6.7 EC50 SourceDRUGCENTRAL |
| Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1) | Blocker | 4.4 IC50 | DRUGCENTRAL | TargetPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1) ActionBlocker Affinity4.4 IC50 SourceDRUGCENTRAL |
| Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (Hcn2) | Blocker | 5.1 IC50 | DRUGCENTRAL | TargetPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (Hcn2) ActionBlocker Affinity5.1 IC50 SourceDRUGCENTRAL |
| Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4) | Blocker | 5 IC50 | DRUGCENTRAL | TargetPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4) ActionBlocker Affinity5 IC50 SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 1A (HTR1A) | — | 5.49 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 1A (HTR1A) Action— Affinity5.49 Ki SourceDRUGCENTRAL |
| Adrenergic receptor alpha-2 (Adra2b) | — | 8.82 Ki | DRUGCENTRAL | TargetAdrenergic receptor alpha-2 (Adra2b) Action— Affinity8.82 Ki SourceDRUGCENTRAL |
| Alpha-1A adrenergic receptor (ADRA1A) | — | 6.5 Ki | DRUGCENTRAL | TargetAlpha-1A adrenergic receptor (ADRA1A) Action— Affinity6.5 Ki SourceDRUGCENTRAL |
| Alpha-1B adrenergic receptor (ADRA1B) | — | 6.5 Ki | DRUGCENTRAL | TargetAlpha-1B adrenergic receptor (ADRA1B) Action— Affinity6.5 Ki SourceDRUGCENTRAL |
| Alpha-1D adrenergic receptor (ADRA1D) | — | 6.22 Ki | DRUGCENTRAL | TargetAlpha-1D adrenergic receptor (ADRA1D) Action— Affinity6.22 Ki SourceDRUGCENTRAL |
| Alpha-2A adrenergic receptor (Adra2a) | — | 9.41 Ki | DRUGCENTRAL | TargetAlpha-2A adrenergic receptor (Adra2a) Action— Affinity9.41 Ki SourceDRUGCENTRAL |
| Alpha-2B adrenergic receptor (Adra2b) | — | 8.08 Ki | DRUGCENTRAL | TargetAlpha-2B adrenergic receptor (Adra2b) Action— Affinity8.08 Ki SourceDRUGCENTRAL |
| Beta-1 adrenergic receptor (ADRB1) | — | 4.4 Kd | DRUGCENTRAL | TargetBeta-1 adrenergic receptor (ADRB1) Action— Affinity4.4 Kd SourceDRUGCENTRAL |
| Multidrug and toxin extrusion protein 1 (SLC47A1) | — | 4.48 IC50 | DRUGCENTRAL | TargetMultidrug and toxin extrusion protein 1 (SLC47A1) Action— Affinity4.48 IC50 SourceDRUGCENTRAL |
| Nischarin (NISCH) | — | 8.05 Ki | DRUGCENTRAL | TargetNischarin (NISCH) Action— Affinity8.05 Ki SourceDRUGCENTRAL |
| Solute carrier family 22 member 1 (SLC22A1) | — | 4.65 IC50 | DRUGCENTRAL | TargetSolute carrier family 22 member 1 (SLC22A1) Action— Affinity4.65 IC50 SourceDRUGCENTRAL |
| Solute carrier family 22 member 2 (SLC22A2) | — | 4.796 IC50 | DRUGCENTRAL | TargetSolute carrier family 22 member 2 (SLC22A2) Action— Affinity4.796 IC50 SourceDRUGCENTRAL |
Mechanism of actionPH
Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G<sub>o</sub> and G<sub>i</sub>. G<sub>i</sub> inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla.
Intravenous infusion of clonidine causes an acute rise in blood pressure, apparently because of activation of postsynaptic alpha2 receptors in vascular smooth muscle. The affinity of clonidine for these receptors is high, although the drug is a partial agonist with relatively low efficacy at these sites. The hypertensive response that follows parenteral administration of clonidine generally is not seen when the drug is given orally. However, even after intravenous administration, the transient vasoconstriction is followed by a more prolonged hypotensive response which results from decreased central outflow of impulses in the sympathetic nervous system. ... The effect appears to result from activation of alpha2 receptors in the lower brain stem region. This central action has been demonstrated by infusing small amounts of the drug into the vertebral arteries or by injecting it directly into the cisterna magna.
Clonidine decreases discharges in sympathetic preganglionic fibers in the splanchnic nerve as well as in postganglionic fibers of cardiac nerves. These effects are blocked by alpha2-selective antagonists ... Clonidine also stimulates parasympathetic outflow, and this may contribute to the slowing of heart rates as a consequence of increased vagal tone as well as diminished sympathetic drive.
THE SITES OF ACTION OF CLONIDINE INDUCED ADRENAL-SUPPRESSANT EFFECT WERE INVESTIGATED IN SPONTANEOUSLY HYPERTENSIVE RATS. FIVE TO 10 MINUTES AFTER IV ADMINISTRATION OF CLONIDINE (3-100 MG/KG), THERE WAS A DECREASE IN BOTH SYMPATHETIC ADRENAL NERVE ACTIVITY AND ADRENAL CATECHOLAMINE SECRETION RATES, ALONG WITH THE DECREASE IN ARTERIAL BLOOD PRESSURE AND HEART RATE. APPARENTLY, BOTH THE ADRENAL MEDULLA AND THE SPINAL AND SUPRASPINAL STRUCTURES ARE THE RESPONSIBLE SITES OF ACTION OF CLONIDINE-INDUCED ADRENAL SUPPRESSION. THE CENTRAL ACTION OF CLONIDINE APPEARS TO PREDOMINATE OVER THE PERIPHERAL ACTION IN THIS SUPPRESSION.
Clonidine appears to stimulate alpha2-adrenergic receptors in the CNS (mainly in the medulla oblongata), causing inhibition, but not blockade, of sympathetic vasomotor centers. Cardiovascular reflexes remain intact, and normal homeostatic mechanisms and hemodynamic responses to exercise are maintained. The central effects of the drug result in reduced peripheral sympathetic nervous system activity, reduced peripheral and renovascular resistance, reduction of systolic and diastolic blood pressure, and bradycardia. Peripheral venous pressure remains unchanged. It has been postulated that the hypotensive response to clonidine may result from reduced angiotensin II generation because of inhibition of renin release or from reduced stimulation of medullary vasomotor centers responsive to circulating angiotensin II; however, the exact relationship between the action of the drug in reducing renin activity and excretion of aldosterone and catecholamines and the hypotensive effect of the drug has not been fully elucidated.
PharmacodynamicsPH
Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily.
Pharmacokinetics
Half-lifePH
The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h.
The elimination half-life of the drug ranges from 6 to 24 hours, with a mean of about 12 hours.
THE PHARMACOKINETICS OF CLONIDINE WERE INVESTIGATED IN HEALTHY VOLUNTEERS OVER A TIME MORE THAN 3 TIMES LONGER THAN PREVIOUSLY REPORTED. THE COMPLETE BIOAVAILABILITY OF CLONIDINE AND ITS ELIMINATION T/2 (20 TO 25.5 HOURS) REMAINED CONSTANT AFTER SINGLE AND MULTIPLE DOSES.
The plasma half-life of clonidine is 6-20 hours in patients with normal renal function. The half-life in patients with impaired renal function has been reported to range from 18-41 hours. The elimination half-life of the drug may be dose dependent, increasing with increasing dose.
AbsorptionPHDM
Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a Cmax of 400.72pg/mL with an AUC of 5606.78h\*pg/mL and a bioavailability of 55-87%.
Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces.
The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source.
The clearance of clonidine is 1.9-4.3mL/min/kg.
Animal studies indicate that clonidine is widely distributed into body tissues; tissue concentrations of the drug are higher than plasma concentrations. The mean volume of distribution of clonidine is reported to be 2.1 L/kg. After oral administration, highest concentrations of the drug are found in the kidneys, liver, spleen, and GI tract. High concentrations of the drug also appear in the lacrimal and parotid glands. Clonidine is concentrated in the choroid of the eye and is also distributed into the heart, lungs, testes, adrenal glands, fat, and muscle. The lowest concentration occurs in the brain. Clonidine is distributed into CSF. Following epidural infusion, clonidine is rapidly and extensively distributed into CSF and readily partitions into the plasma via epidural veins. In vitro, clonidine is approximately 20-40% bound to plasma proteins, mainly albumin. Clonidine crosses the placenta1 and is distributed into milk. In one lactating woman who received approximately 0.04 mg of oral clonidine hydrochloride twice daily and 25 mg of oral dihydralazine 3 times daily, clonidine concentrations were 0.33 ng/mL in a plasma sample obtained 1 hour after a dose and 0.6 ng/mL in a milk sample obtained 2.5 hours after a dose; the drug was not detected in the plasma of the infant 1 hour after nursing.
...IN HEALTHY VOLUNTEERS... AFTER IV INFUSION OF 300 UG CLONIDINE IN 10 MINUTES, PLASMA LEVELS OF DRUG DECLINED BI-EXPONENTIALLY WITH RAPID AND SLOW HALF-LIFE VALUES OF 11 MINUTES AND 8.5 HOURS, RESPECTIVELY.
MetabolismPH
The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites.
Clonidine hydrochloride is metabolized in the liver. In humans, 4 metabolites have been detected but only one, the inactive p-hydroxyclonidine, has been identified.
...Seventeen cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.
CLONIDINE SHOWS SPECIES DIFFERENCES IN THE EXTENT OF BIOTRANSFORMATION. THE FATE OF (14)C-CLONIDINE IN THE DOG HAS BEEN REPORTED AND SIX COMPONENTS WERE ISOLATED AND IDENTIFIED. UNCHANGED CLONIDINE AND ITS P-HYDROXYLATED DERIVATIVE WERE DETECTED. DICHLOROPHENYLGUANIDINE, WHICH HAS PREVIOUSLY BEEN REPORTED AS A METABOLITE IN DOGS, WAS ALSO IDENTIFIED. THREE METABOLITES NOT PREVIOUSLY DESCRIBED WERE ALSO ISOLATED FROM DOG URINE. THE MAJOR METABOLIC ROUTES FOR CLONIDINE ARE PHENYL RING HYDROXYLATION AND SPLITTING OF THE IMIDAZOLIDINE RING. COMPARATIVE STUDIES SHOWED THAT THE METABOLISM OF CLONIDINE IS RATHER SIMILAR IN RAT, DOG, AND MAN, BUT MAN EXCRETED MOST UNCHANGED DRUG AND DOG SHOWED THE MOST EXTENSIVE METABOLISM.
Hepatic. Metabolized via minor pathways. The major metabolite, <i>p</i>-hydroxyclonidine, is present in concentrations less than 10% of those of unchanged clonidine in urine. Four metabolites have been detected, but only <i>p</i>-hydroxyclonidine has been identified.
Half Life: 6-20 hours; 40-60% is excreted in urine unchanged, 20% is excreted in feces. Less than 10% is excreted by <i>p</i>-hydroxyclonidine.
Protein bindingPH
Clonidine is 20-40% bound to plasma proteins, especially albumin.
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