Pharmacology
DrugBankDescription
Clonidine is an imidazole derivate that acts as an agonist of alpha-2 adrenoceptors. This activity is useful for the treatment of hypertension, severe pain, and ADHD. Clonidine was granted FDA approval on 3 September 1974.
Mechanism of Action
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 Go and Gi. Gi 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.
Pharmacodynamics
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.
Metabolism
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.
Absorption
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%.
Toxicity
Oral LD50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring.
Indication
Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal.
Half-life
The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h.
Protein Binding
Clonidine is 20-40% bound to plasma proteins, especially albumin.
Elimination
Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces.
Volume of Distribution
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.
Tolerance & Pharmacokinetics
drugs.wikiTolerance Decay
Experience Report Analysis
ErowidDemographics
Gender Distribution
Age Distribution
Reports Over Time
Effect Analysis
ErowidEffects aggregated from 25 experience reports (25 Erowid)
Effect Sentiment Distribution
Confidence Distribution
Positive Effects 6
Adverse Effects 2
Dosage Distribution
Dose distribution from experience reports
Real-World Dose Distribution
62K DosesFrom 31 individual dose entries
Oral (n=26)
Form / Preparation
Most common forms and preparations reported
Body-Weight Dosing
Dose relative to body weight from reports with weight data
Redose Patterns
Redosing behavior across 20 reports