Clonidine is an imidazoline derivate and centrally-acting alpha-adrenergic agonist, with antihypertensive activity. Clonidine binds to and stimulates central alpha-2 adrenergic receptors, thereby reducing the amount of norepinephrine (NE) release and thus decreasing sympathetic outflow to the heart, kidneys, and peripheral vasculature. The reduction in sympathetic outflow leads to decreased peripheral vascular resistance, decreased blood pressure, and decreased heart rate. In addition, clonidine binds to imidazoline receptor subtype 1 (I1), which may also contribute to a reduction in blood pressure.
Clonidine is a medication used to treat high blood pressure, attention deficit hyperactivity disorder, anxiety disorders, tic disorders, withdrawal (from either alcohol, opioids, or smoking), migraine, menopausal flushing, diarrhea, and certain pain conditions. It is classified as a centrally acting α2 adrenergic agonist and imidazoline receptor agonist.
Mechanism of Action of Clonidine
Clonidine is an α-adrenergic agent that acts specifically on α2-receptors. α2-receptors regulate a number of signaling pathways mediated by multiple Gi proteins, Gαi1, Gαi2, and G&alphai3. Stimulation of α2-receptors mediates effects such as inhibition of adenylyl cyclase, stimulation fo phospholipase D, stimulation of mitogen-activated protein kinases, stimulation of K+ currents and inhibition of Ca2+ currents. 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. Low levels of the α2C-subtype are also found in the kidneys. The α2B-receptor is located primarily in the periphery (kidney, liver, lung, and heart) with low levels of expression in the thalamic nuclei of the central nervous system. 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 are 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. Its actions in the nervous system decrease blood pressure in patients with hypertension and decrease sympathetic overactivity in patients undergoing opioid withdrawal. Clonidine is also a potent sedative and analgesic and can prevent post-operative shivering in intensive and post-operative care. Its use in differential diagnosis of pheochromocytoma owes to the fact that hypertension in patients with pheochromocytoma is refractory to antihypertensive treatment with clonidine.
Clonidine treats high blood pressure by stimulating α2 receptors in the brain, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, thus inhibiting the release of norepinephrine (NE). The net effect is a decrease in sympathetic tone
Indications of Clonidine
- Attention Deficit Disorder With Hyperactivity
- Gilles de la Tourette’s syndrome
- Growth hormone deficiency
- High blood pressure
- Menopausal hot flushes
- Opiate withdrawal symptoms
- Oppositional defiant disorder
- Pheochromocytomas
- Postherpetic Neuralgia
- Sialorrhea caused by clozapine
- Diabetic
- Diarrhea
- Methadone withdrawal
- Severe Cancer pain
It may be used as an adjunct in the treatment of hypertension, as an epidural infusion as an adjunct treatment in the management of severe cancer pain that is not relieved by opiate analgesics alone, for differential diagnosis of pheochromocytoma in hypertensive patients, prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, management of vasomotor symptoms associated with menopause, rapid detoxification in the management of opiate withdrawal, treatment of alcohol withdrawal used in conjunction with benzodiazepines, management of nicotine dependence, topical use to reduce intraocular pressure in the treatment of open-angle and secondary glaucoma and hemorrhagic glaucoma associated with hypertension, and in the treatment of attention-deficit hyperactivity disorder (ADHD).
Contra-Indications of Clonidine
- Depression
- Dry eye
- Heart attack
- Diminished blood flow through arteries of the heart
- Atrioventricular heart block
- Sinus bradycardia
- Disorder of the blood vessels of the brain
- Occasional numbness
- Prickling
- Tingling of fingers and Toes
- Recent operation
- Chronic kidney disease stage 5 (failure)
- Allergies to alpha 2 Adrenergic Agonist
Dosage of Clonidine
Strengths: 0.1 mg; 0.2 mg; 0.3 mg; 0.1 mg/24 hr; 0.2 mg/24 hr; 0.3 mg/24 hr;
Hypertension
Oral
- Initial dose: 0.1 mg orally 2 times a day (morning and bedtime)
- Titration: Increments of 0.1 mg orally per day may be made at weekly intervals to the desired response
- Maintenance dose: 0.2 to 0.6 mg orally per day in divided doses
- Maximum dose: 2.4 mg orally per day in divided doses.
Transdermal patches
- Initial dose: 0.1 mg/24 hr patch applied every 7 days
- Maintenance dose: If, after 1 to 2 weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another 0.1 mg/24 hr patch or changing to a larger system
- Maximum dose: Doses above two 0.3 mg/24 hr patches applied every 7 days is usually not associated with additional efficacy
Attention Deficit Disorder
Extended-release, 6 years and older
- Initial dose: 0.1 mg orally at bedtime
- Titration: Increase in 0.1 mg/day increments every 7 days until desired response; doses should be administered twice daily (either split equally or with the higher split dosage given at bedtime)
- Maximum dose: 0.4 mg/day in 2 divided doses
Side Effects of Clonidine
The most common
- Dizziness
- Orthostatic hypotension
- Xerostomia (dry mouth)
- A headache
- Fatigue
- Skin reactions
- Hypotension
- Anxiety
- Constipation
- Sedation (dose-dependent)
- Nausea/vomiting
- Weight gain/loss
- Pain below the ear (from salivary gland)
- Erectile dysfunction
More common
- Abdominal or stomach pain, discomfort, or tenderness
- chills or fever
- difficulty with moving
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in the chest
- discomfort in arms, shoulders, neck or upper back
- excessive sweating
- feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
- sudden tingling or coldness in an arm or leg
- sudden slow or difficult speech
- sudden drowsiness or need to sleep
- fast breathing
- sharp pain when taking a deep breath
- fast or slow heartbeat
- coughing up blood
- rust colored urine
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- a cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- fainting
- hallucinations
- a headache
- irritability
- lightheadedness
- mood or mental changes
- muscle pain or cramps
- muscle spasm or jerking of all extremities
- nervousness
Drug Interactions
Clonidine may interact with the following drug, supplements, & may change the efficacy of the drug
- alpha-1 blockers (e.g., doxazosin, prazosin, tamsulosin)
- alpha-2 blockers (e.g., clonidine, dexmedetomidine, methyldopa)
- angiotensin-converting enzyme inhibitors (ACEIs; e.g., captopril, ramipril)
- angiotensin II receptor blockers (i.e., irbesartan, losartan, valsartan)
- antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone)
- atorvastatin
- azole antifungals (e.g., itraconazole, ketoconazole, posaconazole)
- barbiturates (e.g., phenobarbital)
- benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
- beta-agonists (e.g., formoterol, salbutamol, salmeterol)
- other beta-blockers (e.g., propranolol, metoprolol)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- carbamazepine
- cyclosporine
- dexamethasone
- diuretics (water pills; e.g., furosemide, hydrochlorothiazide)
- duloxetine
- levodopa
- lidocaine
- MAO inhibitors (e.g., phenelzine, moclobemide, selegiline)
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- nilotinib
- nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen, naproxen)
- other beta-blockers (e.g., atenolol, metoprolol, propranolol)
- pentoxifylline
- phosphodiesterase-5-inhibitors (e.g., sildenafil, tadalafil)
- selective serotonin reuptake inhibitors (SSRI; e.g., fluoxetine, paroxetine, sertraline)
- sunitinib
- theophyllines (e.g., aminophylline, oxtriphylline, theophylline)
Pregnancy Catagory of Clonidine
FDA Pregnancy Category C
Pregnancy
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Lactation
Clonidine has complex, dose-related actions on both oxytocin and prolactin secretion. The net effect of the drug on nursing mothers has not been well studied. A case of hyperprolactinemia and gynecomastia occurred in a 6-year-old boy taking clonidine for hyperactivity and valproic acid for a seizure disorder. Galactorrhea ceased within 3 weeks of discontinuing clonidine. A case of clonidine-induced postpartum galactorrhea has also been reported.
References
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