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Clonidine; Indications/Uses, Dosage, Side Effects, Interaction ,Pregnancy

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 G_i proteins, Gα_i1, Gα_i2, and G&alpha_i3. 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: α_2A, α_2B, and α_2C. Each subtype has a unique pattern of tissue distribution in the central nervous system and peripheral tissues. The α_2A-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. α_2A-receptors are also expressed in the kidneys, spleen, thymus, lung and salivary glands. The α_2C-receptor is primarily expressed in the central nervous system, including the striatum, olfactory tubercle, hippocampus, and cerebral cortex. Low levels of the α_2C-subtype are also found in the kidneys. The α_2B-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 α_2A– and α_2C-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 α_2A-receptors, while peripheral α_2B-receptors mediate constriction of vascular smooth muscle. α_2A-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.

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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.

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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)

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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.