Apraclonidine

Uses

Apraclonidine is used for Anxiety, Cancer pain, Generalized anxiety disorder, Hypertension, Hypertensive crisis, Menopausal flushing, Migraine, Panic disorder, Severe anxiety disorders, Social anxiety disorder

Apraclonidine is also used to associated treatment for these conditions: Attention Deficit Hyperactivity Disorder (ADHD), Gilles de la Tourette's Syndrome, High Blood Pressure (Hypertension), Hot Flushes, Human Growth Hormone Deficiency, Opiate withdrawal symptoms, Oppositional Defiant Disorder, Pheochromocytomas, Postherpetic Neuralgia, Sialorrhea caused by clozapine, Diabetic diarrhea, Methadone withdrawal, Severe Cancer pain, Cessation, Smoking

How Apraclonidine works

Apraclonidine 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_o and G_i. G_i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Apraclonidine 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. Apraclonidine 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.

Dosage

Apraclonidine dosage

Adults: The dose of Apraclonidine tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration.

Initial Dose: 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.

Maintenance Dose: Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects ofdry mouthand drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.

Side Effects

Headache, dizziness, drowsiness, dry mouth, constipation, depression, anxiety, nausea, fatigue, anorexia, parotid pain, paraesthesia, delusional perception, sleep disturbances, vivid dreams, impotence and loss of libido, urinary retention or incontinence, orthostatic hypotension, itching or burning sensations in the eye, accommodation disorder, decreased lacrimation, fluid retention, pruritus and rashes (transdermal), bradycardia, other ECG disturbances, heart failure, hallucinations, cramp, Raynaud's syndrome, gynaecomastia, transient abnormalities in LFTs.

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.

Precaution

Patient with cerebrovascular disease, ischaemic heart disease including MI, occlusive peripheral vascular disorders (e.g. Raynaud's disease), or those w/ history of depression. Avoid abrupt withdrawal. Renal impairment. Pregnancy and lactation.

Interaction

Increased hypotensive effect with other antihypertensives e.g. diuretics, β-blockers, vasodilators, Ca antagonists, ACE inhibitors. Reduced antihypertensive effect and induced orthostatic hypotension with TCAs or neuroleptics with α-receptor blocking properties. Reduced therapeutic effect with NSAIDs.

Food Interaction

• Avoid alcohol.
• Take with or without food. The absorption is unaffected by food.

Apraclonidine Alcohol interaction

[Moderate]

Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation.

Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

Caution and close monitoring for development of hypotension is advised during coadministration of these agents.

Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs.

Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

Apraclonidine Drug Interaction

Moderate: duloxetine, duloxetine, pregabalin, pregabalin, quetiapine, quetiapine, alprazolam, alprazolamUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, furosemide, furosemide, levothyroxine, levothyroxine, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Apraclonidine Disease Interaction

Moderate: bradyarrhythmia, depression, hypotension, renal dysfunction, sedatives/alcohol

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.

Elimination Route

Apraclonidine 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 C_max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%.

Half Life

The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h.

Clearance

The clearance of clonidine is 1.9-4.3mL/min/kg.

Elimination Route

Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces.

Pregnancy & Breastfeeding use

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Severe bradyarrhythmia secondary to 2nd- or 3rd-degree AV block or sick sinus syndrome.

Special Warning

Renal Impairment: Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

Acute Overdose

Symptoms: Lethargy, pupillary constriction, hypotension, hypothermia, bradycardia, decreased or absent reflexes, irritability, miosis, weakness, somnolence (including coma) and resp depression (including apnoea). Paradoxical HTN may occur.

Management: Perform gastric lavage following recent ingestion or admin activated charcoal and/or a cathartic. Supportive treatment may include admin of atropine sulfate for symptomatic bradycardia; IV fluids and/or inotropic sympathomimetic agents for hypotension; vasodilators for HTN. Naloxone may be used as adjunct for clonidine-induced resp depression, hypotension and/or coma.

Storage Condition

Store between 20-25°C.

Innovators Monograph

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