Arkamin H

Uses

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

Hydrochlorothiazide is used for-

• Edema associated with congestive heart failure, hepatic cirrohosis, various forms of renal dysfunction and corticosteroid and estrogen therapy
• Management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe form of hypertension
• Management of diabetes insipidus
• Management of proximal renal tubular acidosis
• Idiopathic hypercalciuria and calcium nephrolithiasis, osteoporosis and exercise induced hyperkalemia

Arkamin H 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, SmokingAcidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsia

How Arkamin H works

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_o and G_i. G_i 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.

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Dosage

Arkamin H dosage

Adults: The dose of Clonidine 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.

Adults-

For Edema: The usual adult dosage is 25 to 100 mg daily as a single or divided dose.

For Control of Hypertension: The usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium. In some patients (especially the elderly) an initial dose of 12.5 mg daily may be sufficient.

Infants and children-

For diuresis and for control of hypertension: The usual pediatric dosage is 1 to 2 mg/kg/day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 3 mg/kg/day in two divided doses may be required.

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.

Generally, Hydrochlorothiazide is well tolerated. However, a few side effects may occur like weakness, restlessness, dizziness, headache, fever, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia, and hypotension. In rare case hyperglycemia, glycosuria, hyperuricemia and muscle spasm may occur.

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.

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

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.

Thiazides should be used with caution in patients with severe renal disease, impaired hepatic function or progressive liver disease and gout.

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.

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): Thiazides can impair control of diabetes mellitus by diet and antidiabetic Drugs. Antihypertensive Drugs: Additive effect or potentiation.

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.

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

Elimination Route

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

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

Half Life

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

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

Clearance

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

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

Elimination Route

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

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

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.

Pregnancy: Evidence of fetal risk in hydrochlorothiazide therapy is found, but it is indicated if benefits outweigh risks. Thiazides are indicated in pregnancy when edema is due to pathologic causes.\

Lactation: Neonatal side effects have been seen incase of hydrochlorothiazide therapy and therefore it is not recommended.

Contraindication

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

Hydrochlorothiazide is contraindicated to the patients of anuria and those who are sensitive to hydrochlorothiazide or to other sulfonamide-derived drugs. Therapy is not to be initiated in diabetes mellitus.

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.

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

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.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Rarely, autoimmune hemolytic anemia and other hypersensitivity reactions may complicate the picture.

In the event of over dosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. Hemodialysis can be used successfully to treat severe intoxication.

Storage Condition

Store between 20-25°C.

Store between 15-30°C. Protect from light, moisture and freezing.

Innovators Monograph

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