Clonidine and chlorthalidone

Uses

Chlorthalidone is used for the management of hypertension. Chlorthalidone is used for adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.

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

Clonidine and chlorthalidone is also used to associated treatment for these conditions: Calcium NephrolithiasisAttention 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 Clonidine and chlorthalidone works

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects.

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.

Dosage

Clonidine and chlorthalidone dosage

Therapy should be initiated with the lowest possible dose and then titrated according to individual patient response. A single dose given in the morning with food is recommended; divided doses are unnecessary.

Edema: Up to 50 mg daily.

Hypertension: 25 mg daily in the morning, increased to 50 mg daily if necessary.

Heart failure: 25-50 mg daily in the morning, increased if necessary to 100-200 mg daily (reduce to lowest effective dose for maintenance).

Maintenance doses may often be lower than initial doses and should be adjusted according to the individual patient.

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.

Side Effects

Dry mouth, thirst, nausea, vomiting, feeling weak, drowsy, restless, or light-headed, fast or uneven heartbeat, muscle pain or weakness, urinating less than usual or not at all, easy bruising or bleeding, unusual weakness, red or purple spots on skin, numbness or tingly feeling, nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools.

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

Renal impairment: Chlorthalidone dosage should be reduced in moderate renal failure - every 24 or 48 h - and should not be used in advanced renal failure.

Liver disease: There is a risk of precipitating hepatic encephalopathy in patients with liver cirrhosis and ascites.

Use in pregnancy: It is better to avoid Chlorthalidone as it crosses the placenta.

Use in Lactation: In lactating mother, significant amount of Chlorthalidone enter breast milk; like other long-acting thiazides, it can suppress lactation. Chlorthalidone should not be prescribed for lactating mother.

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

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs.

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.

Volume of Distribution

Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large 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

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%.

Half Life

40-50 hours

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 the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase.

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

Pregnancy category B. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from chlorthalidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Patients with anuria and known hypersensitivity to Chlorthalidone or other sulfonamide-derived drugs.

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

Special Warning

Pediatric Use: Safety and effectiveness of Chlorthalidone tablets in pediatric patients have not been established.

Geriatric Use: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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 of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

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 in a cool & dry place, away from children

Store between 20-25°C.

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