Clonidine

Clonidine has a vast array of uses including anxiety, ADHD, hypertension, withdrawal (opitates, alcohol and smoking), migraines, menopausal flushing, diarrhoea and finally pain. It causes the classic triad of drowsiness, miosis and bradycardia in overdose.

USED IN

1. Hypertension:
   • Lowers blood pressure and heart rate by relaxing arteries and increasing heart blood supply.
   • Pediatric use for hypertension is off-label.
2. Attention Deficit Hyperactivity Disorder (ADHD): for extended-release form in children.
3. Management of Tics: Commonly found in Tourette syndrome.
4. Adjunct Therapy for Cancer-Related Pain: Enhances pain control in severe cases.
5. Neonatal Opioid Withdrawal Syndrome: Used as an adjunct treatment.

Off-Label Uses

• Withdrawal Symptoms: Managing symptoms from opioids, benzodiazepines, and alcohol.
• Anxiety and Insomnia: Treatment for various anxiety disorders and insomnia.
• Post-Traumatic Stress Disorder (PTSD): Management of PTSD symptoms.
• Menopause: Control of hot flashes.
• Restless Leg Syndrome: Symptomatic relief.
• Migraine Prophylaxis: Preventive treatment for vascular migraines.
• Clonidine Suppression Test: Diagnostic test for pheochromocytoma.

Mechanism of Action

centrally acting alpha-2 adrenergic agonist. Its primary effects involve the reduction of sympathetic outflow from the central nervous system (CNS), leading to various clinical benefits including lowering blood pressure, managing pain, and treating ADHD.

Alpha-2 Adrenergic Agonism

• Central Nervous System (CNS) Action:
  • Alpha-2 Adrenergic Receptors: Clonidine primarily stimulates these receptors located in the brainstem, particularly in the nucleus tractus solitarii (NTS).
  • Inhibition of Sympathetic Activity: Activation of these receptors leads to the inhibition of excitatory cardiovascular neurons. This inhibition reduces the release of norepinephrine and other excitatory neurotransmitters, resulting in decreased sympathetic outflow from the CNS.

Effects on Blood Pressure

• Reduction in Sympathetic Tone:
  • Clonidine’s stimulation of central alpha-2 receptors leads to reduced sympathetic nervous system activity. This reduces peripheral resistance, heart rate, and blood pressure.
  • Vasodilation: By decreasing the release of norepinephrine, clonidine causes relaxation of blood vessels, leading to vasodilation and a subsequent drop in blood pressure.

Pain Management

• Dorsal Horn of the Spinal Cord:
  • In the spinal cord, particularly in the dorsal horn, clonidine acts on alpha-2 receptors.
  • Inhibition of Pain Transmission: It decreases the release of nociceptive neurotransmitters, thereby inhibiting the transmission of pain signals to higher centers in the CNS.
  • Norepinephrine Release: Clonidine enhances the release of norepinephrine from descending inhibitory pathways, which binds to alpha-2 receptors in the dorsal horn, reducing pain signal transmission.

ADHD Treatment

• Prefrontal Cortex Activity:
  • The exact mechanism in ADHD is not fully understood, but it is believed that clonidine’s action in the prefrontal cortex improves attention and reduces hyperactivity.
  • Enhanced Neural Signaling: The reduction in norepinephrine activity in certain brain regions may help normalize the signaling pathways involved in attention and impulse control.

Epidural Use

• Combination with Local Anesthetics:
  • When used epidurally, clonidine works through multiple mechanisms:
    • Alpha-2 Receptor Stimulation: Directly reduces pain transmission in the dorsal horn.
    • Local Vasoconstriction: Limits the vascular removal of local anesthetics, prolonging their effect.
    • Enhanced Opioid Action: When combined with opioids like fentanyl, clonidine produces an additive effect, reducing the required doses of both drugs for effective pain relief.

Administration

Forms and Dosages

1. Transdermal Patch (Extended-Release):
   • Dosage: 0.1 mg/day, 0.2 mg/day, 0.3 mg/day; changed every seven days.
   • Indications: Hypertension, smoking cessation, cyclosporine nephrotoxicity, menopausal flushing, opioid withdrawal.
2. Tablet (Immediate-Release):
   • Dosage: 0.1 mg, 0.2 mg, 0.3 mg.
   • Indications: Hypertension, acute hypertension, opioid withdrawal, pheochromocytoma.
3. Tablet (Extended-Release):
   • Dosage: 0.1 mg.
   • Indications: Alcohol withdrawal, smoking cessation, restless-leg syndrome, ADHD, Tourette syndrome, menopausal flushing, dysmenorrhea, postherpetic neuralgia, psychosis.
4. Injectable Solution:
   • Dosage: 100 mcg/ml, 500 mcg/ml.
   • Indications: Epidural infusion for cancer pain not controlled by opioids and as an adjunct in anesthesia.
   • Initial dose of 30 mcg/hr with necessary titration for pain management or side effects.

Adverse Effects

Common Reactions (Often Resolving with Continued Therapy)

• Abdominal pain, headache, hypotension, fatigue, nausea, emotional instability, constipation, xerostomia, diarrhea, sexual dysfunction, dizziness, sedation.

Serious Reactions

• Angioedema, depression, hypersensitivity, atrioventricular block, bradycardia, syncope, severe hypotension.
• Rebound Hypertension: Risk if medication is abruptly discontinued.

Other Symptoms

• Fever, headache, fatigue, bradycardia, congestive heart failure, decreased sexual activity, thrombocytopenia, agitation, depression (rare but possible with chronic use).

Contraindications

• Hypersensitivity: To clonidine or other alpha-2-agonists.
• Epidural Use: Not recommended above C4 dermatome.
• Abrupt Discontinuation: Avoid due to rebound hypertension and withdrawal risk.
• Renal Impairment: Dose adjustment necessary.
• Cardiovascular Conditions: Use caution in patients with bradycardia, hypotension, severe coronary artery disease, recent myocardial infarction, and syncope.
• Depression History: Monitor patients with a history of depression.
• Pregnancy and Breastfeeding: Weigh risks vs. benefits; potential for infant sedation, hypotonia, apnea, and reduced breast milk production.

Clonidine Toxicity

Classic Triad in Overdose

• Drowsiness
• Miosis (pupil constriction)
• Bradycardia

Toxic Mechanism

• Centrally acting alpha-2 adrenergic agonist
• Acts as a sympathoplegic agent
• Increases endothelial nitric oxide levels
• Decreases renin activity

Toxicokinetics

• Rapid absorption
• Peak serum concentration: 1-3 hours
• Large volume of distribution: 3-6 L/kg
• Metabolized by the liver
• Excreted by urine (50% unchanged)
• Half-life: 6-24 hours

Resuscitation

• CNS Depression: Intubation and ventilation usually required only in large overdoses
• Hypotension:
  • 20 ml/kg crystalloid bolus
• Bradycardia:
  • Usually well tolerated; treat if symptomatic with hypotension
  • Atropine: 0.01-0.03 mg/kg IV (typically 600 microgram boluses, max 1.8 mg)
  • Isoprenaline: 1-10 micrograms/min IV infusion (0.05-1.0 microgram/kg/min in children)
  • Adrenaline infusion: 0.15 mg/kg in 50 ml D5W at 1-10 ml/hr (0.05-0.5 mcg/kg/min)