What are the uses and dosing guidelines for alpha 2 (alpha 2) agonists, such as clonidine (clonidine), in treating hypertension and attention deficit hyperactivity disorder (ADHD)?

Alpha-2 Agonists: Clinical Uses and Dosing

Hypertension Management

Alpha-2 agonists, particularly clonidine, should be reserved as last-line antihypertensive agents due to significant CNS adverse effects, especially in older adults. 1

Positioning in Treatment Algorithm

• Not first-line therapy: Alpha-2 agonists are generally reserved as last-line agents when other antihypertensive classes have failed 1
• Mechanism: These agents reduce sympathetic activity through central and peripheral alpha-2 receptor stimulation in the brainstem and posterior hypothalamus, decreasing peripheral vascular resistance and lowering plasma norepinephrine and renin concentrations 2, 3

Clonidine Dosing for Hypertension

Oral formulations:

• Initial dose: 0.1 mg twice daily (morning and bedtime); elderly patients should start at lower doses 1, 4
• Maintenance titration: Increase by 0.1 mg per day at weekly intervals as needed 1, 4
• Usual therapeutic range: 0.2-0.8 mg per day in divided doses (typically twice daily) 1
• Maximum effective dose: 2.4 mg daily, though doses this high are rarely employed 4
• Dosing strategy: Taking the larger portion at bedtime minimizes transient side effects of dry mouth and drowsiness 4

Transdermal patch:

• Dosing: 0.1-0.3 mg applied once weekly 1

Renal impairment: Patients benefit from lower initial doses with careful monitoring; minimal removal during hemodialysis means no supplemental dosing is needed post-dialysis 4

Guanfacine Dosing for Hypertension

• Dosing range: 0.5-2 mg once daily 1

Critical Safety Considerations for Hypertension Use

⚠️ NEVER abruptly discontinue clonidine - this can induce hypertensive crisis with rebound hypertension due to sympathetic overactivity; clonidine must be tapered gradually 1, 2, 3

Common adverse effects limiting use:

• Significant CNS effects including sedation, drowsiness, and fatigue 1, 2
• These effects are particularly problematic in older adults 1
• Can be minimized by using lower doses 2

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ADHD Management

Clonidine and guanfacine are effective nonstimulant options for ADHD, particularly useful for reducing aggression, controlling symptoms after stimulant wear-off, and counteracting stimulant-induced insomnia. 1

Clinical Role in ADHD

• Monotherapy efficacy: Meta-analyses demonstrate that clonidine alone has efficacy in treating ADHD 1, 5
• Combination therapy: Commonly combined with methylphenidate to reduce aggression, provide better symptom control after stimulant wear-off, and counteract insomnia 1
• Mechanism: Guanfacine binds more selectively to alpha-2A receptors (versus clonidine's binding to all three alpha-2 subtypes A, B, and C), which appears to enhance prefrontal cortical function 5

Clonidine Dosing for ADHD

• Initial dose: 0.05 mg at bedtime (half a tablet) 1
• Titration: Increase slowly, never exceeding 0.3 mg/day 1
• Dosing frequency:
  • Once daily at bedtime for sleep disturbances 1
  • Four times daily if controlling aggressive behavior 1

Guanfacine Dosing for ADHD

• Starting dose: 0.05-0.1 mg at bedtime 1
• Titration: Increase by 0.1 mg BID to TID to a maximum of 0.4 mg per day 1

Safety Monitoring for ADHD Use

Pre-treatment screening:

• Obtain comprehensive medical history of patient and first-degree family members 1
• Contraindications: History of sudden death, repeated fainting, or arrhythmias in family members likely rules out use 1

Combination with stimulants:

• Historical concern about four deaths reported to FDA MEDWATCH led to warnings, but no further reports have emerged and clinicians continue using this combination 1
• Routine ECG monitoring at baseline is NOT advised based on largely negative findings 1
• Side effects (bradycardia, hypotension, hypertension) occur at rare to infrequent rates (less than 1/100) 1

Common adverse effects:

• Sedation, fatigue, and somnolence are associated with both clonidine and guanfacine 5
• Modest reductions in heart rate and blood pressure rarely lead to treatment discontinuation 5
• Improvements seen in hyperactivity, impulsiveness, and inattention across ADHD, tic disorders, and pervasive developmental disorders 5

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Special Populations

Pregnancy and Lactation

Clonidine in pregnancy:

• Could be considered as an adjunct ADHD agent following risk-benefit discussion, acknowledging limited safety and efficacy data in adults 1
• Studies for hypertension/hyperemesis treatment found no increased risk for major or minor malformations 1
• One case report of Roberts syndrome with clonidine use throughout pregnancy for hypertension 1
• Recent large studies showed no increased risks for methylphenidate, amphetamine, atomoxetine, or clonidine on long-term outcomes 1

Clonidine during breastfeeding:

• Little published data available; majority of cases reported no adverse infant effects 1
• Critical exception: One case report of infant developing drowsiness, hypotonia, suspected seizures, and apnea with 0.15 mg daily maternal dose; all symptoms resolved within 24 hours of breastfeeding cessation 1
• Clonidine is found in human milk and detectable in infant serum; milk-to-plasma ratio reported as 2 with relative infant dose up to 7.1% 1
• Monitor infants carefully for drowsiness, hypotonia, vomiting, diarrhea, jitteriness, sedation, and/or seizures 1

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Hypertensive Emergencies

Oral clonidine with "loading dose" strategy is safe and effective for hypertensive emergencies, potentially offering advantages over parenteral agents. 6

• Loading protocol: 0.2 mg initial dose, followed by 0.1 mg hourly until blood pressure substantially reduced or total dose of 0.8 mg administered 6
• Efficacy: 82% response rate with reduction from 210/145 mmHg to 145/98 mmHg after 6 hours; average effective dose 0.5 mg 6
• Advantages: Minimal side effects, oral administration avoids need for IV access 6