Mechanism of Action of Clonidine
Clonidine stimulates alpha-2 adrenergic receptors in the brainstem, which reduces sympathetic nervous system outflow from the central nervous system, and in the prefrontal cortex, postsynaptic alpha-2 agonism enhances noradrenergic neurotransmission to strengthen attention, thought, and working memory. 1, 2
Central Nervous System Effects
Brainstem Action
- Clonidine's primary antihypertensive site of action is in the medulla oblongata at post-synaptic alpha-2 adrenergic receptors, most likely at the lateral reticular nucleus. 3
- This activation results in reduced sympathetic outflow from the CNS, leading to decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. 2
- The drug effectively enhances the inhibitory effect of neurons from the nucleus tractus solitarii on sympathetic outflow from the vasomotor center. 4
Prefrontal Cortex Effects
- In the prefrontal cortex, postsynaptic alpha-2 agonism enhances noradrenergic neurotransmission, which strengthens the regulatory role of the prefrontal cortex in attention, thought, and working memory—explaining its efficacy in ADHD treatment. 1
Peripheral and Systemic Effects
Cardiovascular Changes
- Clonidine produces a dose-dependent suppression of norepinephrine appearance rate in plasma (32% reduction at low doses, 52% at high doses) without changing norepinephrine clearance. 5
- The drug causes moderate reduction (15-20%) of cardiac output in the supine position with no change in peripheral resistance initially; during long-term therapy, cardiac output returns to control values while peripheral resistance remains decreased. 2
- Blood pressure declines within 30-60 minutes after oral dosing, with maximum decrease occurring within 2-4 hours. 2
Receptor Selectivity
- Clonidine binds to all three subtypes of alpha-2 receptors (A, B, and C), which differs from guanfacine that binds more selectively to alpha-2A receptors. 6
- Clonidine is approximately 10 times more potent than guanfacine but has less selectivity for alpha-2A receptors. 1
Additional Pharmacologic Effects
- Clonidine reduces plasma renin activity and decreases excretion of aldosterone and catecholamines. 2
- The drug acutely stimulates growth hormone release in both children and adults, though it does not produce chronic elevation with long-term use. 2
- Normal postural reflexes remain intact, which explains why orthostatic symptoms are mild and infrequent despite the blood pressure reduction. 2
Clinical Pharmacokinetics
- Absolute bioavailability is 70-80% with oral administration, and the drug displays dose-proportional pharmacokinetics in the 100-600 mcg range. 2
- Clonidine is primarily metabolized via CYP2D6 and excreted both renally and hepatically in equal shares. 7, 1
- The elimination half-life ranges from 12-16 hours in normal renal function but increases up to 41 hours in severe renal impairment. 2