alpha-2 agonist

**Mechanism:** Alpha-2 receptors are Gi/o-coupled. Activation inhibits adenylyl cyclase, which lowers cAMP, and it opens K+ channels and closes Ca2+ channels. Presynaptic alpha-2 receptors in the CNS (brainstem vasomotor center, locus coeruleus) and on peripheral sympathetic nerve terminals act as an autoreceptor negative feedback loop. Stimulating them reduces norepinephrine release and lowers central sympathetic outflow. Alpha-2 receptors are also found on pancreatic beta cells (inhibit insulin release), platelets (promote aggregation), and in the spinal cord (analgesia).

**Key drugs and uses:** - **Clonidine:** Resistant or urgent hypertension, opioid/alcohol/nicotine withdrawal (reduces autonomic hyperactivity), ADHD, Tourette syndrome, and epidural analgesia. Also used for hot flashes and in cancer pain. - **Guanfacine:** ADHD (non-stimulant option) and hypertension. It is more selective for alpha-2A receptors in the prefrontal cortex. - **Methyldopa:** A prodrug converted to alpha-methylnorepinephrine, a central alpha-2 agonist. It is first-line for hypertension in pregnancy (along with labetalol and nifedipine). - **Dexmedetomidine:** ICU and procedural sedation. It causes minimal respiratory depression, and patients remain arousable. - **Tizanidine:** Spasticity (multiple sclerosis, spinal cord injury). - **Brimonidine:** Open-angle glaucoma. It decreases aqueous humor production and increases uveoscleral outflow. It is also used topically for rosacea. - **Apraclonidine:** Glaucoma, and diagnosis of Horner syndrome (denervation hypersensitivity causes pupil dilation and eyelid elevation on the affected side).

**Adverse effects:** - Sedation, drowsiness, and dry mouth (very common) - Bradycardia and hypotension - Constipation - **Rebound hypertension** with abrupt clonidine discontinuation, from a surge of catecholamines (tachycardia, headache, anxiety, sweating). Risk is higher with concurrent beta-blockers (unopposed alpha stimulation), so stop the beta-blocker first. - Methyldopa: positive direct Coombs test with possible autoimmune hemolytic anemia, drug-induced lupus, hepatotoxicity, and hyperprolactinemia (inhibits dopamine synthesis). - Tizanidine: hepatotoxicity and hypotension.

**High-yield contrasts:** - Alpha-2 agonists decrease sympathetic tone. Alpha-2 antagonists (yohimbine, mirtazapine) increase NE release. - Alpha-1 agonists (phenylephrine) cause vasoconstriction and a reflex bradycardia. Alpha-1 blockers (prazosin, tamsulosin) lower BP and treat BPH. - Clonidine's lack of significant respiratory depression makes it useful as an adjunct in opioid withdrawal. It treats the autonomic symptoms but not the drug craving.

**Clinical pearls:** In a pregnant patient with chronic hypertension, think methyldopa. In a patient with hypertension who misses clonidine doses, think rebound hypertension. For ICU sedation without respiratory depression, think dexmedetomidine.