Centrally Acting Alpha2 Agonist

a prodrug that is metabolized to an active molecule, alpha-methylnorepinephrine

Adverse Effects:

methyldopa induces autoimmune hemolytic anemia, hepatitis, and lupus-like syndrome

Indications:

Centrally Acting Alpha2 Agonist

Also binds to post-synaptic alpha2 receptors, which causes vasoconstriction

Adverse Effects:

sudden withdrawal of clonidine and guanabenz can produce severe rebound hypertension with tachycardia, sweating, and anxiety

Indications:

Central Acting Alpha2 Agonist

similar to clonidine in terms of its peripheral post-synaptic alpha2 agonist activity which causes vasoconstriction

Adverse Effects: 

sudden withdrawal of clonidine and guanabenz can produce severe rebound hypertension with tachycardia, sweating, and anxiety

Indications:

Central Acting Alpha2 Agonist

similar to clonidine in terms of its peripheral post-synaptic alpha2 agonist activity which causes vasoconstriction

Indications:

• act at presynaptic autoreceptors (alpha2) in the CNS
• reduce central sympathetic nervous outflow
• increase vagal outflow (parasympathetic) from the vasomotor center
• reduces both peripheral arterial and venous tone 
• methyldopa is a prodrug that is metabolized to alpha-methylnorepinephrine
• clonidine also binds to post-synpatic alpha2 receptors which causes vasoconstriction
• guanabenz and guanfacine are similar to clonidine

1. sympathetic blockade: failure of ejaculation, postural hypotension (less with clonidine due to its direct peripheral action)
2. unopposed parasympathetic action: diarrhea
3. dry mouth (xerostomia)
4. CNS effects: sedation, drowsiness, depression
5. fluid retention
6. sudden withdrawal of clonidine and guanabenz can produce severe rebound hypertension with tachycardia, sweating, and anxiety
7. methyldopa induces autoimmune hemolytic anemia, hepatitis, and lupus-like syndrome

• adverse effects limit the use of centrally acting alpha2 agonists
• these agents are primarily used when other drugs are ineffective or for the treatment of hypertensive emergencies
• methyldopa is drug of choice in the treatment of hypertension in pregnancy
• clonidine has been used in hypertensive patients for the diagnosis of pheochromocytoma

1. hypertension (all)
2. ADHD (clonidine, guanfacine)
3. hypertensive emergency (methyldopa, clonidine)
4. management of severe cancer pain (clonidine)
5. management of opiate withdrawal symptoms (clonidine, guanabenz)

• specifically inhibit the function of peripheral postganglionic adrenergic neurons
• taken up into the neuron by uptake1 that is responsible for the reuptake of NE
• replaces NE in the secretory vesicles
• deplete NE in the secretory vesicles
• released by stimuli but inactive
• when given intravenously these agents initially can replace NE in an amount sufficient to increase arterial blood pressure, leading to hypertensive crisis 

1. hypotension during standing, exercise, ingestion of alcohol, hot weather; this is the result of lack of sympathetic compensation
2. fatigue, weakness
3. congestive heart failure due to drug-induced fluid retention - compensatory mechanism
4. impotence
5. diarrhea

• Levodopa and alcohol: additive hypotension activity
• MAO Inhibitors: contraindicated for combination with these agents
• Oral contraceptives, sympathomimetics: can decrease hypotensive activity
• Tricyclic antidepressants: block the uptake of these agents into nerve endings and prevent their actions

• Not used in the monotherapy of hypertension
• Used chiefly as an additional agent when patient is not responding to 2 or more hypertensive medications
• Contraindicated in patients with pheochromocytoma

Inhibits synthesis of NE by blocking tyrosine hydroxylase (the enzyme that converts tyrosine to DOPA) --> this is the rate-limiting step of catecholamine synthesis

Used in patients with pheochromocytoma along with phenoxybenzamine and other alpha blockers

Adverse Effects:

1. orthostatic hypotension
2. sedation
3. diarrhea
4. anxiety

MOA:

• binds tightly to storage vesicles and prevents storage of NE, dopamine, serotonin
• Catecholamines leak in the cytoplasm and are destroyed by MAO
• recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug