Unopposed Alpha Stimulation

[Mdickson]

Hello, I am a PA student currently on rotations looking for some clarification- Epocrates does not have a good description.

I had a pt that presented with rebound HTN after running out of Clonidine (alpha-2 agonist) but continued on his Propranolol (BB).

I know that it is unopposed alpha stimulation but not really understanding how stopping an alpha agonist (Clonidine) and continuing a BB causes this? If someone has a clear explanation of the physiology/MOA behind it that would be great.

 

[Rouelle]

Alpha-1 and beta-2 receptors work somewhat in opposition. Alpha-1 stimulation causes vasoconstriction. Beta-2 stimulation causes vasodilation. (I probably should say smooth muscle constriction or relaxation to be accurate, but who cares). Clonidine works centrally to decrease sympathetic outflow (norepi, other catecholamines). When you abruptly take that away, you suddenly get a lot of sympathetic outflow (rebound). If beta receptors are blocked (propranolol), then alpha receptors are stimulated preferentially (vasoconstriction). Thus, "unopposed alpha stimulation"

This is an over-simplified explanation, but I think that is probably what you were after.

 

[RxPreceptor]

Main take home message is SNS overactivity/NE response (simplified). Beta 1 & 2 receptors are most dense in heart & lungs respectively vs. central/CNS alpha-2
From Lexicomp (Clondine):

Warnings/Precautions section
"Discontinuation of therapy: Gradual withdrawal is needed (taper oral immediate release or epidural dose gradually over 2 to 4 days to avoid rebound hypertension) if drug needs to be stopped. Patients should be instructed about abrupt discontinuation (causes rapid increase in BP and symptoms of sympathetic overactivity). In patients on both a beta-blocker and clonidine where withdrawal of clonidine is necessary, withdraw the beta-blocker first and several days before clonidine withdrawal, then slowly decrease clonidine. In children and adolescents, extended release formulation (Kapvay) should be tapered in decrements of no more than 0.1 mg every 3 to 7 days. The clonidine withdrawal syndrome is more pronounced after abrupt cessation of long-term therapy than after short-term therapy (1 to 2 months). It has usually been associated with previous administration of high oral doses (>1.2 mg daily in adults) and/or continuation of beta-blocker therapy. The danger of abrupt discontinuation may be increased in patients with hypertension and/or other cardiovascular considerations. Blood pressure may increase 8 to 24 hours after last dose, but has occurred 60 hours after the last clonidine dose. Rebound hypertension has occurred with discontinuation of transdermal and epidural clonidine."

MOA:
"Stimulates alpha2-adrenoceptors in the brain stem, thus activating an inhibitory neuron, resulting in reduced sympathetic outflow from the CNS, producing a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure; epidural clonidine may produce pain relief at spinal presynaptic and postjunctional alpha2-adrenoceptors by preventing pain signal transmission; pain relief occurs only for the body regions innervated by the spinal segments where analgesic concentrations of clonidine exist. For the treatment of ADHD, the mechanism of action is unknown; it has been proposed that postsynaptic alpha2-agonist stimulation regulates subcortical activity in the prefrontal cortex, the area of the brain responsible for emotions, attentions, and behaviors and causes reduced hyperactivity, impulsiveness, and distractibility. Epidurally administered clonidine produces dose-dependent analgesia not antagonized by opiate antagonists. The analgesia is limited to the body regions innervated by the spinal segments where analgesic concentrations of clonidine are present. Clonidine is thought to produce analgesia at presynaptic and postjunctional alpha-2-adrenoceptors in the spinal cord by preventing pain signal transmission to the brain."

 

[Apotheker2015]

Alpha-1 and beta-2 receptors work somewhat in opposition. Alpha-1 stimulation causes vasoconstriction. Beta-2 stimulation causes vasodilation. (I probably should say smooth muscle constriction or relaxation to be accurate, but who cares). Clonidine works centrally to decrease sympathetic outflow (norepi, other catecholamines). When you abruptly take that away, you suddenly get a lot of sympathetic outflow (rebound). If beta receptors are blocked (propranolol), then alpha receptors are stimulated preferentially (vasoconstriction). Thus, "unopposed alpha stimulation"

This is an over-simplified explanation, but I think that is probably what you were after.

Nice job, there.

 

[Farcus]

Clonidine is a centrally acting alpha 2 agonist and going back to basic pharmacology, if I remember correctly, alpha 2 receptor that reside in CNS act very differently than what you'd expect. they are in fact autoreceptors if I remember correctly. These autoreceptor suppress release of vesicles that contain neurotransmitter/catecholamine. This is turn how its reported to decrease sympathetic outflow since reduce catecholamine less sympathetic activation. This is also true of mirtazpine, which we know is actually an antidepressant with alpha 2 ANTAGONIST effect, and as you'd expect this would indeed lead to increase in both serotoneric and catecholamine release thus its effect on antidepressant effect along w/ a side effect of htn. Its also not surprisingly that clonidine thus has a lot of use off label for addiction, withdrawl and couple other psychiatric effect as it technically modulating neurotransmitters. I feel like this aspect of alpha 2 autoreceptor is not taught well in pharmacy school, much less other professional program.

 

[Old Timer]

The main MOA that causes this is receptor down regulation after chronic blockade. I'm pretty sure most of the studies are high dose (0.9 mg/day). Once you block the receptors for a long period of time they become more numerous and more sensitive to the ligand. Remove the alpha blockade and not only do you get a crap load of sympathetic release but you also have way more receptors quantitatively and those receptors have a higher affinity for catecholamines. Then you are off to the races....