Alpha 2 Agonists and Antagonists Flashcards
What are alpha2 agonists commonly used for
sedation and pre-anesthetic medication
Are alpha2 agonists reversible?
Yes
What is an overview of the mechanism of action for alpha2 agonists?
They bind to alpha2 and alpha1 adrenergic receptors (adrenoceptors).
What is the alpha2 to alpha1 ratio for dexmedetomidine?
1620:1
What is the alpha2 to alpha1 ratio for medetomidine?
1620:1
What is the alpha2 to alpha1 ratio for romifidine?
340:1
What is the alpha2 to alpha1 ratio for detomidine?
260:1
What is the alpha2 to alpha1 ratio for clonidine?
220:1
What is the alpha2 to alpha1 ratio for xylazine?
160:1
How many alpha2 subtypes have been identified?
Three: alpha2A, alpha2B, alpha2C
Are there any other alpha2 subtypes that have been identified?
Yes, in some species: cattle, and rats, an alpha2D receptor has been identified that functions similarly to alpha2A
What is the mechanism of action of an alpha2 agonist?
So it binds to the adrenoceptors which are G-protein coupled receptors with an inhibitory action.
What happens when you activate an adrenoceptor?
inhibition of cAMP production, a decrease in cellular activity, cellular hyperpolarization
How does cellular hyperpolarization occur when an adrenoceptor is activated?
inhibition of voltage-gated Ca2+ channels and stimulation of inwardly rectifying K+ channels
What kind of effect do alpha2 agonists have within the CNS?
antisympathetic
where are alpha2 adrenoceptors located?
in the CNS and PNS as well as other tissues and organs
Are alpha2s pre or post-synaptic?
They can be both
What kind of receptors are presynaptic alpha2s?
autoreceptors and heteroreceptors
what kind of effects do autoreceptor alpha2s have?
adrenergic effects - norepinephrine
What kind of effects to heteroreceptor alpha2s have?
non-adrenergic effects - serotonin, GABA, acetylcholine
What kind of effects do alpha2s have on the nervous system?
sedation, hypothermia, muscle relaxation (can lead to ataxia/recumbency)
How do alpha2s cause sedation?
they activate the alpha2 receptors in the locus coeruleus in the brain
Where is analgesia “induced” in the CNS
the brainstem and dorsal horn of the spinal cord. Analgesia is co-localized with opioid receptors, potential for synergy
What are the initial CV effects of an alpha2?
vasoconstriction, increased SVR, baroreceptor-mediated bradycardia, decreased CO
What is the secondary CV effects of an alpha2?
decreased sympathetic tone via central effects, peripheral vasodilation, bradycardia
What kind of arrhythmias can you see with alpha2s?
sinus bradycardia, profound sinus arrhythmia in some species, first and second-degree AV block
What kinds of effects can you see on the respiratory system secondary to alpha2 administration?
decreased respiratory rate, central ventilatory drive is decreased in dogs, upper airway resistance increases in horses
Does hypoxemia occur with alpha2 administration?
generally very minimally
Of all the species, which one is more sensitive to the respiratory effects of alpha2s?
ruminants
What happens to sheep when you give an alpha2?
hypoxemia! D/t pulmonary hypertension and interstitial edema
What are the renal effects of an alpha2 administration?
renal blood flow decreases, decreases in ADH results in diuresis
What are the endocrine effects of an alpha2 administration?
decreased stress response, decreased insulin release, can lead to hyperglycemia and osmotic diuresis
What are the GI effects of alpha2 administration?
relaxed LES, vomiting, nausea, inhibition of gastric emptying, decreased intestinal motility
What is clonidine used for in dogs?
An oral anxiolytic
What pharmacological profile do you need to be aware of with clonidine?
highly lipid soluble, large volume of distribution, two compartment model, centrally-mediated hypotensive effects will predominate
What kind of hypotensive effects are seen with clonidine?
Centrally-mediated hypotensive effects predominate
What pharmacological profile do you need to be aware of with xylazine?
Highly lipid soluble, large volume of distribution
EXTENSIVE liver metabolism, phase I transformation via CYP3A microsomes
In what species is xylazine particularly used in?
Equines! Sedation, short-term analgesia, and a preanesthetic
Does xylazine result in increased uterine tone?
Yes.
What species is the most sensitive to xylazine? The least sensitive to xylazine?
Most = cattle
Least = pigs
Where is detomidine metabolised?
Liver
Which has the longer duration of action: xylazine or detomidine?
Detomidine
What is medetomidine a derivative of?
detomidine
How and where is medetomidine metabolised?
liver metabolism via hydroxylation and conjugation in DOGS. the hydroxylated compound is excreted in urine in cats (as they are glucuronide deficient)
Dexmedetomidine is the inactive enantiomer of medetomidine - T or F?
FALSE! Dexmedetomidine is the active enantiomer of medetomidine
How and where is dexmedetomidine metabolised?
Liver metabolism via hydroxylation and glucuronidation (species differences in efficiency)
What are the pharmacological profile highlights of romifidine?
similar duration of action to detomidine, marketed for horses in the US, may produce less ataxia compared to other alpha2s in equines
Where is romifidine metabolised?
liver metabolism and renal excretion
What is the alpha2 to alpha1 ratio of yohimbine?
40:1
Does yohimbine have a large or small volume of distribution?
LARGE volume of distribution, but a relatively slow clearance
What happens when yohimbine is used as an alpha2 reversal in cats/dogs?
sedation may be incompletely reversed, side effects: dysphoria, vocalization, GI effects are reversed
What can be seen with yohimbine administration in equines?
respiratory distress, tachycardia, and death have been seen in equines after IV administration. IM administration is recommended
Which reversal has the lowest affinity for alpha2 receptors?
Tolazoline
What negative effect can be seen in camelids that receive tolazoline?
death
