5 Alpha-2 Agonists and Antagonists

What are some examples of a2-adrenoceptor agonist sedatives/analgesics? (6)

clonidine

xylazine

detomidine

medetomidine

dexmedetomidine

romfidine

Cellular mechanism of a2-agonist:

a2-agonist binds to a2-receptor -> activates ___ protein -> opens ___ channels in the neuronal membrane -> lose ___ to the extracellular space -> membrane is (choose one: depolarized/replolarized/hyperpolarized) -> cells becomes unresponsive to ____________ input -> inhibition of release of ____________ from presynaptic nerve ending -> _________, inhibits (choose one: afferent/efferent) pathway

G

K

K

hyperpolarized

excitatory

norepinephrine

sedation

afferent

T/F With a2-agonists, there is a decrease in action potentials due to hyperpolarization so more calcium is lost to the extracellular space and there is a decreased influx of potassium

False, there is more POTASSIUM lost to the extracellular space and there is a decreased influx of CALCIUM

Which two a2 agonists are most selective for a2 receptors?

medetomidine

dexmedetomidine

What is the function of a2 adrenoceptor agonists working at terminal adrenergic axons?

Inhibition of norepinephrine release

What is the function of a2 adrenoceptor agonists working at cell bodies of norepinephrine neurons?

hyperpolarization (inhibition of firing)

What is the function of a2 adrenoceptor agonists working at cholinergic neurons?

inhibition

What is the function of a2 adrenoceptor agonists working at the CNS? (3)

decrease norepinephrine turnover

cardiovascular depression

sedation

What is the function of a2 adrenoceptor agonists working at smooth muscle?

contraction

What is the function of a2 adrenoceptor agonists working at platelets?

aggregation

What is the function of a2 adrenoceptor agonists working at adipose tissue?

inhibition of lipolysis

What is the function of a2 adrenoceptor agonists working at pancreatic islets?

inhibition of insulin release

T/F there are 4 sub types of a2-adrenoceptor agonists widely distributed throughout the body

true

where are a2A adrenoceptors located?

prefrontal cortex (CNS)

what are the functions of a2A adrenoceptors? (3)

sedation

analgesia

decrease sympathetic outflow

where are a2B adrenoceptors located? (2)

vascular smooth muscle

uterus

what is the function of a2B adrenoceptors?

vasoconstriction

where are a2C adrenoceptors located?

locus coeruleus (CNS)

what are the functions of a2C adrenoceptors? (2)

anxiolytic

decrease sympathetic output

Stimulation of a2A receptors at the blood vessels leads to (choose one: vasoconstriction/vasodilation) while stimulation of a2B receptors at the blood vessels leads to (choose one: vasoconstriction/vasodilation)

vasodilation

vasoconstriction

a2 adrenoceptors are (choose one: excitatory/inhibitory) presynaptic receptors

inhibitory

activation of (choose one: presynaptic/postsynaptic) (central) a2 receptors offer a negative feedback mechanisms that inhibits norepinephrine release and decreases sympathetic drive

presynaptic

activation of (choose one: presynaptic/postsynaptic) (peripheral) a2 receptors causes vasoconstriction and mimics stimulation of a1 receptors

postsynaptic

When a2 agonists stimulate imidazoline receptors, they mediate the central cardiovascular effects of a2-agonists by causing central ___________ and _____________ effects

hypotension

antiarrhythmogenic

which two specific a2 agonists have potent antihypertensive effects because they bind imidazoline receptors?

clonidine

dexmedetomidine

a2 agonists may also stimulate a1 receptors in the CNS which may attenuate the a2 effect causing ________, increased __________ activity, and ___________

arousal

locomotor

vigilance

what are the CNS effects of a2 agonists? (3)

sedation

analgesia

central muscle relaxation

what region of the CNS is targeted by a2 agonists to cause sedation?

Locus ceruleus in brainstem

what region of the CNS is targeted by a2 agonists to cause analgesia? (2)

locus ceruleus in brainstem

sustantia gelatinosa of dorsal horn of spinal cord

T/F a2 agonists provide excellent analgesia in the CNS and work synergistically with opioids

true

a2 agonists provide central muscle relaxation by inhibition of ___________ reflexes in ___________ neurons in the spinal cord

polysynaptic

internuncial (interneurons)

are horses or ruminants more sensitive to xylazine? By how much?

ruminants

10x

which common veterinary species is the least sensitive to xylazine?

pigs

order these animals from which need the smallest to the largest dose of xylazine:

camelids

horses

pigs

ruminants

dogs, cats

ruminants < camelids < dogs, cats < horses < pigs

Do sheep or goats require a larger dose of xylazine?

sheep

do llamas or alpacas require a larger dose of xylazine?

alpacas

order these cattle breeds for which require the smallest to largest dose of xylazine:

hereford

brahmans

holstein

brahmans < hereford < holstein

T/F there is no species variation when it comes to administering xylazine but there is species variation with detomidine

false, its the opposite

T/F with detomidine, medetomidine, dexmedetomidine, and romfidine a similar dose is used for ruminants, horses, dogs, and cats

true

T/F the cardiovascular effects of a2 agonists is biphasic -> hypertension followed by hypotension when administered IV

true

phase 1 of the cardiovascular effects of a2 agonists is (choose one: hypotension/hypertension) and phase 2 is (choose one: hypotension/hypertension)

hypertension

hypotension

during the phase 1 cardiovascular effects of a2 agonists, hypertension occurs due to stimulation of (choose one: central/peripheral) (choose one: a1/a2/a1 and a2) adrenoceptors

peripheral

a1 and a2

during the phase 1 cardiovascular effects of a2 agonists, there is increased ___ and the phase is (choose one: short/long) lasting compared to phase 2

SVR

short

during the phase 2 cardiovascular effects of a2 agonists, hypotension occurs due to stimulation of (choose one: central/peripheral) (choose one: a1/a2/a1 and a2) adrenoceptors

central

a2

during the phase 2 cardiovascular effects of a2 agonists, there is a decrease in central ________ outflow, depression of the __________ center, (choose one: vasoconstriction/vasodilation), and it is (choose one: shorter/longer) lasting than phase 1

sympathetic

vasomotor

vasodilation

longer

a2 agonists have (choose one: positive/negative) (choose one: ionotropic/chronotropic/both) effects

negative

both

T/F a2 agonists are contradicted for use in neonates because the patients cannot meaningfully increase their stroke volume to maintain blood pressure (this is why they have a higher resting heart rate than adults). If given these drugs, their heart rate decreases and therefore so does their blood pressure

true

a2 agonists can sensitize the myocardium to _____________

catecholamines

what type of arrhythmias can a2 agonists cause?

1st and 2nd degree AV block

sinus arrhythmis

how can dexmedetomidine protect patients from arrhythmias compared to other a2 agonists?

decreasing norepinephrine release

In phase 1 of the cardiovascular effects of a2 agonists, there is hypertension plus a protective reflex ___________. So the blood pressure will be (choose one: lower/unchanged/elevated) and the heart rate will be (choose one: lower/elevated/unchanged)

bradycardia

elevated

lower

In phase 1 cardiovascular effects of a2 agonists, peripheral a2 and a1 adrenoceptors are activated and the (choose one: vasoconstrictive/vasodilatory) effects dominate

vasoconstrictive

T/F in phase 1 of the cardiovascular effects of a2 agonists, if there is severe bradycardia you should administer a reversal

true

T/F it is safe to treat bradycardia during the phase 1 cardiovascular effects associated with a2 agonists with an anticholinergic

false, would cause heart to work harder under vasoconstrictive effects

in the phase 2 cardiovascular effects of a2 agonists, there is hypotension plus persistent __________ and (choose one: vasoconstrictive/vasodilatory) effects dominate

bradycardia

vasodilatory

T/F it is safe to treat bradycardia during the phase 2 cardiovascular effects associated with a2 agonists with an anticholinergic

true, is patient is bradycardic and hypotensive you can use anticholinergics

With a2 agonists, you would expect a(n) (choose one: increased/decreased) respiratory rate and a(n) (choose one: increased/decreased) tidal volume

decreased

increased

xylazine can cause a very (choose one: increased/decreased) respiratory rate in sheep and calves and a very (choose one: increased/decreased) PaO2 leading to ___________ due to extensive damage to _________ and fulminant ___________ edema in these animals so xylazine is not recommended in these animals

increased

decreased

hypoxemia

alveoli

pulmonary

what animals is hypoxemia due to xylazine a concern with and therefore, the use of xylazine is typically avoided with these patients? (2)

sheep

calves

with xylazine administration in sheep and calves, you can see hypoxemia characterized by a severely decreased (choose one: PaO2/PaCO2) and a slight change in (choose one: PaO2/PaCO2)

PaO2

PaCO2

hypoxemia due to respiratory effects can be seen in sheep and goats due to the administration of what two drugs?

dexmedetomidine

romifidine

T/F once damage occurs in the alveoli as a result from hypoxemia caused by xylazine administration, it cannot be reversed

true

__________ can reverse the sedation caused by xylazine but they cannot eliminate the respiratory effects completely

antagonists

T/F all a2 agonists can cause vomiting in cats

true

a2 agonists can cause vomiting in cats due to stimulation of the ___ and activation of _______ __ receptors

CTZ

postsynaptic a2

T/F xylazine can induce vomiting in 90% of cats and 30% of dogs and medetomidine can induce vomiting in 50-65% of cats and 10-20% of dogs

true

a2 agonists can cause (choose one: increased/prolonged) GI transit time in ruminants, dogs, and horses

prolonged

because a2 agonists can lead to prolonged GI transit time in ruminants, they are predisposed to ____ and ________

bloat

regurgitation

For reproductive effects, a2 agonists lead to increased _________ contraction and pressure as well as decreased uterine ______ ______ in all species

intrauterine

blood flow

T/F xylazine can cause premature parturition in dogs and horses but won't cause it in ruminants

false, will cause it in ruminants but not dogs or horses

what reproductive effects can detomidine and medetomidine have at low doses in dogs, cows, and horses?

decreased myometrial contractions

what reproductive effects can detomidine and medetomidine have at high doses in dogs, cows, and horses?

increased intrauterine pressure and contraction

T/F the reproductive effects caused by detomidine/medetomidine are less severe than those caused by xylazine

true

T/F there has been no premature parturition reported with detomidine/medetomidine

true

what effects to a2 agonists have on the kidneys?

promote diuresis (patients practically always pee after administration)

a2 agonists can cause (choose one: hyperglycemia/hypoglycemia) and (choose one: hyperinsulinemia/hypoinsulinemia)

hyperglycemia

hypoinsulinemia

a2 agonists can cause decreased release of ________ from B cells and increased hepatic _________ production

insulin

glucose

a2 agonists can cause (choose one: hyperthermia/hypothermia)

hypothermia

T/F a2 agonists can be used for epidural analgesia

true

epidural analgesia using a2 agonists can be done by stimulating a2 receptors in pain pathways in _________ and ________ _______ of spinal cord

brainstem

dorsal horn

epidural analgesia using xylazine is (choose one: short/long) lasting

long (3-4 hours)

epidural or spinal analgesia using detomidine can last >_ ______

3 hours

onset of epidural analgesia using medetomidine is in _-__ ________ and perineal analgesia can last for _ ______ in cats and _-_ _______ in cattle

5-10 minutes

4 hours

4-7 hours

T/F a2 agonists increase the duration of epidural analgesia when given with opioids or lidocaine

true

Contraindications for a2 agonists:

__________ abberation

_____________ or in shock

________ or _______ dysfunction

___________ in last trimester and in ruminants

___________ obstruction

__________ disease

___________ or very _______ animals

cardiac

hypotension

hepatic

renal

pregnancy

urethral

wobblers

neonates

young

T/F a2 agonists are federally controlled substances

false, they are state controlled substances

what is the first a2 agonists used in vet med?

xylazine

xylazine is approved for use in what veterinary species? (5)

dogs

cats

horses

deer

elk

xylazine has the (choose one: lowest/highest) a2:a1 selectivity ratio of the a2 agonists

lowest

xylazine is the (choose one: least/most) potent of the a2 agonists

least

with IV sedation, xylazine sets in in about _-_ ________ and lasts __-__ _________

3-5 minutes

30-40 minutes

xylazine undergoes rapid _________ metabolism

hepatic

T/F xylazine is more effective in animals with high circulating catecholamines (excitement, fear, pain, stress)

false, less effective

an intracarotid injection of xylazine can cause short duration of violent _______ by stimulating _______ __ receptors

seizure

central a1

what is the treatment for giving xylazine intracarotid? (2)

bezodiazepines

general anesthesia

what veterinary species is detomidine approved for use in?

horses

T/F although detomidine is only approved for use in horses, it is also used in cattle and pigs and less frequently in small ruminants

true

is detomidine or xylazine more potent?

Detomidine (20-30x)

detomidine causes more profound ________ and _________ relaxation than xylazine

analgesia

muscle

detomidine offers the (choose one: shortest/longest) duration of sedation and ataxia of the a2 agonists

longest