Alpha2-agonists

Question 1

What is the MOA of a2 agonists?

Answer 1

stimulate presynaptic α2-adrenergic receptors in CNS –> Gi receptors:
–> inhibition of adenylyl cyclase –> decreased cAMP –> activation of receptor-operated K+ channels –> hyperpolarization
–> inhibition of voltage-gated Ca++ channels –> decreased NT (NE) release –> decreased SNS activity
–> stimulation of Na+/H+ exchanger (renal)

• sedation
• analgesia
• muscle relaxation
• reduced HR

Question 2

Name the subtypes of Alpha2 receptors?

Answer 2

• alpha-2A
• alpha-2B
• alpha-2C

Question 3

Where do you find alpha2-Adrenoceptors?

Answer 3

• presynaptic: membrane of noradrenergic neurons
• CNS: medullary dorsal motor complex
• Postsynaptic: vascular smooth muscle, liver, pancreas, PLTs, kidney, adipose tissue, eye

Question 4

How do alpha2-agonists cause sedation?

Answer 4

bind to presynaptic α2 adrenergic receptors in the locus coeruleus (upper brainstem) –> inhibition of NE release –> decreased SNS activity –> activation of endogenous sleep pathways (non-REM sleep)

Question 5

How do alpha2-agonists cause analgesia?

Answer 5

• stimulation of receptors in the dorsal horn of spinal cord + brainstem –> modulation of nociceptive signals
• inhibition of nociceptive neurons
• direct activation of GABA-ergic inhibitory interneurons by norepinephrine

Question 6

What effects do alpha2-agonists have on opioids?

Answer 6

• potentiate opioid-induced analgesia
• decrease the development of tolerance to opioids

Question 7

How and how much does administration of a2-agonists decreases the requirements for anesthetic drugs?

Answer 7

decrease in norepinephrine release, mainly from the locus ceruleus

• 80%

Question 8

How much reduction of MAC (minimal alveolar concentration) can be achieved by total abolishment of noradrenergc transmission through alpha2-agonists?

Answer 8

• maximum of 40%

Question 9

How do alpha2-agonists cause neuroprotective effects?

Answer 9

• a2-adrenoceptor-mediated decrease in NE or glutamate
• activation of imidazoline receptors
• inhibition of the acute expression of immediate early genes involved in cerebral damage
• inhibition of massive NE release afer brain injury
• may prevent vasospasm after subarachnoid hemorrhage
• anticonvulsant effects

Question 10

Name 6 effects of alpha2-agonists?

Answer 10

1. sedation
2. analgesia
3. hypothermia
4. neuroprotection
5. prevention of thermoregulatory response to infection
6. control of delirium

Question 11

How do alpha2-agonists induce hypothermia?

Answer 11

inhibition of the central noradrenergic mechanisms responsible for the control of body temperature in hypothalamus

Question 12

Describe the clinical cardiovascular response after alpha2-agonist administration?

Answer 12

Biphasic response:

1. BP + SVR increase, whereas HR + CO decrease
2. decrease in arterial pressure; HR + CO remain lower than normal
   SVR either declines progressively toward normal or remains elevated

• dose-dependent (near-maximum effects are reached at dosages close to lower end of recommended range –> low dosaages only minimally reduce CV effects)

Question 13

How do alpha2-agonists cause bradycardia?

Answer 13

• stimulation of postsynaptic a2-adrenoceptors on vascular smooth muscle –> vasoconstriction –> increases arterial BP–> activation of baroreceptors –> bradycardia
• central sympatholytic action of a2-agonists leave vagal tone unopposed
• presynaptically mediated reduction in NE release in cardiac sympathetic nerves

Question 14

How do alpha2-agonists affect stroke volume?

Answer 14

Stroke volume is only minimally affected

Question 15

How do alpha2-agonists effect CO?

Answer 15

Reduction of CO, mainly mediated through bradycardia

Question 16

Discuss the effects of combining alpha2-agonists with anticholinergic drugs?

Answer 16

• resulted in large increases in arterial pressure (MAP 200 mmHg)
• detrimental to CV performance

Question 17

What effects have alpha2-agonists on blood flow?

Answer 17

Blood flow redistribution:
- Blood flow to more vital organs (e.g., heart, brain, kidney) might be partially or totally preserved at the expense of poor blood flow to less vital organs (e.g., skin, muscle, intestine)

However:
Cerebral blood flow decreases in response to a2-agonist administration

Question 18

How does dexmedetomidine affect myocardial oxygen demand and supply?

Answer 18

dexmedetomidine maintains the balance between myocardial oxygen demand and supply

Question 19

Discuss the arrythmogenic potential of alpha2-agonists?

Answer 19

• reduction in HR may reveal foci that are normally inhibited by the impulses coming from the sinoatrial node.

Xylazin (also a1 activity): sensitizes heart to catecholamine-induced arrhythmias

Newer alpha2-agonists that are more specific for the a2-adrenoceptors:
- do not appear to induce arrhythmias
- may increase threshold for epinephrine-induced arrhythmias (imidazoline receptor mediated?)
- protective against VT or VFib after ischemia–reperfusion
- perioperative use may decrease the incidence of arrhythmias post cardiac surgery

Question 20

Discuss the benefits of using calcium channel blockers together with alpha2-agonists?

Answer 20

preserving central effects (e.g. sedation, analgesia) but inhibition of peripheral vascular effects (e.g. vasoconstriction)

Question 21

Name one peripheral a2-antagonist and explain why it only exerts its effects peripherally?

Answer 21

• vatinoxan
• cannot cross blood-brain-barrier

Question 22

Discuss the effects of alpha2-agonists on the respiratory system?

Answer 22

• RR decreases but minute ventilation is maintained
• paCO2 + paO2 remain within the normal range
• potentiate respiratory depression induced by other agents (e.g. opioids)

Question 23

Discuss the effects of alpha2-agonists on catecholamines?

Answer 23

• inhibition of sympathetic outflow
• modulate the stress response to anesthesia and surgery
• decrease plasma level of circulating catecholamines

Question 24

Discuss the effects of alpha2-agonists on insulin?

Answer 24

• Stimulation of a2-adrenoceptors on the beta cells of the islets of Langerhans causes direct inhibition of insulin release, resulting in hyperglycemia

Question 25

Discuss the effects of alpha2-agonists on growth hormone?

Answer 25

increase the release of growth hormone, which could contribute to the observed hyperglycemia

Question 26

What effects do alpha2-agonists cause on the level of the kidney?

Answer 26

- promote diuresis (inhibition of ADH release) - promote natriuresis - inhibition of renin release

Question 27

What effect do alpha2-agonists have on ANP?

Answer 27

- increase the secretion of atrial natriuretic factor (ANP)

Question 28

Name 6 hormones affected by alpha2-agonists?

Answer 28

- insulin (decreased) - renin (decreased) - growth hormone (increased) - ADH (decreased) - catecholamines (decreased) - ANP (increased)

Question 29

What effects do alpha2-agonists have on the GI tract?

Answer 29

- decrease in salivation - decrease in gastroesophageal sphincter pressure - decrease in esophageal, gastric, and small intestinal motility - decrease in gastric secretion

Question 30

Why do alpha2-agonists mediate vomiting and how often has this been reported in dogs an cats?

Answer 30

stimulation of a2-adrenoceptors in CRTZ - Dogs: 8-20% - Cats: up to 90%

Question 31

Name one alpha2-agonist that does not affect imidazoline reeptors?

Answer 31

xylazine

Question 32

Name 8 effects that binding of alpha2-agonists to imidazoline mediate?

Answer 32

- increase sodium excretion and urine flow rate - neuroprotective effects - blood pressure regulation - inhibition of catecholamine-induced arrhythmias - regulation of small intestinal motility - control on central noradrenergic and hypothalamic-pituitary-adrenal axis activity - modulation of the effects of opioids - inhibition of insulin secretion (hyperglycemia)

Question 33

Name 2 types of imidazoline receptors and their role?

Answer 33

I1 receptor: - BP regulation - may act synergistically with a2-adrenoceptors - inhibition of catecholamine-induced arrhythmias I2 receptor: - control on central noradrenergic + hypothalamic-pituitary-adrenal axis activity (>a2-adrenoceptors) - regulation of SI motility - modulation of opioid effects

Question 34

Name 5 beneficial effects of using dexmedetomidine in critically ill patients?

Answer 34

- reversal possible - lack of respiratory depression - maintenance of hemodynamic stability and sympatholysis - decreased opioid consumption - control of delirium

Question 35

Why is dosage of alpha2-agonists often based on surface area rather than body weight?

Answer 35

at similar dosages based on body weight, the level of sedation was lower in smaller dogs than in larger dogs

Question 35

Name 2 alpha2-antagonists?

Answer 35

Atipamezole Vatinoxan

Question 36

What effects of alpha2-agonists are reversed by atipamezole?

Answer 36

- analgesia - sedation - cardiovascular effects (ecxeption: may be ineffective at diminishing dexmedetomidine induced bradycardia in anaesthetized dogs/cats)

Question 37

Why is i.m. administration of atipamezole preferred over i.v. and what is the onset of action after i.m. administration?

Answer 37

- IV: dyspohria, aggression, hypotension - 5 to 10 minutes

Question 38

How can the cardiovascular effects of alpha2-agonists be mitigated without affecting sedation and analgesia?

Answer 38

administration of alpha2-antagonist vatinoxan

Question 39

What did Shebabi et al. (NJEM 2019) find in "Early Sedation with Dexmedetomidine in Critically Ill Patients"?

Answer 39

Primary outcome - death at 90 days: --> MV: no significant difference in 90d death between dexmed and usual-care Secondary outcome: - Dexmedetomidine CRI group required supplemental sedatives to achieve the prescribed level of sedation - More adverse events and serious adverse events [most commonly bradycardia, hypotension and prolonged sinus arrest (asystoly)] were reported in the dexmedetomidine group - The number of days that patients were free from coma or delirium and the number of ventilator-free days were 1 day more in the dexmedetomidine group

Question 40

What has the use of dexemedetomidine in mechanically ventilated ICU patients been associated with?

Answer 40

- shorter time to extubation - higher number of days free from coma or delirium - shorter duration of unresponsive sedation

Question 41

What has been shown according to Shebabi et al in NJEM 2019 with the use of dexmedetomidine in sepsis?

Answer 41

lower mortality associated with dexmed­etomidine than with other agents in patients with sepsis, along with lower rates and shorter durations of coma and delirium (both associated with higher mortality rates).

Question 42

How are a2 agonists metabolised and eliminated?

Answer 42

Metabolism: liver Excretion: renal (inactive metabolites)