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Alpha2-agonists Flashcards

1
Q

What kind of receptors are Alpha2 receptors?

A

Gi/0 protein-coupled receptors with 7 transmembrane domains of the amine- binding subfamily

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2
Q

Name the subtypes of Alpha2 receptors?

A
  • alpha-2A
  • alpha-2B
  • alpha-2C
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3
Q

What is the mechanism of action of alpha2 agonists?

A
  • inhibition of adenylyl cyclase
  • activation of receptor-operated K+ channels
  • acceleration of Na+/H+ exchange
  • inhibition of voltage-gated Ca++ channels
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4
Q

Where do you find alpha2-Adrenoceptors?

A
  • presynaptic: membrane of noradrenergic neurons
  • Postsynaptic: various tissues (vascular smooth muscle, liver, pancreas, platelets, kidney, adipose tissue, eye)
  • medullary dorsal motor complex in the brain (high density of receptors)
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5
Q

What happens on activation of alpha2-Adrenoceptors?

A

inhibition of norepinephrine release (negative feedback)

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6
Q

What does stimulation of presynaptic a2-adrenoceptors in the CNS lead to?

A

Decreases release of norepinephrine

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7
Q

How do alpha2-agonists cause sedation?

A

inhibition of noradrenergic neurons in the locus ceruleus (upper brainstem)

activation of endogenous sleep pathways

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8
Q

How do alpha2-agonists cause analgesia?

A
  • 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
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9
Q

What effects do alpha2-agonists have on opioids?

A
  • potentiate opioid-induced analgesia
  • decrease the development of tolerance to opioids
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10
Q

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

A

decrease in norepinephrine release, mainly from the locus ceruleus

  • 80%
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11
Q

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

A
  • maximum of 40%
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12
Q

How do alpha2-agonists cause neuroprotective effects?

A
  • a2-adrenoceptor-mediated decrease in norepinephrine or glutamate
  • activation of imidazoline receptors
  • inhibition of the acute expression of immediate early genes involved in cerebral damage
  • inhibition of massive norepinephrine release afer brain injury
  • may prevent vasospasm after subarachnoid hemorrhage
  • anticonvulsant effects
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13
Q

Name 6 effects of alpha2-agonists?

A
  1. sedation
  2. analgesia
  3. hypothermia
  4. neuroprotection
  5. prevention of thermoregulatory response to infection
  6. control of delirium
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14
Q

How do alpha2-agonists induce hypothermia?

A

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

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15
Q

Describe the clinical cardiovascular response after alpha2-agonist administration?

A

Biphasic response:

  1. BP (maybe not with i.m. administration) and SVR increase, whereas HR and CO decrease
  2. decrease in arterial pressure; HR and 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)
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16
Q

How do alpha2-agonists cause bradycardia?

A
  • stimulation of a2-adrenoceptors located on the vascular smooth muscle of both arteries and veins lead to vasoconstriction –> increases arterial blood pressure –> activation of baroreceptors –> bradycardia
  • central sympatholytic action of a2-agonists leave vagal tone unopposed
  • increase in parasympathetic efferent neuronal activity
  • presynaptically mediated reduction in norepinephrine release in cardiac sympathetic nerves
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17
Q

How do alpha2-agonists affect stroke volume?

A

Stroke volume is only minimally affected

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18
Q

Do alpha2-agonists induce direct negative inotrope effects?

A

No

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19
Q

How do alpha2-agonists effect CO?

A

Reduction of CO, mainly mediated through bradycardia

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20
Q

Discuss the effects of combining alpha2-agonists with anticholinergic drugs? What would be the theory behind this combination?

A

Because the decrease in cardiac output appears to be related mainly to the bradycardia

Dogs:
- resulted in large increases in arterial pressure, with mean blood pressure around 200 mm Hg in one study.
- addition of glycopyrrolate to romifidine appeared detrimental to CV performance

Cats: addition of glycopyrrolate to xylazine appeared detrimental to CV performance

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21
Q

What effects have alpha2-agonists on blood flow?

A

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, and during hypoxia, adequate cerebral oxygenation may not be maintained

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22
Q

How does dexmedetomidine affect myocardial oxygen demand and supply?

A

dexmedetomidine maintains the balance between myocardial oxygen demand and supply

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23
Q

Discuss the arrythmogenic potential of alpha2-agonists?

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

Older a2-agonists who activate a1-adrenoceptors (e.g. xylazin):
- sensitize the heart to catecholamine-induced arrhythmias.

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

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24
Q

Explain the role of alpha2-agonists in ischemia-reperfusion injury?

A

protection against ventricular tachycardia or fibrillation

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25
Q

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

A

–> preserve beneficial effects with fewer hemodynamic changes
-preserving central effects (e.g. sedation, analgesia) but inhibition of peripheral vascular effects (e.g. vasoconstriction)

26
Q

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

A
  • vatinoxan
  • cannot cross blood-brain-barrier
27
Q

Discuss the rational of adding vatinoxan to an alpha2-agonist?

A

inhibition of the peripheral vascular effects of a2-agonists (i.e., vasoconstriction) with preservation of central alpha2-agonist mediated effects (i.e., sedation, analgesia)

  • abolishment of alpha2-agonist induced bradycardia (in one study in dogs) –> bradycardia produced by a2-agonists seems to be peripherally rather than centrally mediated
28
Q

Is bradycardia induced by alpha2-agonists centrally or peripherally mediated and how could this be abolished?

A
  • peripherally mediated
  • adding an alpha2-antagonist like vatinoxan
29
Q

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

A
  • RR decreases but minute ventilation is maintained
  • paCO2 + paO2 remain within the normal range
  • potentiate respiratory depression induced by other agents (e.g. opioids)
30
Q

Discuss the effects of alpha2-agonists on catecholamines?

A
  • inhibition of sympathetic outflow
  • modulate the stress response to anesthesia and surgery
  • decrease plasma level of circulating catecholamines
31
Q

Discuss the effects of alpha2-agonists on insulin?

A
  • Stimulation of a2-adrenoceptors on the beta cells of the islets of Langerhans causes direct inhibition of insulin release, resulting in hyperglycemia
  • effect is dose-dependent: 10 to 20 mcg/kg of medetomidine was reported to decrease the plasma insulin level without causing significant hyperglycemia in dogs
32
Q

Discuss the effects of alpha2-agonists on growth hormone?

A

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

33
Q

Discuss the effects of alpha2-agonists on ADH?

A

inhibit the release of ADH and its effect on renal tubules

34
Q

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

A
  • promote diuresis
  • promote natriuresis
  • inhibition of renin release
35
Q

What effect do alpha2-agonists have on ANP?

A
  • increase the secretion of atrial natriuretic factor (ANP)
36
Q

Name 6 hormones affected by alpha2-agonists?

A
  • insulin
  • renin
  • growth hormone
  • ADH
  • catecholamines
  • ANP
37
Q

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

A
  • decrease in salivation
  • decrease in gastroesophageal sphincter pressure
  • decrease in esophageal, gastric, and small intestinal motility
  • decrease in gastric secretion
38
Q

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

A

stimulation of a2-adrenoceptors in the chemoreceptor trigger zone (CTZ)

  • Dogs: 8-20%
  • Cats: up to 90%
39
Q

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

A

xylazine

40
Q

What receptors do apha2-agonists bind to?

A

alpha2-adrenoceptors
imidazoline receptors (exept xylazine)

41
Q

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

A
  • 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)
42
Q

Name two types of imidazoline receptors and their role?

A

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

43
Q

What alpha2-agonists are approved for use in dogs and cats?

A
  • dexmedetomidine
  • medetomidine
  • xylazine

(romifidine has been studied but not approved)

44
Q

Name one difference between xylazine and dexmedetomidine/medetomidine that explains why usage in critically ill animals is not recommended?

A

Xylazine has moderate selectivity for a2-adrenoceptors and activates a1-adrenoceptors at clinical doses –> additional adverse effects

45
Q

What receptor does medetomidine selectively bind to?

A

highly selective for a2-adrenoceptors

46
Q

Explain the difference between dexmedetomidine and medetomidine?

A

Medetomidine is a racemic mixture of dexmedetomidine and levomedetomidine (appears devoid of effects)

Dexmedetomidine is the active isomer.

47
Q

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

A
  • reversal possible
  • lack of respiratory depression
  • maintenance of hemodynamic stability and sympatholysis
  • decreased opioid consumption
  • control of delirium
48
Q

What is the difference of alpha2-agonists effects on the cardiovascular sytem in humans and dogs/cat?

A

cardiovascular effects (particular vasoconstriction) may be more pronounced and/ or last longer in dogs and cats than in humans

49
Q

What dose of dexmedetomidine has been studied in dogs and cats for analgesia and what was the conclusion?

A

management of postoperative pain in dogs:
- loading dose of 25 mcg/m2 followed by a CRI of 25 mcg/m2/hr provided adequate analgesia in some (but not all) patients (= 0.9-mcg/kg loading dose and 0.9-mcg/kg/hr infusion in a 20-kg dog)
- sedation was similar to that produced by a morphine CRI

49
Q

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

A

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

50
Q

Name 2 alpha2-antagonists?

A

Atipamezole
Vatinoxan

51
Q

What drugs can atipamezole antagonise and what is the recommended dose?

A
  • dexmedetomidine and medetomidine
  • 5 times the administered dose of medetomidine
  • 10 times the administered dose of dexmedetomidine
52
Q

What effects of alpha2-agonists are reversed by atipamezole?

A
  • analgesia
  • sedation
  • cardiovascular effects (ecxeption: may be ineffective at diminishing dexmedetomidine induced bradycardia in anaesthetized dogs/cats)
53
Q

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

A
  • i.v. administration can result in transient dysphoria
  • 5 to 10 minutes
54
Q

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

A

administration of alpha2-antagonist vatinoxan

55
Q

What is an undesired adverse effect of vatinoxan during anaesthesia in cats?

A

vatinoxan decreases the magnitude of the decrease in anesthetic requirements produced by dexmedetomidine in cats

56
Q

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

A

Primary outcome - death at 90 days:
Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine (29.1%) for sedation had a rate of death at 90 days (primary outcome) similar to that in the usual-care group (29.1%). There was no significant difference in the primary outcome between the subgroup of patients with suspected or proven sepsis at randomization and those without sepsis.

Secondary outcome:
- 180d mortality difference was not significant
- 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 than in the usual-care 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 than in the usual-care group

57
Q

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

A
  • shorter time to extubation
  • higher number of days free from coma or delirium
  • shorter duration of unresponsive sedation
58
Q

What is the biologic rationale for a potential benefit of dexmedetomidine in mechanically ventilated ICU patients according to Shebabi et al in NJEM 2019?

A
  • protective effects against neuronal, myocardial, and renal injury
  • reduction in inflammatory mediators after CPB
  • reduced mortality in animal models
  • lower mortality in patients with sepsis
  • lower rates and shorter durations of coma and delirium (both associated with higher mortality rates)
59
Q

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

A

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).

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