10 – Alpha2-Agonists Flashcards
Alpha2 agonists provide
- Sedation
- Analgesia
- Muscle relaxation
- Anxiolysis
Alpha2 agonists examples
- Dexmedetomidine
- Xylazine
Alpha2 agonists pharmacology
- High lipophilicity (BBB, placenta, gut wall, mucous membranes)
- Hepatic metabolism
- Renal excretion
Post-ganglionic neurons of SYMPATHETIC system are
- Adrenergic
o NE released from nerve terminal
o Stimulates post-synaptic alpha1 and alphs2 receptors
o Acts at pre-synaptic alpha2 receptors to INHIBIT its own release (negative feedback on itself)
Alpha 1 receptors
- Generally, post-synaptic
- 3 different subtypes
Alpha2 agonists act both centrally and peripherally and their actions depend on
- Interaction with alpha2 (and alpha1) receptors
- Interaction with Imidazoline (I1 and I2) receptors (Dexmedetomidine)
Alpha 2 receptors
- Widely distributed in body
- Pre-, post-, and extra-synaptic
- Peripheral and central
- 4 different subtypes
Alpha2 agonists: sedative effects
- Inhibit NE release
- Decrease sympathetic outflow
- Inhibit release of other NTs (ACh, serotonin, dopamine)
- Produces GENERALIZED CNS depression, sedation and analgesia (ex. other side effects)
Alpha1 receptor: CV effects
- Vascular smooth muscle: vasoconstriction
- Myocardium: positive inotropy
Alpha 2 receptor, post/extra synaptic: CV effects
- Vascular smooth muscle: vasoconstriction
- Endothelium: vasoconstriction or vasodilation
Alpha 2 receptor, pre-synaptic: CV effects
- Vascular smooth muscle: alleviation of vasoconstriction
Beta 1 receptor: CV effects
- Vascular smooth muscle: vasodilation
- Myocardium: positive inotropy and chronotropy
Beta 2 receptor: CV effects
- Vascular smooth muscle: vasodilation
- Myocardium: positive inotropy and chronotropy
Alpha2-agonists are NOT pure alpha2-agonists
- Newer alpha2 agonists have more SPECIFIC action on alpha2 and less action on alpha 1
- Ex. dexmedetomidine (much more specific)
Action at alpha 1 receptors
- CNS stimulation: arousal, excitement, restlessness
- Can exacerbate pain
- Smooth muscle constriction
- Vasoconstriction
- Increased peripheral resistance
- Increased BP
- Mydriasis
- Relaxes GIT smooth muscle
- Contraction
- Contraction of uterus and bladder sphincter
- Bronchoconstriction
- Decrease insulin secretion
Action at alpha 2 receptors
- Anxiolysis and sedation
- Anesthetic sparing effect
- CNS depression
- Anticonvulsant activity
- Neuroprotectant: decrease total intracranial blood volume
- Analgesia
- Muscle relaxation
- Increase uterine tone
Alpha2 agonists: CV effects
- Peripheral vasoconstriction and increased BP (hypertension)
- Reflex increase in vagal tone (baroreceptor reflex)->BRADYCARDIA
- Arterial BP returns to near normal
- Heart is unable to increase SV dueto high afterload=decreased CO
*do NOT want to use in an animal that already has a low CO OR kidney or liver failure
*use in YOUNG, HEALTHY patients
Alpha2 agonists: bradycardia
- Central pre-synaptic alpha2 receptor and Imidazoline receptor activation=central sympatholytic and relative increase in PS tone
- Peripheral pre-synaptic alpha2 receptor activation=reduced NE release at the sympathetic nerve terminals in the heart
*arterial BP returns to normal: due to decreased vasoconstriction and HR
Alpha2 agonists: ECG abnormalities
- Due to increased PS tone!
- Bradycardia
- Second degree AV block
o Normal P w/QRST, then a P with no QRST, then P with no QRST
Would you treat a second degree AV block from alpha2 agonists?
- Depends on how often it occurs and their BP
- If BP good=normal
- Low heart rate = give anti-cholinergics
Alpha2 agonists: respiratory effects
- RR may be reduced (compensate by increasing TV
- Blood gases remain unchanged
- *when combine with other sedation drugs (opioids)=can see respiratory depression
Alpha2 agonists musculoskeletal relaxation (side effect)
- Manifests as ataxia or recumbency
- Central actions as: Imidazoline, glycine, and GABAa receptors
- Possible local anesthetic actions
Alpha 2 agonists: endocrine (diuresis) (side effect)
- Reduced ADH secretion and responsiveness leads to diuresis
- Reduced insulin: hyperglycemia and glycosuria/osmotic diuresis
- Decreased urine specific gravity due to INCREASE in urine volume
- *most evident when doing a standing procedure in a horse
Alpha2 agonists: uterine (side effects)
- May effect uterine tone and intra-uterine pressure
- *1st and 3rd trimester pregnancy
o Could result in abortion or early labor and delivery
Alpha2 agonists: GI (side effects)
- Reduced motility, secretions and blood flow
- Prolonged transit time
- Nausea and vomiting
Alpha2 agonists: thermoregulation (side effects)
- Central suppression of thermoregulation
- Reduction in heat production may be offset by REDUCTION in heat loss from peripheral constriction
- Monitor for hyperthermia
Alpha2 agonists: liver (side effects)
- Reduces blood flow
Alpha2 agonists: kidneys (side effects)
- Reduces blood flow
- Imay improve glomerular filtration rate?
Alpha2 agonists: ocular effects (side effects)
- Mydriasis
- Reduced aqueous humour production
- Decrease in intraocular pressure
Alpha2 adrenergic and opioid receptors are intimately related
- Combination of alpha2 and opioid=profound synergistic analgesia
Widespread location of alpha2 receptors: may suppress nociceptive signals at VARIOUS points in PAIN PATHWAYS
- Inhibit NT release from primary afferent fibers to second order neurons
- Affect pre- and post-synaptic modulation occuring in dorsal horn
- Influence DESCENDING modulatory systems from the brain stem
- Alter ASCENDING modulation of nociception in the diencephalon and limbic areas
Alpha2 agonists: potent analgesia for moderate to severe pain
- Depends on route of administration
- Effective for visceral AND somatic pain
- *can be used as a rescue analgesic for opioid tolerance and chronic pain (Ketamine)
Alpha2 particularly useful for large animals
- More efficacious than opioids and NSAIDs in horses
- Less unwanted side effects
Low doses of alpha2 agonists:
- Sedative and analgesic effects are DOSE-DEPENDENT
- *increasing doses produces a ceiling on degree of analgesia produced
o Further increasing only lengthens duration and severity of side effects
Alpha2-agonists: analgesic and antihyperalgesic effects most profound during inflammation
- Effects depend on stage of inflammatory process
- Greatest effects often in middle of inflammatory process
- Up regulation of alpha2 or imidazoline recptors
Alpha2 antagonist examples
- Antipamezole
- Yohimbine
- Tolazoline
Atipamezole
- Most selective alpha2 antagonist available
- Competitive antagonists
- *reversal of SEDATION and ANALGESIA
- Only labelled for IM administration
- *start low and titrate to effect
Atipamezole is often accompanied by (side effects)
- Muscle tremors
- Tachycardia
- Over-alertness
- Transient hypotension
- Panting
- Defecation
- Vomiting
- *opposite of the alpha2 agonists side effects
Yohimbine
- General CNS stimulant with antagonist action at alpha2 receptors
- Tachycardia is possible
- Used for xylazine (horse, dogs, cats)
- Not in cattle: volume is TOO large
Tolazoline
- True alpha2 antagonist
- More suitable volume in cattle
- Can cause excitement when administered IV
- *give half dose IV and half IM to decrease excitement
