Exam 1: Alpha2-adrenoreceptor agonists

what is the relationship between the two alpha-adrenoceptor agonists

• alpha1 and 2 receptors are in feed back with each other

• drugs classed as a2 are more selective to those receptors but a small amount will bind to a1 receptors

generally describe a2 receptors

• mostly presynaptic
  -decreasing SNS outflow via inhibition of NE release from terminal axons, inhibition of firing NE neurons, decreased NE turnover in CNS

• post and extra-synaptically in liver cells, platelets, and smooth muscle of blood vessels

what is the MOA of a2-adrenoceptor agonists

• G protein coupled receptor - Gi/Go

• inhibition of adenylate cyclase activity decreasing cAMP formation \

what is the post-synaptic role of a2-adrenoceptors

• decrease insulin release

• decrease platelet aggregation

• decrease CNS discharge

what are the a2-receptor subunits

• A (present in humans)

• B

• C

• D- species variant of A seen in ruminants

what is the anatomical location of a2A receptors

• CNS

• pancreatic beta cells

• kidneys

• aorta

• skeletal muscle

• spleen

• lungs

what is the physiological response of a2A

• sedation

• supraspinal analgesia

• centrally mediated bradycardia and hypotension

• hyperglycemia

what is the location of a2B

• little in brain

• dorsal root ganglia of spinal cord

• vascular endothelium

  • wha

what is the physiological response of a2B

• vasoconstriction

• reflex bradycardia (peripherally mediated)

• spinal analgesia

• anti-shivering

what is the location of a2C

• spinal cord

what is the physiological response of a2C

• spinal analgesia

• possibly thermoregulation

what is the role of the Imidazoline non-adrenergic binding site of alpha2-agonists- I1 receptor

• blood pressure regulation

• decreases sympathetic tone centrally by stimulating a2 adrenoceptors

• interact syngergistically in being antihypertension

what is the role of I2 receptors

• found in liver, pancreas, platelets, adipocytes, kidneys, adrenal medulla, brain

• mainly found on the outer mitochondrial membrane

what is the role of I3 receptors

regulates insulin secretoon

what are the commonly used a2-agonsts

• xylazine

• detomidine

• romifidine

• medetomidine

• dexmedetomidine

• clonidine (humans)

what are the commonly used a2-antagonists

• atipamezole

• yohimbine

• tolazoline

what are the central effects of a2-agonists

• sedation (a2 receptors in the locus coeruleus)

• analgesia

• muscle relaxation

• cardiovascular depression (can cause 2nd degree atrioventricular block)

what are the peripheral effects of a2-agonists

• increase in systemic vascular resistance (afterload)

• reflex bradycardia

what is the clinical use of a2 agnosts

• sedation and ease of handling

• wildlife immobilization

• analgesia

• muscle relaxation

• anti-anxiety

• decrease in MAC of inhaled anesthetics

• mostly used in heathy pt, though dex in very low doses is exception

what is the impact of a1 receptor agonists

• excitation

• increased motor activity

• vasoconstriction

order the common a2 agonosts by lowest to highest a2/a1 selectivity ratios

xylazine< detomidine < romifidine <medetomidine/dexmedetomidine

what determines the degress of sedation with a2 agonists

• dose rate

• route o administration

• mental state of pat

• species and breed

• physical condition

• concurrent drugs used for sedation

• hypnosis at higher doses

• (hemodynamic side effects depend on dose and speed)

what other considerations must be made with a2-agonists

• highly lipophilic → readily cross BBB, very rapid onset

• hepatic metabolism

• urinary excretion of inactive metabolites

• REVERSIBLE

how is analgesia described with a2-agonists

• activate same signal transduction as opioid receptor agonists

• G protein coupled mediated activation of K+ conductance and inhibition of Ca2+ → spinal inhibition of sustance P

• comparable to opiods and can reduce opioid requirements by 50-75%

what is the effect of a2- agonists on the respiratory system

• blood gases are generally unchanged, but PCO2 and PaO2 may change when combined with opioids, other sedatives, and inhalants

• pale/bluish MM color due to peripheral vasoconstriction despite normal PaO2

• hypoxemia in sheep
  -activation of pulomanry intravascular macrophage → pulmonary parenchymal damage → pulomary edema
  -very very low doses or avoid

what are the peripheral cardiovascular effects of a2-agonists

• vasoconstriction → increased blood pressure → reflex bradycardia → increased afterload

what are the central cardiovascular effects of a2-agonists

• vasodilation

• 30-50% decrease in cardiac output

• decreased myocardial contractility

• bradycardia

• peripheral → central

• cardiac arrhythmias

  • sinus bradycardia

  • 1st and 2nd degree AV blocks

  • other arrhythmias

how do you treat bradycardia with a2 agonists

• only treat with hypotension, as treating with hypertension can cause additional hypertension, increased O2 consumption, dysrhythmias and ultimately collapse

• if hypotensive → anticholinergic + inotropes

what are the GI effects of a2-agonists

• decreased GI motility in equine, rabbits, ruminants

• may decrease gastric emptying time, may not be the best choice for pregnant pt

• emesis in dogs and cats based on route and dose

  • IM and high does

what are the genitourinary effects of a2-agonists

• increased urine production → decreased specific gravity and osmolality due to inhibition of ADH and release of ANP

• increase myometrial tone and intrauterine pressure in cattle, can cause last trimester abortion

• reduce O2 delivery to fetus

what are other effects of a2-agonists

• hyperglycemia, avoid in diabetics

• sweating and piloerection in horses

order the a2 agonists by potency

• dexmedetomidine >medetomidine>detomidine>romifidine>xylazine

what are the pharmokinetics and pharmacodynamics of xylazine

• IM injections take full effect in 15 minutes

• elimination HL = 30 min in cattle and dogs (cannot use in cattle), hrses up to 60min

• fast onset of sedation and analgesia when IV

• subq provdies poor sedation

what are the effects of xylazine on CV and resp

• Co reduced by 5-%

• severe bradycardia and 2nd degree AV blocks very common

• decreased RR with unchanged blood gas parameters (increased tidal volume)

• high doses decrease volume minute, increase physiologic dead space, decrease O2 delivery to tissues

what are the clinical applications of xylazine

• neiroleptanalgesia when combined with opioid

• often given with ketamine for 15-20 min proceduces

• in horses, most common premedication, used for standing sedation, part of a triple drip (guaifenesin + ket+ xylazine)

• sensitivity depends on species )bovine > small ruminants > camelids >SA > horses> swine)

what are the pharmacokinetics and pharmacodynamics of dexmedetomidin

• peak sedation at 10-20 minutes

• duration of effects up to 60 minutes in dogs, cats and ponies

• peak analgesia in 20 minites in dogs and cats, correlates with sedation

• moderated sedation up to 40 minutes

• great MAC reduction- dose dependent

what are the cardiovascular effects of dexmedetomidine

• myocardial contractlity is not significantly affected

• high does have same effects as xylazine

• low doses= less bradycardia, fewer A/V blocks, less hypertension and hypotension

• doses lower than 1mcg/kg should lack effect

• preserves blood flow to vital organs

what are the other effects of dexmedetomidine

• loses its a2 receptor selectivity as dose increases on IV or rapid infusion

• extreme care should be taken in volume depleted or hypertensive pt

• very favorable for infusions due to its context-sensitive half life

• GI inflammatory properties, neuroprotective properties, may be used for sedation in cats with HCM

what are the clinical doses of dexmedetomidine used at LSU

• sedation of nervous/aggressive animals = 5mcg/kg IM

• sedation of happy dogs and cats = 3mcg/kgIM, 0.5-2.0mcg/kg IV

• sedation of young pigs 5-10mcg/kg IM

• expensive to be used in horses and bovine

how is detomidine described

• primary used in horses

• more potent than xylazine

• analgesia and sedation last at least 60 min, longer than xylazine

• high cost

• potent gastrointestinal analgesic in horses that may last several hours and may negatively impact blood flow

• facilitates standing sedations where there is a need for more time

• high potential for 2nd degree AV block and bradycardia

how is Romifidine used

• primarily used in horses, off label use in dogs and cats

• peak sedation in horses in 15 minutes followed IV

• sedative effects up to 2 hrs

• causes less ataxia, great for standing procedures

what are the indications for a2 agonists

• happy healthy animals

• anxious or aggressive

• CNS pathology

• hypertrophic cardiomyopathy

• heavy reliable sedation

• excruciating pain

• REVERSIBEL

what are the contraindications for a2-agonists

• cardiac disease and pre-existing arrhythmias

• hypovolemic shock

• hypovolemia

• diabetes

• pregnancy in LA

• newborns

• urinary obstruction if not being immeiately addressed

what are the a2-adrenergcic antagonists

• used to arouse patient or in emergency, aka reversal agents

• Yohimbine

• Tolazoline

• Atipamazole

• A>Y>t

• does not reverse relfex bradycardia

how is Yohimbine used

• horses and dogs

• IV, IM, SQ

how is Tolazoline used

• FDA approed for horses only

• well used i farm animals

• usually the total volume is gven half IV and half IM

how is Atipamazole used

• FDA approved for IM injections in dogs only

• IV injections may cause severe hypertension with CNS arousal followed by dysphoria and or convulsions

• IV only in emergency cases

• IV injections of diluted solutions has not beed studied