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Boards: Pharmacology > Premedications, Sedatives, Tranquilizers > Flashcards

Premedications, Sedatives, Tranquilizers Flashcards

1
Q

Role of premeds in ax protocol

A

■ Calming the patient
■ Facilitating IV placement
■ Reduced sympathetic responses to surgical stimulation
■ Reduced anesthetic requirements
■ Promoting smooth induction and recovery

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2
Q

Tranquilizers

A

Induce a feeling of calm (anxiolysis)

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3
Q

Sedatives

A

while reducing anxiety, also reduce the overall response to external stimuli
■ Analgesia can be a feature of some sedatives

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4
Q

Phenothiazine Tranquilizers in Humans

A

used for antipsychotic, antiemetic effects
■ At clinically relevant doses inhibit conditioned avoidance behavior, reduce spontaneous motor activity
■ Extrapyramidal Side-effects in long-term use or overdose
● Tremors, coma/catalepsy, rigidity

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5
Q

MOA Sedative effects of phenothiazine tranquilizers

A

blockade of dopamine receptors (D2 receptors)
■ Pre-and Postsynaptic GPCR blockade leads to decrease in cAMP and adenylate cyclase activity - Gi/o
● Decreased Ca2+ conductance
● Alterations in postsynaptic K+ conductance

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6
Q

Other potential MOAs of phenothiazines

A

○ Blockage of ɑ1-adrenergic, muscarinic, and histamine (H1) receptors may also play a role
■ Ɑ1-adrenergic R antagonism mediates decrease in BP
● Decrease in thermoregulatory control
● Serotonin blockade

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7
Q

ACP Classification

A

Phenothiazine derivative, major tranquilizer, antiemetic

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8
Q

ACP

A

■ Labeled for use in small and large animals
● Not used in human medicine
■ Muscle relaxation is hallmark
■ No analgesic properties

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9
Q

ACP AEs

A

● Decreased systemic vascular resistance
● Decreased blood pressure

a1 R antagonism

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10
Q

ACP MOA

A

○ Produce sedation by inhibiting postsynaptic central dopaminergic receptors (D2)
■ Antagonism of D2 receptor decreases neurotransmission resulting in behavioral changes (calming and sedation

Gi/o

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11
Q

Promazine HCl

A

similar to ACP
○ Rarely used parenterally - popular as granular oral medication mixed with feed for use in horses

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12
Q

Chlorpromazine HCl

A
  • Antiemetic in dogs, cats
  • Contraindicated in horses - high incidence of ataxia and altered mentation
  • No veterinary approved products, used off-label
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13
Q

Hemodynamic Effects a2s

A

● Highly variable depending on the individual
● Block binding of norepinephrine at the ɑ1-adrenergic receptors
■ Peripheral vasodilation
○ Decreases in SV, CO and ABP
■ 20-30% in dogs (0.1mg/kg IV)
■ 20-30% dec in ABP in horses (0.1mg/kg IV)
■ 10-15% dec in CO

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14
Q

Arrhythmogenic Effects of ACP

A

Premedication will increase the dose of Epinephrine required to induce Vent Arrhythmias
○ Likely due to ɑ1 receptor blockade

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15
Q

ACP: effects on pulmonary function

A

● Little effect on function
● Increased TV with decreased RR: maintain adequate minute volume
● Shown to attenuate shunt of V/Q mismatches in horses sedated with a2 agonists +/- dissociative anesthetics (Marntell et al. 2005)
○ Likely DT combo of improving CO, permitting normal HPV

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16
Q

ACP, MAC

A

● Significant dose-dependent impact on inhalant requirements
○ 0.2mg/kg in dogs decreased halothane req by 28% and isoflurane by 48%
○ 0.05mg/kg in ponies decreased halothane MAC by 37%

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17
Q

Hematologic Effects of ACP

A
  1. decreased PCV
  2. Reduction in platelet aggregation

Rarely clinical in abnormal bleeding

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18
Q

Hematologic Effects of ACP: Decreased PCV

A

○ Splenic engorgement, sequestration of RBCs after ɑ1-receptor blockade
■ 20-30% reduction in dogs and horses
■ Effect can last several hours
● Blood samples should be interpreted accordingly

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19
Q

ACP Antiemetic Properties

A

● D2 antagonism (Gi/o) at the chemoreceptor trigger zone in the medulla
● Administration 15 min prior to opioids reduced incidence of vomiting from 18-45%
● Lower esophageal tone, reduced gastric emptying in dogs
● Similar effects in horses

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20
Q

ACP, Assoc Penile Prolapse in Stallions

A

● 2.4% of males lasting 1-4 hours (Driessen et al.)
○ Incidence is low but may be catastrophic in valuable breeding stallions
● Pathological paraphimosis unlikely to occur when total dose does not exceed 10mg/horse

Also avoid in intact bulls

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21
Q

ACP Urinary Effects

A

● Glomerular filtration is maintained in dogs
● Reduces urethral pressure in male cats anesthetized with halothane

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22
Q

ACP, Thermoregulation

A

● Patients cannot thermoregulate appropriately
● Decreased catecholamine binding in the hypothalamus (central control) and altered vasomotor tone in peripheral vessels (heat retention, elimination)

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23
Q

Phototoxicity with Phenothiazine Derivatives

A

■ Demonstrated in laboratory animals (Elisei et al. 2002)
● Caution with excessive sunlight exposure (especially scant/white hair coat)

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24
Q

Antihistamine Effects, ACP

A

○ Antihistaminic (H1) properties
■ Drugs should not be used when skin testing for histamine-caused wheal formation is assessed.

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25
Q

ACP, Assoc with Sz

A

● High-dose chlorpromazine altered EEG activity in epileptic dogs
○ Recent studies: ACP used in dogs with sz disorders does not lead to higher incidence
○ Some studies suggest it may be anticonvulsant (Tobias et al. 2006; McConnell et al. 2007).

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26
Q

Clinical Applications of ACP

A

● Considered a reliable sedative in dogs, cats, horses and cattle
● 0.05mg/kg IV in dogs - mild to moderate sedation in 10 min
○ Sedation scores elevated out to 80 min following 0.02mg/kg IV
● Long duration

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27
Q

ACP and Horses

A

● Associated with DECREASED perianesthetic morbidity and mortality in horses

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28
Q

ACP, Boxers

A

● Some Boxer dogs have an exaggerated response (Brock, 1994)
○ Sedation and hypotension greater than expected
■ Possible syncopal episodes

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29
Q

ACP, Dogs - high resting vagal tone

A

● Dogs with increased vagal tone have been reported to have greater morbidity and mortality
○ Presumed adrenergic blocking effects

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30
Q

MH and ACP

A

● May prevent the occurrence of halothane-induced malignant hypothermia in susceptible pigs (McGrath et al., 1981)

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31
Q

Contraindications for ACP

A

● Contraindicated in patients that are dehydrated, hypovolemic, bleeding, or in shock

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32
Q

ACP Regulatory Information

A

■ Non-scheduled drug
■ No listed withdrawal times for dog, cat, horse
● Should not be used in horses intended for human consumption

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33
Q

Initial PK Parameters ACP

A

■ Large volume of distribution
■ Highly protein bound
■ Time to effect:
● ~10-15 min following IV admin
● ~30 min after IM
■ Long acting
● Elimination half-life 3.1 hr (horse); 7.1 hr (dog)
■ Oral bioavailability (dogs): ~20%

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34
Q

ACP Metabolism

A

Extensive hepatic metabolism

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35
Q

ACP Excretion

A

Urine

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36
Q

ACP Antagonist?

A

None

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37
Q

ACP Formulations

A

■ Yellow aqueous solution at 10 mg/ml and 5, 10, 25- mg tablets
■ Solution should be protected from light

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38
Q

ACP Dosing - cats, dogs

A

0.01-0.05mg/kg IV, IM, SQ

PO 0.5-2mg/kg

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39
Q

ACP Dosing - LA

A

Horses: 0.01-0.05
Pigs: 0.03-0.2
Carrie: 0.01-0.1
Sheep, Goats: 0.05-0.1

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40
Q

ACP Dosing, Rabbits

A

1mg/kg IM or SQ

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41
Q

Azaperone

A

Butyrophenone Derivative
○ Used for sedation in swine and zoo/wildlife medicine
○ Classification: neuroleptic sedative

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42
Q

Azaperone MOA

A

■ Antagonism of D2 (Gi/o) receptors in mesolimbic-mesocortical pathways in the brain
■ Less affinity for ɑ1-adrenergic receptors (Gq)
● Less hypotension than acepromazine

Some D1 antagonism as weak

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43
Q

Indications for Azaperone

A

■ Swine for calming effects
■ Anesthetic adjunct and sedative in wildlife

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44
Q

PD Effects Azaperone: CNS

A

varying levels of sedation
● Isolated reports on paradoxical excitement following IV admin to a horse

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45
Q

PD Effects, Azaperone: CV

A

reduction in SVR from ɑ1-adrenergic receptor blockade (Gq)
● Decreased BP and possibly increased HR
● CV effects last longer than sedation

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46
Q

PD Effects, Azaperone - Resp

A

mild respiratory depression
● Enhanced when combined with other CNS depressants
● Some reports of increased resp rates in rats, horses, and pigs

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47
Q

PD Effects, Azaperone - MSK

A

muscle relaxation similar to ACP

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48
Q

PD Effects, Azaperone - PCV

A

decreased following administration
● Presumed secondary to vasodilation and splenic sequestration

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49
Q

PD Effects, Azaperone - analgesia

A

None

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50
Q

PK Effects, Azaperone

A

■ Onset less than 10 min after IM injection
■ Peak effect seen ~30 min
■ Duration of action ~ 2-4 hrs in pigs
■ Biotransformed in the liver with 13% excretion in feces (pigs)
● Most drug eliminated within 16 hours

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51
Q

Azaperone Regulatory Information

A

■ Nonscheduled drug
■ FARAD has no withdrawal times listed for azaperone in pigs
● Recommended 10-day withholding period prior to slaughter

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52
Q

AEs, Azaperone

A

■ Decreased ability to thermoregulate
■ Some dysphoric effects especially in patients with high levels of anxiety
● Extrapyramidal signs can be seen
■ Doses >1mg/kg IM may cause penile prolapse in boars
■ No antagonists, overdose tx focus on supportive care
■ May inhibit effect of dopamine on renal blood flow

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53
Q

Azaperone formulations

A

■ 40 mg/ml, in a 100 ml multidose bottle
● Discard after 28 days

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54
Q

Azaperone dosing - swine, horses

A

Swine: 0.4-2.2mg/kg IM
Horses: 0.4-0.8 IM - IV admin not recommended (paradoxical excitation)

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55
Q

Deer Azaperone

A

0.3mg/kg IM + xyla 1mg/kg IM

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56
Q

Azaperone - rhinos

A

0.04mg/kg IM

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57
Q

Azaperone - elephants

A

50-120mg per elephant IM

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58
Q

Benzodiazepines

A

○ Classified as Minor Tranquilizers
● Sedative-hypnotics due to ability to cause anxiolysis, sedation and sleep
● Sedation more reliable in neonates, geriatrics and ill patients

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59
Q

Benzo MOA

A

○ Benzodiazepine binding site located on the ɑ1, ɑ2 and 𝛾 subunits of 𝛾- Aminobutyric acid (GABA) receptor in cell membrane
● Synergistic effects with barbiturates, ethanol, etomidate and propofol (action at GABAA receptors) results in significant CNS depression
● Benzos enhance endogenous GABA binding to the receptor

lack of direct agonist activity leads to wide safety margin (for CNS depression)

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60
Q

GABA A R

A

pentameric combination of homologous subunits with a central pore, spanning the cell membrane
■ GABA is the primary inhibitory neurotransmitter in the CNS
● Few receptor sites found outside the CNS, hence the minimal cardiopulmonary effects
■ Binding results in INC Chloride conductance and hyperpolarization of postsynaptic cell membranes

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61
Q

Factors that Affect Patient’s Response to Benzos

A

■ Location of ɑ1 and ɑ2 subunits on the receptor
■ Location of the receptor in the CNS
■ Specific drug affinity
■ Lipid solubility
■ Overall pharmacokinetics

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62
Q

Benzodiazepine Structure

A

Benzene ring linked to 7 membraned diazepine ring

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63
Q

Agonists at the GABA A R/benzo binding site

A

facilitate activity of GABA
● Results in sedation, muscle relaxation and anticonvulsant effects
● Diazepam and Midazolam

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64
Q

Inverse Agonist at the GABA A/benzo R site

A

produce an effect opposite that of Agonists when bound to the receptor site
● Results in seizures and anxiety
● β-carbolines such as methyl-6,7-dimethoxyl-4-ethyl-β-carboline-3-carboxylate (DMCM)

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65
Q

Antagonists at the GABA A/Benzo Site

A

have affinity for the receptor but little or no intrinsic activity
● Block the effects of both agonists and inverse agonists
● No antagonistic effect on other GABA agonists (propofol, ethanol, barbiturates)
● Flumazenil is only commercially available benzodiazepine antagonist in the US

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66
Q

Endogenous Benzos

A

exist but synthetic pathways remain unelucidated

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67
Q

5 main pharmacological principles of benzos

A

● Anxiolysis
● Sedation
● Anticonvulsant actions
● Spinal-cord skeletal muscle relaxation
■ Not adequate for surgical procedures
■ Does not influence required doses of NMB drugs
● Anterograde amnesia (acquiring/encoding NEW information)
■ Amnestic potency greater than sedation

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68
Q

CV Effects - benzos

A

○ Minimal CV depression

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69
Q

Resp effects - benzos

A

○ May decrease respiratory rate, but rarely affect ventilation and oxygenation
● High doses can cause dose-dependent respiratory depression
■ Exaggerated when combined with other depressants or in debilitated patients

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70
Q

Benzos and NMBA

A

○ Effects on nondepolarizing neuromuscular antagonists are unclear
● In vitro cat muscle study should that benzos potentiate neuromuscular blockade (Driessen et al., 1987a)

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71
Q

Metabolism - Benzos

A

● Liver metabolism but pathway (reduction, glucuronidation) differs based on drug and species
● Active metabolites: desmethyldiazepam, oxazepam, temazepam
● Following glucuronide conjugation - excreted in urine
■ Cats perform much slower
● Midazolam and Diazepam first undergo oxidation
■ Reduced metabolism if coadministered with cimetidine, erythromycin, isoniazid, ketoconazole, propranolol and valproic acid
■ Rifampin will INCrease metabolic rate

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72
Q

Benzo Overdose/Toxicity - CS

A

ataxia/disorientation, CNS depression or agitation, respiratory depression, weakness, tremors, vocalization, tachycardia, tachypnea, hypothermia

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73
Q

Tx Benzo Overdose

A

Administration of Flumazenil and supportive care

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74
Q

regulatory information - benzos

A

■ Schedule IV drugs (Diazepam, Midazolam and Lorazepam)
■ None of the benzodiazepines are intended for food producing animals, no established withdrawal times
■ No FDA veterinary approved products

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75
Q

Diazepam

A

standard against which all other benzodiazepines are measured

Used as: ■
● Anticonvulsant
● Mild sedative (small animal species)
● Adjunct to ketamine anesthesia

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76
Q

Diazepam: Water solubility

A

■ Poor water solubility
● Supplied for injection in a solution of organic solvent (propylene glycol and ethanol)
○ Large volumes or CRI admin should be used with caution due to hyperosmotic vehicle
○ Can lead to erratic absorption by any route other than IV
○ Can cause lysis of RBCs (greater in cats)
○ Risk of thrombophlebitis

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77
Q

Diazepam - other features

A

■ pH of 6.6-6.9
■ Viscid - potential pain with IV and IM administration
■ Light sensitive (photodegredation)
● Binds to plastics if exposed to light for long periods

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78
Q

Diazepam Metabolism

A

■ Rapidly absorbed from GI tract (high bioavailability)
■ Metabolized by hepatic microsomal enzymes
● Oxidative pathway
● Repeated oral administration has been associated with severe life-threatening hepatic necrosis in cats (Center et al., 1996)

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79
Q

Diazepam PK - dogs

A

● Elimination half-life following IV administration is approx. 3.2 hours
● Active metabolites appear within 2 hours and eventually exceed diazepam concentrations
○ Nordiazepam (T1/2 3.6 hr)
○ Oxazepam (T1/2 5.7 hr)

High protein binding, high volume of distribution

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80
Q

Breed Differences with Diazepam PK

A

Breed differences:
○ Greyhounds have decreased terminal half-life (1 hr) following 0.5 mg/kg IV
➢ Oxazepam T1/2 6.3 hr

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81
Q

Diazepam PK in cats

A

● High doses (5, 10 and 20 mg/kg) IV show a half-life of 5.5 hr
○ 50% quickly converted to nordiazepam (T1/2 of 21 hr)

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82
Q

Diazepam PK in horses

A

● 0.05-0.4 mg/kg IV half-life 2.5-21.6 hr
○ Nordiazepam and oxazepam not detected in plasma but present in urine suggest rapid excretion
● Terminal half-life is unchanged during 1st 21 days of life**
○ Repeated doses should be given with caution in foals

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83
Q

Diazepam PD

A

■ Clinical doses result in minimal depression of ventilation, CO, and DO2
■ HR, myocardial contractility, CO and ABP are effectively unchanged in dogs after IV admin of 0.5, 1.0 and 2.5 mg/kg
■ Blood gas values were unchanged in horses given 0.05-0.4mg/kg

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84
Q

Diazepam Clinical Application - Ax

A

■ Unreliable sedative but useful for muscle relaxation and anticonvulsant
■ Given with Ketamine to ameliorate central excitatory effects of cyclohexamines
● May not be required with additional premedications (ex. Opioids, ɑ2-adrenergic receptor agonists)
■ Use with propofol to reduce dose required for induction and minimize hemodynamic changes
■ Inhalant MAC is modestly reduced

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85
Q

Diazepam Use as Anticonvulsant

A

■ Use as anticonvulsant:
● Higher doses used (0.5-1.0 mg/kg in dogs and cats, IV or rectally; 0.2mg/kg IV in horses)
● Care with repeat dosing due to active metabolites slow clearance (sedative but not anticonvulsant effects)

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86
Q

Changes on EEG with diazepam

A

■ Caused a reduction in theta, delta, alpha, and beta-frequencies of the EEG of anesthetized dogs without any changes to CV parameters

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87
Q

Diazepam Appetite Stimulation

A

● In cats and goats
● MOA is unknown but may be associated with decreased inhibitions of serotonergic mechanisms
● Anorexia due to GI stasis should NOT be treated with diazepam as it slows gastric emptying

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88
Q

Midazolam PK - water solubility

A

■ Highly water soluble
● At physiologic pH, diazepine ring closes and renders the drug lipid soluble and able to cross the BBB rapidly to causes central effects

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89
Q

Midaz routes of admin

A

■ Rapid absorption IM
● Bioavailability (dogs) greater than 90%
● Peak plasma concentrations in 15 min
■ Can also be absorbed intranasally
■ Rectal administration does not result in clinically useful plasma concentrations and cannot be recommended

■ Intranasal gel formulation
● 70.4% bioavail in dogs

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90
Q

Midazolam Formulation

A

■ Sensitive to light
pH <4.0

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91
Q

Absorption, Metabolism of Midazolam

A

■ High enteral bioavailability
● Affected by pH in GI tract
■ Elimination half-life - dose dependent kinetics
● dogs, admin 0.5mg/kg: 77 min
● Horses, 0.05mg/kg; 1.0 mg/kg: 216 min; 408 min (respectively)
■ Metabolized by hepatic microsomal enzymes

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92
Q

Midazolam PD

A

■ More potent than Diazepam but similar PD
■ CV effects are minor
● HR and CO decrease by 10-20% in dogs (0.25-1.0 mg/kg)
● Blood pressure may decrease as a result of central effects on vasomotor centers
■ Blood gas values are minimally affected
■ Effects on ventilation considered similar to diazepam

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93
Q

Midazolam Clinical Application

A

■ Unpredictable as sedative
● Dogs admin 0.5mg/kg display mild sedation, muscle relaxation or occasional agitation
● Cats show more excitement and agitation with less sedation as doses increase
● Ferrets, small mammals and birds sedate well (mild to moderate sedation)
■ Frequently administered with ketamine or propofol/alfaxalone (similar to diazepam)
■ Reduction in inhalant MAC noted
■ Can be used as anticonvulsant

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94
Q

Lorazepam Clinical Application

A

○ Drug of choice for status epilepticus due to higher binding affinity to the benzodiazepine receptor and elevated brain concentrations
■ Therapeutic levels IV but not rectally
■ Unknown IM bioavailability

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95
Q

Lorazepam

A

○ Supplied in propylene glycol
■ Pain on administration and hemolysis
○ Uncommonly used in vet med as sedative but oral bioavailability makes it suitable as an anxiolytic

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96
Q

Zolazepam

A

○ Water-soluble
○ Available in US only in combination with tiletamine (Telazol)
■ Little clinical information exists on zolazepam alone
○ Metabolized at different rates in different species
■ Recovery time and smoothness may be different

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97
Q

Telazol Formulation

A

○ Supplied with Tiletamine in powder
■ Reconstituted to 5 ml (50 mg zolazepam; 50 mg tiletamine)

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98
Q

Telazol Regulatory

A

○ Schedule III drug (Telazol)
■ Only FDA approved benzodiazepine for use in dogs and cats

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99
Q

Flumazenil

A

○ Only antagonist available in the US
○ Specific and exclusive benzodiazepine competitive antagonist
■ High affinity for the benzodiazepine receptor site of GABAA Receptor
■ No agonist activity
○ Only binds and antagonizes the benzo binding site
■ No antagonism of other sedative-hypnotics (propofol, ethanol)

100
Q

Flumazenil - CNS effects

A

■ Reverses the EEG changes induced by benzos in dogs and horses
■ Use in the absence of benzodiazepines does not cause excitement

101
Q

Flumazenil - CV changes

A

■ No direct effect on left ventricular function or coronary hemodynamics in humans
● In cats, antagonism of fall in blood pressure was observed

102
Q

Flumazenil MSK

A

■ Reverses muscle relaxation

103
Q

Flumazenil Respiratory Effects

A

■ Tidal volume and minute ventilation are restored to normal
● Response curve of the respiratory center may still be depressed

104
Q

Flumazenil effects - ophthalmologic

A

reverses decrease in IOP seen after admin of benzos

105
Q

Metabolism Flumazenil

A

■ Limited information in veterinary species
● Extensive metabolism by the liver in humans
● Metabolites excreted in urine (none appear to be active)

106
Q

PK Flumazenil

A

■ Rapid onset of active
● Rapid uptake, distribution
■ Human half-life 0.7-1.3 hours
● Time to reversal in dogs: 120+/-25 seconds IV; 310+/- 134 seconds IM
● Due to liver metabolism, liver disease can lengthen elimination
■ Multiple routes of admin: IV, IM, sublingual and rectal
■ High first-pass effect - oral route not recommended

107
Q

Flumazenil Dose

A

■ Dogs: 0.01-0.04 mg/kg IV, IM, sublingual, endotracheal or rectal
● Repeated doses may be required
■ Horse: 0.01-0.02 mg/kg IV

108
Q

Regulatory Info - Flumazenil

A

○ Not a schedule drug
○ No withdrawal times have been formulation
○ There are no FDA approved veterinary products

109
Q

a2 agonists

A

● Provide sedation, analgesia, and muscle relaxation
● Can be reliably reversed with selective antagonists

110
Q

Locations of a2 R

A

● ɑ2-Adrenergic receptors are scattered throughout the body
○ Neural tissue
○ Most organs
○ Extra-synaptically in vascular tissue and platelets

Why have variety of undesired effects

111
Q

alpha 2a

A

receptors are located in the cerebral cortex and brainstem
● Primary source of sedation and supraspinal analgesia
● Centrally mediated bradycardia and hypotension

112
Q

alpha 2b

A

receptors are located in the spinal cord and vascular endothelium
● Stimulation results in spinal analgesia, vasoconstriction and peripherally mediated bradycardia

113
Q

alpha 2c

A

receptors are located in the spinal cord
● Modulate spinal analgesia and thermoregulation (+/-)

114
Q

alpha 2d

A

receptors are thought to be similar to ɑ2a in function and distribution

expressed in cattle

115
Q

Are any of the alpha 2 agents subtype specific?

A

No

116
Q

Xylazine specificity for a2 R

A

160:1

117
Q

a2 agonist effect on a1

A

○ Ɑ1-receptor action results in excitation and increased motor activity
○ The less selective for ɑ2-adrenergic receptors a drug is the more likely (in theory) that rigidity and paradoxical excitement might be noted
■ Arterial injection may also result in these effects so should be avoided*
○ Xylazine is the LEAST selective

118
Q

Imidazole R

A

Some a2 bind to/activate imidazole R

detomidine, romifidine, medetomine, dexmedetome (tolazoline)

NOT XYLAZINE

119
Q

a2:a1 specificity detomidine

A

260:1

120
Q

a2:a1 specificity romifidine

A

340:1

121
Q

a2:a1 specificity dexmedetomidine

A

1620:1

122
Q

a2:a1 medetomidine

A

1620:1

123
Q

Which GPCR do a2 agonists work at?

A

Gi/o

124
Q

MOA a2 R

A

G-coupled proteins
○ When stimulated they inhibit adenyl cyclase activity -> decreased cAMP in the cell
○ Located both pre-and postsynaptically in the CNS

Gi/o

125
Q

Which actions of a2s do not require GPCR?

A

Inhibition of platelet aggregation

126
Q

Main Effects of a2s

A

CNS, binding leads to sedation, analgesia, muscle relaxation, and centrally mediated effects on heart rate and afterload (decreased sympathetic nervous system activity)
● Peripherally, increased SVR (afterload) is noted

Dose dependent effects
○ Ceiling effect in some species (horses) - higher doses do not result in recumbency but increase duration of effect

127
Q

CNS Effects, a2s

A

● Occupancy of ɑ2-adrenergic receptors by agonist redacted NE release, may prevent occupancy of receptors
● In brainstem, binding at locus coeruleus, rostroventral lateral medulla (primary areas for sympathetic outflow from the CNS) cause sedation DT slowing of discharge frequency of tracts into the cortex.

128
Q

Consequences of intraarterial xylazine

A

● Rigidity, seizures, and/or excitement have been noted following accidental arterial injection of xylazine in horses

129
Q

Challenge of a2 sedation if already unregulated

A

● Paradoxical excitement can result when the animal is fearful, excited, painful or otherwise stressed
○ High circulating catecholamine levels that medication can not overcome

130
Q

Analgesic Effect of a2s

A

● Binding at various points in nociceptive pathway –> analgesic effect
○ R isolated in dorsal horn of spinal cord, SC
○ Afferent input into dorsal horn from nociceptors in periphery continues but is MODULATED, DAMPENED by decrease in NE release (presynaptic inhibition) and occupancy of those receptors (postsynaptic inhibition), as well as decreased substance P release
○ Descending modulation of nociceptive input via locus ceruleus

131
Q

Binding of a2s at nonadrenergic imidazoline R

A

○ Imadazoline-1 are associated with central blood pressure control
■ May contribute to CV effects
○ Imadazoline-2 binding may contribute to analgesic effects

Everyone but xylazine binds at imidazole R

132
Q

a2 Effects on ICP/CBF

A

● ICP (dogs): unaffected with use of medetomidine
○ Modest increase in CPP (CPP = MAP - ICP)
● Other studies demonstrated a decrease in CBF with dexmedetomidine in dogs and rabbits
○ Decrease in ICP, decrease in DO2
○ Care must be taken when considering ɑ2-adrenergic receptor agonists in patients with altered intracranial hemodynamics

133
Q

a2 Resp Effects - mm

A

often appear ‘muddy’ or pale blue/gray
○ Peripheral VC slows blood flow in periphery –> prolonged capillary transit time
■ Allows for a greater amount of deoxygenated hemoglobin present at end of capillary, > 5mg/dL threshold of observation of cyanosis

134
Q

Resp Effects, a2s - blood gas parameters

A

parameters generally maintained when using ɑ2-adrenergic receptor agonists alone
○ In conjunction with other sedatives, opioids, or anesthetics, values can be variable
■ Often indicative of Respiratory Depression

135
Q

Resp System Effects, a2s - ventilatory drive

A

administration to patients with borderline respiratory function/CNS depression
○ Sheep are prone to hypoxemia with ɑ2-adrenergic receptor agonist administration*
■ Activation of pulmonary intravascular macrophages produce extensive damage to the capillary endothelium and alveolar type 1 cells
■ Pulmonary edema and secondary to pulmonary parenchymal damage
■ Treatment with antagonists will improve clinical signs but not eliminate or reverse damage

136
Q

CV Effects, a2 agonists - species variability

A

distribution of ɑ1- and ɑ2- adrenergic R in periphery –> wide variability in SVR, BP, HR and rhythm, and blood flow

137
Q

Bradycardia assoc with a2s

A

■ Initial DT Baroreceptor (vagal)- mediated reflex due to high SVR
■ As SVR returns to normal, persistent bradycardia = decreased Central Sympathetic outflow
■ Antimuscarinic drugs are effective in increasing the HR early
● Severe hypertension can result
● May be less effective in later stages
○ Ephedrine may be more effective

138
Q

CV a2 - CO

A

usually decreased
○ Secondary to the reduction in HR in attempt to maintain physiological BP in face of increased SVR
○ Decrease in tissue blood flow is result
■ Not uniform: Skeletal muscle, adipose and other non-vital tissues reduced to greatest extent
○ Use of antimuscarinics to increase HR will not proportionally increase CO
■ Lead to hypertension, increased myocardial O2 consumption and arrhythmias with only marginal increase in CO.

139
Q

a2 biphasic CV response

A

○ First phase: activation of central ɑ2-adrenergic R reduce sympathetic outflow (decreased NE)
■ Negative inotropic, chronotropic, dromotropic effects on heart
● 1st, 2nd degree AV block
■ Peripheral VC - increased ABP –> BRR bradycardia

○ Second phase: decreased SVR but sustained low HR due to low NE
■ Hypotension and bradycardia

140
Q

Higher doses assoc with a2s

A

produce more sedation, analgesia, longer DOA but do not necessarily worsen cardiovascular response

141
Q

a2 arrhythmias

A

associated with ɑ2-agonists, anticholinergics are likely DT increased myocardial workload (increased HR and afterload), oxygen consumption
○ Higher incidence with xylazine due to low ɑ2:ɑ1 ratio

142
Q

Renal Effects of a2s

A

● Diuresis by multiple mechanisms
○ Reduce production or release of ADH from pituitary
○ Inhibit actions of ADH on collecting tubules, enhance excretion of Na
○ Decreased Renin levels
● Decrease micturition pressure, bladder capacity, micturition volume and residual volume

143
Q

GI effects, a2s

A

● Motility in decreased
○ Large bowel more sensitive in dogs and horses
● Gastric emptying time delayed
● Used as emetics

144
Q

Emetic Use of a2s

A

○ Xylazine caused vomiting in up to 90% of cats and 30% of dogs
○ Theory: alpha2 agonists interact with the chemoreceptor zone located in area postrema to stimulate dopamine, NE
○ Can be antagonized by atipamezole

145
Q

a2 thermoregulation

A

● Patients may be unable to control body temperature
○ Combination of CNS depression, reduction in motor activity (shivering) and loss of vasomotor control

146
Q

Regulatory Information - xylazine

A

push for xylazine to become controlled, already is controlled in some states eg Florida

○ Withdrawal times - Cattle 24 hour withholding time (milk) and 4 days for slaughter
■ Cervidae: not approved for use during hunting seasons
○ Veterinary approved products:
■ Approved for dog, cat, horse and deer
■ Rompun (20 and 100mg/ml), AnaSed (20 or 100mg/ml), Cervizine (300 mg/ml)

147
Q

Regulatory Information - detomidine

A

○ Withdrawal times - not approved for use in horses intended for human consumption
■ Extralabel use in cattle: 3 days meat, 72 hours milk
○ Veterinary approved products:
■ Approved for horses
■ Dormosedan 10 mg/ml injectable; Transmucosal gel 7.6 mg/ml

148
Q

Regulatory Information - romifidine

A

○ No published withdrawal times: Not approved in horses for human consumption
○ Veterinary approved products:
■ Sedivet 10 mg/ml

149
Q

Regulatory Information - medetomidine

A

○ Not approved for use in food animals
○ Veterinary approved products:
■ Approved for use in dog
■ Domitor 1 mg/ml

150
Q

Regulatory Information - dexmedetomidine

A

○ Not approved for use in food animals
○ Veterinary approved products:
■ Approved for use in dogs and cats
■ Dexdomitor 0.1 and 0.5 mg/ml; Precedex (human) 4 or 100 mcg/ml

151
Q

Xylazine PK

A
  • Elimination Half-life:
  • Dog: 30 min (1.4mg/kg)
  • Cattle: 30 min (0.2 mg/kg)
  • Horse: 50 min (0.6 mg/kg)

After IM admin, plasma levels peaked at 15 min; similar T1/2 after IV

152
Q

Xylazine PD

A

Rapid onset if sedation and analgesia (horse):
5-10 min

Duration: 30-60 min

Poor sedation with SQ admin (reduced absorption with local VC)

153
Q

Xylazine CV

A

Reflex bradycardia (persistent)
Central effects outweigh peripheral

Initial hypertension is brief - subsequent hypotension

CO reduced up to 50% (dogs, horses)
Linked to dec. HR

BP decreased 20-30%

SV is preserved with dec HR

Bradyarrhythmias treated with anticholinergics when appropriate

154
Q

Xylazine Resp Effects

A

Respiratory rate decreases, TV increases maintaining consistent minute ventilation

PaO2, PaCO2, and pH are typically unchanged

High doses can lead to decreased minute ventilation, physiologic dead space, and decrease delivery of O2 to tissues

155
Q

Xylazine Resp Effects - horses

A

Horses anesthetized with halothane showed dec PaO2 after admin of 0.5-1.0 mg/kg: likely due to V/Q mismatch due to altered CO and pulmonary vascular tone

156
Q

Xylazine Resp Effects - sheep

A

PaO2 dec in Sheep due to pulmonary inflammation and edema (intravascular macrophages)

157
Q

Xylazine GI effects

A

Can cause Salivation, emesis and reflux (cent
ral effect); pretreatment with yohimbine limits

GI motility, including rumen contractions reduced; reversible with antagonist administration

Cecal and colonic motility decreases in horses

Reduced intestinal blood flow

158
Q

Xylazine GU Effects

A

Increased urine production

Decreased SG and osmolality

Normal micturition reflexes are maintained

Dec. uterine blood flow and tone (decreased O2 delivery); may impact fetus

Cattle, sheep: oxytocin like effect on uterus with xyla, not detom
* Controversial in pregnant cattle, esp early/late gestation –> premature birth, miscarriages

159
Q

Clinical Application of Xylazine

A

Dogs/Cats: short-term sedation and analgesia

Premedication for induction

Neuroleptanalgesia when combined with opioids

Combined with ketamine IV for short surgical procedures

Standing sedation/restraint in horses

‘Triple Drip’ or ‘GKX’ TIVA

Cattle require much lower doses (1/10 of equine dose)

160
Q

LA a2 sensitivity

A

Goats > cattle > sheep

Cattle > llamas > alpacas > horses

161
Q

Species of cattle sensitivity to xylazine

A

Branham’s (anecdotally) > Herefords > Holsteins

162
Q

Detomidine PK

A

Half-life Horses: 26 min (40mcg/kg IV);
Median clearance of 37 min

IM dose (horse) mean elimination half-life of 53 min

Increased half-life and Volume of distribution with exercise

Available as sublingual gel (some countries): mean bioavailability of 22% compared to 38.2% IM for same dose

163
Q

Use of detomidine gel vaginally in horses, alpacas

A

achieved sedation

164
Q

Detomidine PD

A

Rapid sedation, 5 min onset with IV dosing

Duration: 1 hour

Analgesia, sedation with 20 mcg/kg equipotent to 1.0 mg/kg xylazine but longer duration

165
Q

Detomidine CV Effects

A

Dose-dependent changes that dec with clearance

Impaired systolic function with increases in left ventricular internal diameter

CO decreased up to 50%

Sig increase in MAP and SVR at 10-40 mcg/kg IV

CRI dosing similar CV changes that persist with the duration of the CRI
Decreased HR within 2 min

Sinoatrial block or 2nd-degree block common

166
Q

Detomidine Resp Effects

A

When admin alone: little impact on RR.

Slight increase in PaCO2 with negligible changes in PaO2

O2 delivery decreased as CO decreases

Pulmonary shunt fraction relatively unchanged with modest increases in V/Q

167
Q

Detomidine Effects: GI

A

Potent analgesia for GI pain in horses

Myoelectric activity, motility reduced

Negative impact on GI blood flow

168
Q

Detomidine UG Effects

A

Increased flow

Increased intrauterine pressure (sim to xylazine)

Caution in pregnant mares

Cattle, sheep: oxytocin like effect on uterus with xyla, not detom
* Controversial in pregnant cattle, esp early/late gestation–> premature birth, miscarriages

169
Q

Romifidine PK

A

following IV administration of 80 mcg/kg fit a two-compartment model

Elimination half-life was estimated at 138 min; clearance from plasma was 32 mL/min/kg

170
Q

Romifidine PD

A

Profound sedation in horses at approx. 15 min following IV administration.

Sedative effects noted up to 2 hours (longer lasting than xylazine and detomidine)

IV and SQ (beagles; 20-120 mcg/kg) showed quick uptake and sedation effects

Less ataxia noted than other ɑ2-agonists

171
Q

CV Effects Romifidine

A

Similar to other ɑ2-agonists

Bradycardia noted after 80 mcg/kg dose in horses

Second-degree AV block noted

MAP increased 15% at 5 min, declining to below baseline by 60 min

Significant decrease in Cardiac Index

Similar dose-dependent effects in dogs:

172
Q

Romifidine GU effects

A

Similar to other ɑ2-agonists with respect to intrauterine pressure

Increased urine production

Increased blood glucose concentrations

173
Q

Romifidine Clinical Applications

A

Labeled for use in horses
*not intended for horses meant for human consumption

Off label use in dogs/cats reported

174
Q

Dexmedetomidine vs Medetomidine

A

Dexmedetomidine is dextrorotatory isomer of medetomidine

175
Q

Dexmed/medetomidine PK

A

Medetomidine at 40 mcg/kg IV, dexmedetomidine at 20 mcg/kg IV produced peak sedation at 10-20 min

Terminal half-lifes of 0.96, 0.78, 0.66 hr reported in dogs

Cats: terminal half-life after 10 mcg/kg IV was 198 min

176
Q

Dexmed, medetomidine OTM admin

A

achieves similar sedation to IM with longer time to peak plasma concentrations

177
Q

Levomedetomidine

A

Admin of levomedetomidine produce no sedation or analgesia with faster clearance

178
Q

Dexmed/medetomidine PD

A

Peak sedation (20-40 mcg/kg IV) was achieved at 10 min; peak analgesia at 20 min

Medetom, Dexmed: similar impacts on ax requirements: Dose-dependent decreases in MAC

Analgesia corresponds with sedation (onset, peak and duration)

179
Q

CV Effects of medetomidine, dexmed

A

Similar to other ɑ2-agonists

Decreases in HR, CO (66% in in iso anesth dogs)

Increased SVR

Initial increase in ABP followed by hypotension

Changes in left ventricular work and pulmonary vascular resistance;
Coronary vasoconstriction balance with oxygen demand

Contractility not significantly affected in dogs

CO decreased in horses but returned to baseline after 30 min

Blood flow directed to vital organs (heart, kidneys, liver, brain)

Global oxygen requirements reduced

180
Q

GU Effects dexmed/medetomidine

A

Plasma glucose concentrations increased

Medetomidine at 20 (decreased), 40, 60 (increased) mcg/kg IV in pregnant dogs affected uterine motor activity

Urine production increased

181
Q

Clinical Applications of dexmed/medetomidine

A

Medetomidine (without vatinoxan - see Zenalpha) only available for formulations for wildlife capture/restraint

Dexmedetomidine primarily used in dogs and dogs, horses (CRI)

Frequently used in conjunction with opioids

Premedication for anesthesia

Used as sole agent for imaging or with local anesthetic for minor surgical procedures

Reversible (atipamezole

182
Q

Zenalpha (R)

A

(Medetomidine (0.5mg/mL) and Vatinoxan Hydrochloride (10mg/mL)): Source: ZenalphaPackageInsert.pdf
● For IM injection in DOGS only, sedative and analgesic
● Medetomidine: racemic mixture containing the active enantiomer, dexmedetomidine
● Vatinoxan: peripherally selective alpha2-adrenoreceptor antagonist
○ Partially counteracts CV depressive effects of dexmedetomidine at peripheral alpha2-adrenoreceptors, preserves centrally mediated sedative, analgesic effects

183
Q

Indications for Zenalpha

A

Use as a sedative and analgesic in dogs to facilitate clinical examination, clinical procedures and minor surgical procedures
○ Not intended for use in cats

184
Q

Zenalpha Effects

A

● Time to effect: 5-15 min
● Duration of effect: 38 min (avg)
● Reversal with IM atipamezole at the dose to reverse IM medetomidine
○ Reversal of sedation occurs at 5-10 min

185
Q

What three a2 R antagonists are currently in use?

A

○ Yohimbine and Tolazoline
■ Used in LA due to Xylazine use
○ Atipamezole
■ Has replaced others in small animal/exotic practice due to increase in highly-specific agonists (medetomidine/dexmedetomidine)

186
Q

Classification of a2 R antagonists

A

receptor ligands that are competitive antagonists at ɑ2-receptors
○ Varying degrees of antagonism at the ɑ1-receptor sites

187
Q

a2 reversal

A

● Should not be done without consideration of the potential of patient excitation, loss of analgesia and adverse CV effects (tachycardia and hypotension)

188
Q

a2 reversal - IV ROA

A

○ IV administration results in rapid vasodilation if patient still has high SVR
■ If vasodilation occurs without increase in HR and CO, severe hypotension results (transient but possibly not tolerated)
○ IV administration for ER purpose only

Partial IV dose if no effect with IV - may rapidly result in recovery, wait until increase HR to minimize hypotension

189
Q

Atipamezole

A

○ Highly specific ɑ2-receptor antagonist
■ Does not bind 𝛽-adrenergic, 5-HT, histaminergic, muscarinic or dopaminergic receptors - decreases side effects
○ Approved for IM use in dogs
■ Off label in cats, horses an exotics
○ Label dose in mcg/m2 but most practitioners dose at equal volume to medetomidine/dexmedetomidine (50mcg/kg)

190
Q

Atipamezole Regulatory Information

A

■ Nonscheduled
■ Not approved for use in food producing animals
■ Antisedan 5mg/ml

191
Q

Yohimbine

A

○ Indole alkaloid derived from bark of Pausinystalia yohimbe tree or the root of the Rauwolfia serpentina plant
○ Approved for dogs and cervidae
■ Used off label in cats, horse, cattle and exotics
○ Often administered 25% IV and rest IM to reduce side effects

192
Q

Yohimbine MOA

A

○ Non-selective ɑ2-receptor antagonist
■ High doses activate ɑ1-adrenoreceptos, dopamine and serotonin receptors; inhibit monoamine oxidase production

193
Q

AE of Yohimbine

A

Non-selective a2 antagonist - variety of R effects

○ Potential to cause seizures at high dose due to GABAergic and NMDA-mediated pathways

194
Q

Regulatory Information for Yohimbine

A

■ Nonscheduled
■ Not approved for use in food producing animals
● Should not be used 30 days prior to hunting season
■ Yobine 2mg/ml; Antagonil 5 mg/ml

195
Q

Tolazoline MOA

A

○ Synthetic imidazoline derivative

○ Non-selective ɑ-adrenergic receptor antagonist
■ Has histaminergic and cholinergic effects
■ Direct effects on vascular endothelium causing decreased SVR, vasodilation and increased venous capacitance

196
Q

Uses of Tolazoline

A

○ Reverses detomidine in the horse better than atipamezole
○ Can cause GI hypermotility, diarrhea, colic
○ Has been used to treat pulmonary hypertension in newborns
■ Reduce pulmonary vascular resistance and counteract the hypoxic pulmonary vasoconstriction reflex

197
Q

Species-Specific Effects of Tolazoline

A

○ Reverses detomidine in the horse better than atipamezole
○ Llamas appear to be more sensitive to side effects - recommended to give lower doses (2mg/kg IM) or avoid
○ Appears to be ineffective in Bears - not recommended

198
Q

Regulatory Effects of Tolazoline

A

○ Regulatory:
■ Approved for use in horses
● Off label in cattle, camelids and exotics
■ Not approved for use in horses for human consumption

199
Q

Guanifenesin (GG, glyceryl)

A

Derived from the Guaiacum genus of trees

Centrally acting skeletal muscle relaxant with sedative properties

Primarily co-administered IV with injectable anesthetic agents for induction, maintenance of GA in horses and ruminants

Wide therapeutic origin (safety margin?)

200
Q

GG MOA

A

moderately unknown

Evidence suggests action in BS, subcortical regions, spinal cord (polysynaptic reflex inhibition) affected by interneuron
depression –> sedation and muscle relaxation

201
Q

GG CV Effects

A
  • No change in HR, CO, CVP, or resp rate

*~20% decrease in MAP

*Hypotension, respiratory depression, and apneustic breathing pattern (~70-80% > than that required to induce recumbency in horses)

202
Q

GG Resp Effects

A

*Minute ventilation = maintained
-Increased respiratory rate
-Decreased tidal volume
*Minimal changes in PaO2

203
Q

Effect of GG Overdose in horses

A

Period of muscle spasm and mydriasis

Loss of palpebral reflex then death after respiratory/cardiac arrest

204
Q

Metabolism of GG

A

Hepatic metabolism: Glucuronidation, Renal excretion

Sex differentiation in elimination in ponies
–More rapid elimination in females

205
Q

Formulations of GG

A

–0.9% saline or 5% dextrose solution
–Concentration dependent risk of hemolysis
**Unrelated to speed of injection
**Hemolysis in horse with [ ] > 15% solution
**Hemolysis in cattle with [ ] > 5%

Intravascular thrombus formation is also related with concentration > 7%
(Increased risk of thrombus)

206
Q

GG Storage

A

Drug is prone to precipitate out of solution when stored below 22 degrees C

Reversed with heating (immersion in a warm water)

207
Q

AE of GG

A
  1. Risk of IV thrombus at concentrations >7%
  2. Hemolysis in horses >15%, cattle >5%
  3. Perivascular injection - tissue necrosis
  4. Urticaria
208
Q

Trazodone MOA

A
  • Serotonin reuptake inhibitor, serotonin R antagonist
    o Atypical antidepressant
    o Used to facilitate low stress handling, –> signs of anxiety in hospitalized dogs
209
Q

Other Effects of Trazodone

A

No cholinergic effects
moderate antihistaminergic activity
antagonist of post-synaptic alpha1 adrenergic R

210
Q

PK in dogs - trazodone

A

o Dogs: bioavail after PO admin, variation in time to maximal plasma concentration
o PK data not available in cats

211
Q

Metabolism of trazodone - people

A
  • Humans: cytochrome enzyme CYP2D6 involved in metabolism of trazodone
    o Caution when Rxing with SSRIs that inhibit CYP2D6
    o When given over weeks, produces anxiolytic properties similar to diazepam
    o ER formula now available = Oleptro, has not been evaluated in animals
212
Q

What are other butyrophenoes?

A

Droperidol - not used anymore DT behavior effects
Haloperidol
Azaperone

213
Q

Benzo - protein binding

A

Highly protein bound so hypoalbuminemia will change unbound fraction, enhance clinical effects

*Both diazepam, Midazolam >95-97% (primarily to albumin)

214
Q

a1 benzo subunit

A
  • Likely site of sedation, most abundance - 60% in brain
215
Q

a2 benzo subunit

A

-anxiolytic effects
-more restricted expression vs a1, principally in hippocampus, amygdala

216
Q

Positive vs negative allosteric modulators at the GABA A R

A

Positive - benzodiazepines
Negative - flumazenil

217
Q

Hoffman et al VAA 2018

A

premed of dogs with PO trazodone at 8mg/kg 2h prior to anesthesia induction had significant isoflurane MAC-sparing effect (decrease 17±12%)

218
Q

Kim et al JAVMA 2022

A

trazodone 9-12mg/kg vs placebo 90’ prior to veterinary clinic, trazodone dogs had lower dog stress scores (assessed by owners for PE, video analysis).

No meaningful differences in other behavioral or physiologic outcomes, including serum cortisol concentrations

single dose prior to transport reduced signs of stress prior to veterinary visits in dogs

219
Q

Gabapentin, pregabalin

A
  • Structural analog of GABA; anticonvulsant used for tx of neuropathic and chronic pain, refractory sz, sedative effects , does not interact with GABA R to produce analgesia
220
Q

MOA Gabapentin (LJ)

A

Do not appear to interact with GABA, NMDA or dopamine receptors

Inhibition of N-type voltage-dependent neuronal calcium channels

Inhibition –> decreased Ca2+ influx into neurons, in turn decrease release of range of excitatory and inhibitory NTs

altering channel trafficking and stimulating movement of channels away from the neuronal cell membranes

221
Q

Johnson et al proposed MOA

A

binding to N-type Ca channels in DRG, results in modulation of GABA R and may decrease release of excitatory NTs (eg substance P, glutamate) thus decrease central sensitization, may also act as NMDA R antag (decrease neuropathic pain including allodynia, hyperalgesia)

222
Q

PK in dogs of gabapentin

A

short HL, frequent dosing, 10-20mg/kg PO BID-TID

223
Q

Canine Clinical Uses

A

o Used to successfully improve CS in case series with CKCS with Chiari malformation, syringomyelia
o Prospective clinical trial: gabapentin vs gelatin capsule placebo in dogs undergoing thoracic limb amp did not identify advantage of gabapentin in management of postop pain
o Prospective clinical trial: gabapentin (10mg/kg PO BID) as adjunctive analgesic agent resulting in non-significant reduction in pain scores compared to placebo for hemilaminectomy
* Dose of gabapentin should be tailored to individual animal’s response, as is performed in humans, vs adhering to rigid dosing
o 3 cases of neuropathic pain: successful management with gabapentin or amitriptyline
o Maximal plasma concentrations achieved within 2h

224
Q

Pregabalin vs gabapentin

A

o Pregabalin: better bioavail, longer duration of action – BID dosing vs TID

225
Q

Johnson et al AJVR 2019

A

6 healthy dogs received 20mg/kg gabapentin PO 2’ prior to ax

Mean +/- SD MAC isoflurane 0.91+/- 0.26% vs with gabapentin 0.71 +/- 0.26%, mean reduction in MAC of isoflurane = 20 +/- 14% without any effect on hemodynamic variables/vital parameters

226
Q

PK Data in Cats of Gabapentin

A

o Increase in thermal threshold did not occur when admin orally at 5, 10 or 30mg/kg, doses resulted in plasma concentrations greater than those assoc with analgesia in humans
* Sedation not assoc with any dose
* Not able to show MAC-sparing effect of gabapentin on isoflurane despite achieving plasma drug concentrations almost double those reported to be effective in people

227
Q

PK Data on Gabapentin in Horses

A

o PO bioavailability: 16% horses (no metabolites in equine plasma) vs 80% in dogs
o Frequency of drinking increased, standing at rest decreased, sedation scored as mild to moderate in all horses for 1h following IV injection at 20mg/kg
o No metabolites found in plasma  majority of drug excreted unchanged in urine
o SEDATION
o Maximal plasma concentrations achieved within 2h
o Suggested dosing: 4mg/kg PO Q8hr

228
Q

Young et al VAA 2020

A

gabapentin did not improve subjective or objective measurements of lameness in horses with chronic thoracic limb MSK pain

229
Q

PK, PD data in cows

A

o Gabapentin vs G+meloxicam vs M alone: did not result in significant differences in groups undergoing dehorning or compared with placebo in plasma cortisol concentrations, eye temp
* Mechanical nociceptive threshold equivocal
* Average daily weight gain greater in G+M
* Plasma levels > threshold assoc with analgesia in people
* Peak plasma concentrations not appreciated until 7h post administration

230
Q

Gabapentin absorption in cows

A

o Adult cattle: 8 hr to achieve maximal plasma concentrations when admin orally, concentrations in milk took over 3d to drop below detection levels

231
Q

Metabolism, excretion in dogs

A
  • Dogs: ~30-35% of administered dose undergoes hepatic metabolism, unchanged drug excreted by kidney
232
Q

Species sedated with gabapentin vs no sedation?

A
  • Sedation seen in dogs, horses; NOT cats, cattle
233
Q

Regulatory Information for pregabalin, gabapentin

A

o Pregabalin
* Schedule V
*
o Gabapentin
* Not controlled
* Off label use

234
Q

Dholakia et al 2020 - PK Midaz in cats

A

-0.3mg/kg IV: 5 compartment model, high inter individual variability in plasma of 1-hydroxymidazolam concentrations - low clearance, persisteted in plasma longer than parent drug

-Elimination HL ~80min, clearance rate ~12ml/kg

Midaz did not result in clinically significant changes in physiologic variables

235
Q

Effect of 1-hydroxymidazolam

A

People: active metabolite, high plasma concentrations assoc with sedation

Animals: unknown

236
Q

Hollis et al 2020 (VAA) - horses, standing, MED vs DET

A

MED at 5mcg/kg followed by 2.5mcg/kg/hr produced less sedation than DET at 10mcg/kg IV followed by 6mcg/kg/hr

237
Q

Diez Bernal et al 2020 (VAA) - horses, PK/PD modeling romifidine

A

Two-compartment model best described

mean plasma concentration weakly correlated with nociceptive thresholds. Sedative effects significant at 0.08mg/kg+0.03mg/kg/hr until 160’ but variable, not correlated to plasma concentration and weakly correlated to nociceptive thresholds.

Romifidine elicited marked antinociceptive effect. Romifidine-induced antinociception appeared with delayed onset, lasted longer than sedation after dc admin.

238
Q

Midaz vs diapezam

A

o 3x more potent, 2x more affinity for BZD site, >sedative effect

239
Q

Metabolism, excretion of Midazolam

A

o Principle metabolite (1-hydroxymidazolam) has approx. half the activity
o Conjugated then excreted by kidneys
o Cimetidine, erythromycin, ca channel blockers, antifungal inhibit cytochrome p450 and produce  CNS depression

240
Q

Neuro effects - midaz

A

o Neuro: decreased CMRO2 , CBF – acceptable for ICP concerns

241
Q

Resp effect - midaz

A

o Resp: dose dependent decreases in hypoxic drive; in healthy volunteers no decrease except with synergisms of opioid

242
Q

Midaz: placenta

A

o Crosses the placenta but less than for other benzos

243
Q

What part of the DH are the a2b, c, d R located?

A

substantia gelatinosa

244
Q

a2A Receptors

A

cerebral cortex, brainstem, platelets
 Major sedative effect
 Supraspinal analgesia
 Centrally mediated bradycardia and hypotension
 Gi  low AC  low cAMP  low Ca conductance, alter postsynaptic K conductance  NE from presynaptic terminal –> decreased transmission (i.e. sedation)
 Brainstem (locus coeruleus, rostroventral lateral medulla) – low discharge frequency of tracts into cortex

245
Q

a2B receptors

A

– spinal cord – dorsal root ganglia, vascular endothelium
 Spinal analgesia
 Vasoconstriction and peripherally mediated reflex bradycardia
 CV biphasic response
* Phase 1: Peripheral
o α2B and α1 activation in vascular endothelium = vasoconstriction
o Baroreceptor mediated reflex bradycardia
* Phase 2: Central
o Central VD; HR remains same or bradycardia persists
o Central α2A R activation – low symp outflow (low NE),  parasympathetic tone
o Negative inotropic, chronotropic, dromotropic
o Peripheral vasodilation
* Due to differences in central and peripheral response

Boards: Pharmacology (9 decks)

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