24. Anesthesia and analgesia part 1

What are the requirements for an adequate veterinary Care program? (Hint: there are a total of 8 requirements see chapter 4 of the Guide)

Veterinary care program consists of mgmt of:

1.Animal procurement and transportation

2.preventive medicine (including quarantine, animal biosecurity, and surveillance)

3.clinical dz, disability, or related health issues, and assessment of animal well-being)

4.Protocol associated dz, disability and other sequelae

5.Surgery and perioperative care

6.Pain and distress

7.Anesthesia and analgesia

8.Euthanasia

How do bird react to opiods?

the effects of opioids are very unpredictable in birds

Recommended acclimation period

24 to 72 hr

According to the International Association of the Study of Pain (IASP), what is the definition of pain? What is the definition of chronic pain?

an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage"

3 months of pain → chronic

What is the 1° excitatory neurotransmitter released by nociceptive terminals that is released in response to brief or low intensity noxious stimuli?

Glutamate

What are the different nerve fiber for conduction? conduction speed?

Aβ → fast conduction; touch and proprioception

Aδ → Intermediate conduction; thermal and mechanical; sharp, rapid pain

C → slow conduction; mechanical, thermal and chemical; dull, aching pain

What are the Inhibitory neurotransmitters?

GABA (GABAA and GABAB) & Glycine

Serotonin and norepinephrine

What are the 5 phases of Nociceptive pain occurrence?

1) Transduction, 2) Conduction, 3) Transmission, 4) Modulation, 5) Perception.

What is Analgesiometry?

quantitative sensory testing such as

Thermal assays

- Mechanical assays: dynamic (triggered by brushing), punctate (triggered by touch) and static (triggered by pressure)

- Chemical assays

What does Cold plate test do?

Determines behavioral responses to both noxious and innocuous cold temperatures in both mice and rats

Response time recorded (time to display nociceptive behavior- shaking, jumping, or licking)

Number of flinches over set period of time recorded

What does Acetone Evaporation Test do?

Measures aversive behaviors triggered by evaporative cooling and is typically considered as a measure of cold allodynia

What does Cold plantar assay do?

Animal is placed on a glass floor and a cold stimulus is delivered by applying a cut off syringe filled with dry ice or wet ice to the glass under the paws

What does Temperature preference assays do?

Rodents are allowed to freely move between a reference plate (neutral temperature) and test plate. The time spent on the test plate relative to the reference plate is measured over a set period of time.

(A) Two-temperature choice assay

(B) Continuous temperature gradient assay

What is used in Tail-Flick Test or Tail Withdrawal Test as heat source?

Tail-Flick Test (radiant heat)

Tail-Withdrawal Test (hot water, 46-52 C)

What does Hot-plate Test do?

measure latency to hindpaw licking and/or shaking, or jumping, then animal removed from hot plate

thermal sensitivity unconfounded by stress-induced analgesia associated with restraint

sensitive to repeated measurements, likely via learning

What does Radiant Heat Paw-Withdrawal (Hargreaves') Test do?

light beam focused onto hindpaw; when animal lifts/shakes/licks hindpaw, stimulus terminates

allows independent testing on both sides of body

What does Randall-Selitto test do?

withdrawal from pressure applied to paw; common in rat; not practical in mouse due to necessary restraint

What does Tail-Clip Test do?

constant suprathreshold pressure stimulus is applied to tail; metal artery or binder clip applied to tail at base - latency to lick, bite, grab, or bring nose to w/in 1 cm of clip is recorded; extremely sensitive to repeated testing

What does Von Frey Filament Test do?

nylon fibers vary in diameter & are calibrated to exert a maximal vertical force at point of bending; positioned in plexiglas cubicle on wire mesh floor, fiber applied to plantar surface of hindpaw; rodents display significant variability (even within strain)

What does Formalin Test do?

SQ injection of 1-5% formalin in dorsal or plantar surface of hindpaw → licking & biting in hind paw, short lasting

What does Abdominal Constriction Test do?

experimental model of visceral pain; acetic acid most commonly used irritant - injected IP; animals scored for presence/absence of "writhing" for 30-40 mins post-injection

What are used to create Orofacial Pain Models?

Injection of inflammogens (mustard oil) into TMJ as model of orofacial pain

Transection of the trigeminal nerve used to model neuropathic pain of the face and mouth

What are used to create Muscle Pain Models?

Unilateral injection into gastrocnemius muscle of carrageenan or acidic saline produces acute inflammation with edema and produces mechanical and thermal hyperalgesia

What can be used to induce arthritis?

collagen, oil, pristane (induces autoimmune disease in rodents), streptococcal cell wall

Adjuvant-Induced Arthritis

A reactive arthritis, sometime called Reiter's Syndrome,

What is the mode of action of GABA?

Transmembrane chloride conductance increases when the GABA A receptor is activated, resulting in postsynaptic cell membrane hyperpolarization and postsynaptic neuron resistance to stimulation by excitatory transmitters.

GABA Receptor Agonists

Barbiturates and propofol- decrease the rate of dissociation of GABA from its receptor, thus increasing the duration of the GABA-activated opening of chloride channels

Barbiturates also can mimic the action of GABA by activating the chloride channels directly

Etomidate augments GABA-gated chloride currents (indirect modulation), and produces chloride currents in the absence of GABA at higher concentrations (direct modulation).

Characteristics of Barbiturates: route

High alkaline pH limit route to IV but also PO

Effect: good hypnotic, poor analgesic- better classified as a sedative hypnotic

Impact of Barbiturates on physiology

↓ cerebral blood flow (CBF), ↓ Intracranial Pressure (ICP), ↓ Cerebral metabolic rate of oxygen (CMRO2) = useful for brain surgery

↓ body temperature

↓ blood pressure

↓ renal blood flow

↓ Pack cell volume (PCV) in dogs, miniature swine and mice

What is the glucose effect when using barbiturate?

Reanesthetization ("Glucose effect"): glucose administration to animals recovering from barbiturate anesthesia can result in re-anesthetization

Barbiturates (Thiobutabarbital) is inactive and can be lethal to which species?

rabbit

Characteristics of Barbiturates (Pentobarbital)

Rapid onset, Non-irritating, Ease of IP injection

Generally impaired cardiovascular effects (less with IP)

Inconsistent analgesia in mice, rats and rabbits

Characteristics of Metomidate & Etomidate

No analgesic effect (both), strong muscle relaxant (metomidate)

Minimal cardiorespiratory effect (long term continuous infusion)

Metabolized in the liver, excreted in urine

It is an imidazole, so it inhibits adrenal steroidogenesis through inhibition of 11 beta hydroxylase

Side effects of etomidate

Pain on injection

Nausea/vomiting

Myoclonic movements at induction- follow with IV diazepam to reduce

Side effects of Propofol

Apnea is common in most species except rhesus

Hypotension- concern for use in patients with CV disease

Rapid recovery, little cumulative effect- use as continuous infusion agent

Poor analgesic

Metabolized by the liver, excreted by kidney

Greyhounds have slower clearance

Propofol is Less effective in which species?

rabbit

What does daily administration of propofol in cats cause?

Heinz body formation

Why isn't propofol CRI recommended for C-section anesthesia?

crosses the placenta in a sheep model and reaches the fetus within 2 minutes of administration

What does propofol have impact on the brain?

decreases cerebral oxygen consumption, reduces ICP, and has anticonvulsive activity

What are some of the advantages of Steroidal Anesthetics (Alphadolone/Alphaxalone) Alfaxalone?

Rapid induction with rapid recovery, wide safety margin

Anticonvulsant effects similar to pentobarbital in rats but high incidence of myoclonic jerks occur in mice.

Minimal cardiovascular and pulmonary effects

can be effectively delivered by the i.m. route

Sides effects of Alfaxalone?

hypothermia, apnea, hypotension, hypoxemia, vocalization, muscle tremors

What are some of the advantages of Benzodiazepines?

Sedative, anxiolytic, muscle relaxant, anticonvulsant, no analgesia

Minimal cardiovascular and respiratory effects

Differences between solubility of zolazepam, diazepam and midazolam?

Diazepam - insoluble in water

Midazolam - water soluble

Zolazepam - is water soluble

What is the Antagonists of Benzodiazepines?

Flumazenil

Which of the following is most commonly used in rat renal studies:

a. Ethylmalonyl urea (thiobutabarbital)

b. Alpha chloralose

c. Diazepam

d. xylazine

a. Ethylmalonyl urea (thiobutabarbital)

Which of the following GABA agonists have a narrow margin of safety and are not recommended for use in rabbits?

a. Alpha chloralose

b. tribromoethanol

c. thiopental

d. alphaxalone

c. thiopental

What is the mechanism of Ketamine (NMDA Antagonist) and its effect?

Blocks NMDA receptor (blocks glutamate an excitatory neurotransmitter)

Mild local anesthetic effect by Na+ channel inhibition

Analgesia: musculoskeletal > visceral

High lipid solubility

Rapid induction

Pain on injection, muscle necrosis due to pH (3.5)

Metabolized in liver by P450 pathway, excreted by kidney

What impact does ketamine have on physiology?

Cardiovascular → causes increased myocardial contractility in some species/ arrhythmogenic potential

Respiratory→ Bronchial muscle relaxation and decreased respiratory rate (sympathomimetic)

↑ CBF/ICP (not in rats)

Myoclonic and seizure like activity

What is the reaction Tiletamine (NMDA Antagonist) in rats/mice with low dose versus high dose? Which species doesn't it work?

Low dose: excitation rats/mice

Higher dose: anesthesia produced except rabbits/guinea pigs

IM -rabbits (renal tubular necrosis), ↑ BUN/creatinine

Mild nephrosis (histologically)

Which species are very sensitive to Xylazine (Alpha 2-Adrenoceptor Agonists)? Which species is resistant?

Horse and goat; pig

Side effects of Xylazine?

Dose dependent bradycardia

Dogs- 2nd degree AV block

Initial transient increase in MAP followed by decrease

Decreased CO - ↑ vascular resistance + ↓ HR, arrhythmias

Hypoxemia -sheep

↓ insulin release→ hyperglycemia

Diuresis, ↑glomerular filtration and polyuria

↓ GI motility

Hypothermia (in Rhesus)

Vomiting especially cats

Advantages of xylazine

Analgesia

Rapidly absorbed IM

Minimal respiratory depression

Antagonist of xylazine?

Yohimbine (prototypical reversal); atipamezole

Compared to Xylazine, Dexmedetomidine (Alpha 2-Adrenoceptor Agonists) is more?

More potent

Higher Alpha2-adrenoceptor selectivity

More lipophilic

Faster elimination

Analgesia - most species (inconsistent in rabbits, G pigs, pigs, hamsters)

Antagonist of Dexmedetomidine?

atipamezole

Detomidine can provide Sedation and analgesia in mice/rats but it does not lead to loss of _____?

righting reflex

Which of the following is not correct regarding dexmedetomidine?

a. Can be reversed by atipamezole

b. Analgesia is inconsistent in rodents

c. It rapidly crosses the blood brain barrier

d. It has higher alpha-2 receptor selectivity than xylazine

B (rabbits, gpigs, pigs, hamsters)

Consistent in most species including rodents- inconsistent in rabbits, gpigs, pigs, and hamsters

Acepromazine (Dopaminergic Receptor Antagonists)

Sedative phenothiazines

Tranquilizer effects

What is the mechanism of Dopaminergic Receptor Antagonists?

Sedative effect - antagonistic actions of H1 histamine receptors

Tolerance to sedation effect can occur

Calming effect- antagonism of D2 dopamine receptors in forebrain

What impacts does acepromazine have on physiology?

Cardiovascular- Hypotension with↓ CO, systemic vascular resistance not affected

Respiratory- ↓ RR, minimal effect on blood gas

Renal blood flow and glomerular filtration is maintained during hypotension - acepromazine

Hyperglycemia

↓ Hct (splenic sequestration)

↓ GI secretions

Antipyretic/antiemetic/antihistaminic

What is the mode of action of Eugenol (clove oil)?

through vanilloid receptor 1 (VR1) antagonism

Affinity toward GABA and NMDA receptor also demonstrated

Analgesia/anesthesia

Paralytic (nicotinic receptors)

Mainly used in fish and amphibians

Side effects of Eugenol (clove oil)?

Hypoxemia, hypercapnea, acidosis, hyperglycemia

What is the mechanisms of action of Local Anesthetics?

stop the inflow of sodium and nerve depolarization is prevented

What is in EMLA cream?

lidocaine 2.5% and prilocaine 2.5%

What can be used to buffer MS-222? what's the ratio?

2 parts sodium bicarb to 1 part MS-222

What is the side effect of Halothane in pigs?

Malignant hyperthermia in pigs

Duroc, Yorkshire, Poland China, Landrace, Pietrain

What can be used to treat Malignant hyperthermia?

Dantrolene sodium

Side effects of Isoflurane? effect on cerebral blood flow?

Myocardial depression/ decreased vascular resistance - dose dependent → decreased blood pressure

Respiratory depressant

Cerebral blood flow is also not increased if ventilation is maintained

Sevoflurane can cause renal and hepatic toxicity because it can produce _____?

Decomposes in soda lime producing a toxic compound olefin -compound A

What is the recommended flow rate for sevoflurane to prevent degradation?

flow rate in excess of 20 ml/kg/min

Order the onset time from the fastest to the slowest: Desflurane, isoflurane and sevoflurane

Desflurane > sevoflurane > isoflurane

Why should acetaminophen (P-Aminophenol Derivatives) be avoided in cats?

Cats lack the ability to metabolize through glucuronidation resulting in methemoglobin

Which COX inhibitor is Etodolac (Acetic Acid Derivatives)?

dual COX inhibitor with selectivity for COX-2

Which COX inhibitor are Ibuprofen, ketoprofen, naproxen, carprofen?

Ibuprofen, ketoprofen, naproxen, carprofen

Inhibit both COX-1 and COX-2

Carprofen is 1° COX-2

What is the side effects of COX inhibitor

GI effects- ALL

Alter platelet function ↑ bleeding time

Piroxicam (Oxicams) is Contraindicated in which species?

cats

What should be taken into consideration when using meloxicam in cats?

should only be used as a single dose for postoperative pain, because longer use will result in GI side effects, as would be expected from the higher COX-1 activity in this

What is the cox inhibiting selectivity of meloxicam?

Selective COX-2 dogs, not so selective in cats

What is the cox inhibiting selectivity of Flunixin (Nicotinic Acid Derivatives)?

COX-1 selectivity- dogs and horses

Examples of COX-2 inhibitors?

Celecoxib, deracoxib, firocoxib

Robenacoxib (for cats)

Carprofen

Meloxicam

What type of COX inhibitor is Tepoxalin (Zubrin®)? pros of this drug?

Dual COX and LOX inhibitors

COX inhibition: thromboxane, prostaglandin E2

LOX inhibition: leukotrienes in blood/stomach

almost exempt from gastric toxicity

does not cause neutrophil adhesion in blood vessels

Morphine agonist for which receptor? delta (δ), kappa (κ), mu (μ)

mu (μ)

Characteristics of morphine

drowsiness, respiratory depression, ↓ GI motility, nausea, vomiting, ↓ gastric motility and hydrochloric acid secretions in stomach

Produce vasodilation, ↓ peripheral resistance

May induce histamine release

Mania in cats

↓ NK cell activity, impair immunoglobulin production, suppress phagocytosis

Absorbed well from GI (subject to 1st pass removal by liver), SQ, IM also transdermal and epidural

Crosses BBB slower than other lipid soluble drugs

Which animal species doesn't morphine work?

does not appear to affect ruminant animals

Butorphanal agonist for which receptor? delta (δ), kappa (κ), mu (μ)

kappa (κ), more μ antagonist than agonist.

Fentanyl agonist for which receptor? delta (δ), kappa (κ), mu (μ)

mu (μ)

Characteristics of Fentanyl

80X more potent than morphine

Muscle rigidity, respiratory depression in dose-related manner

Buprenorphine agonist for which receptor? delta (δ), kappa (κ), mu (μ)

partial agonist of mu (μ), antagonist kappa (κ),

Characteristics of Buprenorphine

Schedule III

25X more potent than morphine given IM

Analgesia ceiling effect

Rats- excreted in bile, enterohepatic recirculation, Pica

Duration 3-5 hrs mice, 6-8 hrs rats, 6-7 hrs dogs

Characteristics of Gabapentin

structural analog of GABA, but actually has little interaction with GABA receptors

MOA unknown

Used to treat neuropathic pain and non-neuropathic pain.

Did not outperform buprenorphine

The neuroactive drug 3α-Hydroxy-5α-pregnane-11,20-dione works by acting on which receptor?

a) NMDA antagonist

b) GABA A agonist

c) GABA B agonist

d) α2 agonist

e) α2 antagonist

B. Alphaxalone; GABA A

Which of the following is true about the use of tricaine methanesulfonate in fish?

a) It has a large margin of safety and exhibits dose dependent sedation and anesthesia

b) It is equally efficacious between larvae and adult fish

c) Fish never show aversion if buffered properly

d)It can be stored at 4°C for up to 6 months in an amber bottle

Ｄ

In Xenopus laevis, this substance (MS-222) interferes with ______, resulting in general anesthesia.

A)Chloride channels

B) Potassium channels

C)Sodium channels

D)Uptake of GABA A

E)Uptake of GABA B

D

Which of the following best describes the action of alfaxalone?

A) Blocks nerve conduction by decreasing or preventing transient increase in permeability to Na

B) Produces a dopamine blockage with alpha-adrenergic antagonism

C) Provides sedation and analgesia by stimulation central alpha2-adrenoreceptors

D) Steroidal anesthetic that acts on GABA chloride channels

D

Which of the following is a COX-2 preferential inhibitor in rodents?

A)Meloxicam

B)Ketoprofen

C)Ibuprofen

D)Naproxen

A

Which one of the following statements IS NOT correct regarding the substance (gabapentin) pictured?

A)It is a structural analog of GABA (γ-aminobutyric acid)

B)It was originally developed as an antiepileptic drug

C)It preferentially inhibits cyclooxygenase 2 secondarily to prostaglandin synthesis

D)It has analgesic potential in neuropathic pain models

C

Which of the following species is very sensitive to the effects of xylazine and may require only one tenth or less of the xylazine dose used in other species?

A)Capra hircus

B)Cavia porcellus

C)Mustela putorius furo

D)Sus scrofa

E)Callithrix jacchus

A)Capra hircus