Anesthesia

Define Anesthesia

insensibility/loss of sensation. Anesthesia in veterinary medicine refers to a controlled and reversible state of unconsciousness or insensibility to pain, achieved through the administration of specific drugs and techniques. It allowed for safe and humane medical procedures, surgeries, and diagnostic examinations by temporarily suppressing consciousness, pain perception, and voluntary muscle activity.

Goals of veterinary analgesia

1. Pain → systemic/local analgesia

2. Anxiety and stress → sedation

3. Requires surgical repair → unconsciousness

4. Infected/septic → cardiovascular instability → blood pressure support

5. Impaired thoracic expansion → ventilatory support

ASA Score 1

Patient is systemically healthy

ASA Score 2

Patient with mild systemic disease - Patient has a disease process that is controlled, stable, and the patient is exercise tolerant

Ex. Obesity, pregnancy, heart murmur, mild lung disease, hypertension, stable/mild renal disease, well-controlled diabetes

ASA SCORE 3

Patient with severe systemic disease - Patient with systemic disease that manifests with clinical signs and the patient has functional limitations

Ex. Advanced heart or lung disease, moderate to severe anemia, unstable/advanced renal insufficiency, upper airway dysfunction, uncontrolled diabetes, advanced dystocia

ASA Score 4

Patient with severe systemic disease that is a constant threat to life - Patient has a severe, uncontrolled disease process and is clinically affected

Ex. Congestive heart failure, severe lung or upper airway disease causing dyspnea, septic shock, DKA, hemorrhagic shock

ASA Score 5

A moribund patient not expected to survive without the operation: Patient has severe disease or trauma that cannot be managed or mitigated prior to anesthesia for the procedure

Ex. Advanced septic shock, severe head trauma, advanced uncontrolled intracavitary hemorrhage.

True/false: a patient with an ASA score of III, IV, or V are significantly more at risk for death

true

Fasting times for dogs/cats/ruminants/neonates.

• Adult dogs and cats: 8-12h

• Ruminants: 18-24h

• Neonates: no fasting

True/false: Overall incidence of anesthesia-related GID is 33.4%

true

Three main components of preanesthetic assessment

1. Patient Signalment

2. Patient History

3. Physical Examination

Describe the characteristics of the Autonomic Nervous System

1. Self controlling, not automatic or with autonomy

2. Concerned with involuntary regulation of cardiac muscle, smooth muscle, and visceral functions

3. It mediates visceral effects from somatic stimuli

Anatomy of the autonomic nervous system

• Main site is hypothalamus

• Medulla oblongata and pons (hemodynamics, ventilation, tonicity)

Efferent ANS is a _____ neuron chain. Which is myelinated?

two. Preganglionic is myelinated, postganglionic is not.

Parasympathetic vs. sympathetic = which produces a discrete/diffuse response?

parasympathetic = discrete response (stores energy; rest and digestion) - a preganglionic cell interacts with a small number of post-ganglionic cells

Sympathetic = Produces a diffuse and fight-or-flight (uses energy)

Both parasympathetic and sympathetic preganglionic neurons are nicotinic acetylcholine receptors. What are the postganglionic neuron receptors?

PNS = muscarinic cholinergic receptor

SNS = uses norepinephrine, with 𝛼 and β adrenergic and dopaminergic receptors

Muscarinic receptors: what are the effects of stimulating M1, M2, and M3 receptors

Adrenergic receptors: what are the effects of stimulating a1, a2, B1, B2 receptors

(B2 causes vessel dilation)

Atropine and glycopyrrolate are examples of ___________ agents. What is there general role in anesthesia?

Parasympatholytic agents

• Anticholinergic drugs can block the effects of ACh on M receptors. They are antimuscarinic

• Atropine and Glycopyrrolate are both M blockers See drug chart for information

• Prevent (or reverse) vagally-induced bradycardia

  • Vagal bradycardia is induced by acetylcholine

• Reduce secretions (saliva, bronchial mucus, gastric)

• Bronchodilator

• Slow GI motility (very important in horses -colic and rabbits - GI Stasis)

What are sympathomimetic agents? What are some examples of them?

• Natural and synthetic catecholamines and synthetic noncatecholamines

• Rapidly inactivated by MAO and/or COMT and uptaken to presynaptic cell

• Usually of short duration

• As a group they aren’t liposoluble substances, and hence have limited central effects

  • When injected, they do not pass into the CNS easily and therefore have limited central effects

• Do not last long

• Epinephrine (adrenaline)

• Norepinephrine

• Dopamine

• Isoproterenol

• Dobutamine

• Phenylephrine

• Ephedrine

Reasons for premedication

Primary

• Anxiolytics

• Analgesia

• Chemical restraint

Secondary

• Modify ANS reflexes

  • Parasympathetic: vagus nerve, salivary/airway secretions

  • Sympathetic: arrhythmias, BP alterations

• MAC reduction

• Smooth recovery

• Prevent vomiting/aspiration

• Prevent infection/continue treatment

Anticholinergic premed examples and effects

• BAG

  • Butorphanol. Acepromazine, glycopyrrolate

• SuperBAG

  • Buprenorphine, acepromazine, glycopyrrolate

• Cardiac effects: increase sinus rate

• Respiratory effects: bronchodilation and reduced airway secretions can decrease airway resistance

• GI effects: GI side effects can occur. Lower esophageal sphincter function (increased risk of gastroesophageal reflux) and ileus

Anticholinergic premedication indications

• Treat or prevent anesthetic or preanesthetic bradycardia

• Decrease airway and salivary secretions

• Dilate the pupil

• Block vagally mediated reflexes (viscerovagal, oculocardiac, branham)

• Block effects of parasympathomimetic drugs

• Reduced gastrointestinal motility (gastroscopy)

Anticholinergic contraindications in premedication

• Decreased gastrointestinal motility

• Slight increase in myocardial work and incidence of cardiac dysrhythmias

• Reflex bradycardia given from hypertension (alpha 2 agonist)

• Pre-existing arrhythmias (tachycardias)

• Glaucoma, KCS

• No studies to support net benefit

Which antimuscarinic, glycopyrrolate or atropine, can be used for c-section or on a pregnant animal?

glycopyrrolate

Phenothiazine is a premedication in anesthesia. MOA/indications/contraindications?

MOA: antagonism of D2 dopamine receptors

Indications for use

• CV/R stability for procedural sedation

• Sedation

• Neuroleptanalgesia - tranquilizer and opioid

• Antiemetics

  • Antiemetics - 15 min prior to opioids has reduced vomiting incidence from 45 to 8%

• Muscle relaxation

• Minimal respiratory depression

• Increased threshold for epinephrine induced arrhythmias

• Species specific: equine recovery, Pig MH

• Contraindications or concerns for use

  •  PCV - RBC sequestration/spleen engorgement

  • Hypotension

  • Extrapyramidal effects

  • Abnormal liver metabolism - extensive hepatic metabolism

  • Coagulopathy - mixed research findings (altered coag times, did not alter function on TEG)

Acepromazine

• Dopamine receptor antagonist

• Exclusive veterinary use - sedative, antiemetic

• Muscle relaxation, no analgesia; frequently combined with opioid for neuroleptanalgesia

• Approved for dogs, cats, and horses - penile prolapse

• IV, IM,  SC

• Yellow color, should be protected from light

Chlorpromazine

• Not recommended IM in rabbits due to severe myositis and paralysis

• Not recommended in horses due to high incidence of ataxia and altered mentation

• Primarily used in antiemetic in cats and dogs

Butyrophenone

• DOpamine receptor antagonist

• Phenylbutylpipiridine, heterocyclic compound

• Chemically dissimilar to phenothiazines, but share many functional properties

  • Anxiolytic

  • Antiemetic

  • No analgesic

  • CV, musculoskeletal side effects

• Major psychiatric applications in human medicine; sedative; anxiolytic use primarily in veterinary medicine

• Haloperidol, droperidol

• Indications

  • Behavioral modification in the hospital setting

  • Behavioral modification in farm setting

• Concerns and contraindications

  • Hypotension

  • Extrapyramidal effects

  • Reduced arrhythmia threshold

  • Extensive liver metabolism - careful use in hepatopathy

Azaparone

• Dopamine receptor antagonist

• Strensil

• Approved for use in pigs in 1983

• Sedative neuroleptic

• Commonly used in farm pigs for reduction of aggression

  • Reduce fighting

  • Encourage sows to accept piglets

  • Introducing new animals

• Neuroleptanalgesia common with etorphine or carentanil for use with large wildlife.

Benzodiazepine MOA and two examples

GABAa Receptor agonist = allosteric modulator’

Midazolam and Diazepam

Indications and Contraindications of Benzodiazepines

• Indications

  • Anxiolytics

  • Anticonvulsant

  • Sedative

  • Amnesic

  • Muscle relaxation

  • Minimal V, CO

    • Contractility, BP changes

  • Great sedation in some exotic species (ferret, rabbit, some birds), ruminants

• Contraindications

  • Normal healthy animal

  • Species with paradoxical excitation - Midazolam

  • Aggression (decrease in learned inhibitions)

  • Cat

  • Unreliable sedation on its own.

Midazolam

• Highly water soluble

• pH 4.0

• Light sensitive

• Rapidly absorbed IM

  • At physiologic pH, diazepine ring closes, becomes lipid soluble

• Metabolized by liver

Higher potency than Diazepam (higher anxiolytic, sedative and amnesic effects and R and CV effects)

Slower onset of action and duration of action.

Diazepam

• Poorly water soluble - can precipitate if mixed (ketamine OK)

• Suspended in propylene glycol and ethanol (pH 6.6-6.9)

  • Pain on IM and IV injection

  • Variable IM absorption

  • Preferential for IV administration

• Light sensitive, binds to plastic

• Rapidly absorbed from GI

• Metabolized by liver

Faster onset of action than midazolam, less R and CV effects. Less anxiolytic, sedative, and amnesic qualities. Longer lasting, but less potent than midazolam.

Describe the 4 subtypes of GABA receptors

• ɑ2a

  • Cerebral cortex, brainstem

  • Sedation, analgesia, centrally mediated bradycardia and hypotension

• ɑ2b

  • Spinal cord, vascular endothelium

  • Spinal analgesia, vasoconstriction and peripherally mediated bradycardia

    • In this case, you do not want to treat the bradycardia - this would make the heart work harder. 

• ɑ2c

  • Spinal cord

  • Spinal analgesia, thermodysregulation

• ɑ2d (cloned, thought to be similar to ɑ2a

• It is important to distinguish between ɑ2a and ɑ2b - if the animal is bradycardic and hypotensive, you can treat the heart rate with an antimuscarinic, if the patient is bradycardic and hypertensive, you should not treat the bradycardia.

MOA of alpha 2 agonists

• GPCR

• Alpha 2 adrenergic receptors are found on the presynaptic cleft

• Alpha 2 agonists decrease the release of norepinephrine

• Alpha 2 agonists competitively compete for the same binding site

  • Prevent negative feedback loop

  • Increased release

Which alpha 2 agonist is the most selective? the least?

Receptor selectivity = dexmedetomidine > medetomidine > romifidine > detomidine > xylazine.

Indications for use of alpha 2 agonists. Contraindications?

Indications

• Anxiolytics

• High quality sedation across many species

• Analgesia = adjunctive to opioids, sedation outlasts analgesia.

• Muscle relaxation

• Reliably reversible.

Contraindications

• Significant side effects

  • CO decrease

  • Vasoconstriction

  • Reflex bradycardia

  • Loss of thermoregulation

  • Increase urine production

  • Hyperglycemia

• Neonates/young animals = HR DEPENDENT FOR CO!!!

Alpha 2 antagonist (reversal agents)

• Alpha 2 antagonists = antisedan, yobine, tolazoline

  • Atipamezole

    • A very specific antagonist for ɑ2 receptors

      • Reverse extreme bradycardia/bradyarrhythmias

      • Effective for treating bradycardia in animals sedated with an ɑ2 agonist, BUT beware sedation and analgesia are also reversed

      • Effective for treating bradycardia in animals under inhaled anesthesia that have been premedicated with an ɑ2-agonist, but beware

        • The patients depth of anesthesia might lighten

        • The patient may become dangerously hypotensive (vasodilation)

  • Yohimbine - less specific than atipamezole, but useful for reversing rumen stasis after xylazine. Inexpensive

  • Tolazoline - least specific

  • MK467 - is a member of a new class of ɑ2-antagonists that can’t cross the blood brain barrier - antagonize unwanted (peripheral) side-effects but retain central sedation, analgesia and (maybe) some reduced CO.

Indications of premedication

• Continuation of preoperative therapy

• Anxiolysis/sedation

• Analgesia and neuroleptoanalgesia

• Control of nausea and/or vomiting

• Control of gastric volume or pH

• Modification sympathetic responses

• Prophylaxis against allergic reactions

• Control or airway secretions or bronchospasm.

Why do we want to control nausea and vomiting in dogs undergoing anesthesia?

• Severe cases can lead to increased length of hospital stay, increased bleeding, incisional hernias and aspiration pneumonitis

• Prolonged vomiting may result in loss of hydrogen, chloride, potassium, sodium and water

• In addition to esophageal, laryngeal, and neurological disorders, aspiration pneumonia was associated with vomiting and anesthesia and had a mortality rate of 33%.

Cerenia (Maropitant) MOA

Maropitant is a neurokinin (NK1) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system

Ondansetron MOA

• Antagonizes 5-HT3 receptors both centrally and peripherally

• Blocks serotonin

Current fasting practices at CUHA

• General fasting time: 6h

• Neonates (up to 2wk): 2hr

• Pediatrics (2wk-1mo): 4h

• Young adults/adults (older than 1 mo): 6h

Patients considered to be at risk of gastric reflux and pulmonary aspiration

• Gastrointestinal Sx

• Emergency surgery (particularly for the acute abdomen)

• Pregnancy

• Morbid obesity

• Diabetic gastroparesis

Metoclopramide MOA and purpose in premedication

• Mainly used as a prokinetic agent

• Antagonizes the inhibitory neurotransmitter, dopamine (it augments acetylcholine release and sensitizes the muscarinic receptors of the gastrointestinal smooth muscle)

• Crosses blood brain barrier and may cause acute dystonic reactions and other extrapyramidal effects

Sodium citrate purpose in premedication

•  Non-particulate (clear) anti-acid used as prophylaxis against aspiration pneumonitis

• Peaks in 10 mins - effect not expected to go beyond half an hour

• Can be given to help minimize the damage of vomiting in the chance that vomiting actually does happen

  • To avoid esophagitis from vomiting as a result of opioids premed

  • Anticipated difficult airway

  • Full stomach

  • C-section

Famotidine MOA

• Specific and competitive histamine H2 receptor antagonist at parietal cells

• Gastric pH is raised and the volume of secretions is reduced

• 45-60 minutes before induction of anesthesia

• Rapid IV administration may produce cardiac arrhythmias

Pantoprazole MOA

Proton pump inhibitor - decreases gastric acid production

Which of these anesthetics are vapors vs gasses? Isoflurane, sevoflurane, desflurane, N2O, Xenon

Vapors: Isoflurane, sevoflurane, desflurane

Gasses: N2O, Xenon

Injectable anesthetics

1. Barbiturate

2. Non-barbiturate

3. dissociative agents

4. steroids

• Barbiturate - pentobarbital

• Non-barbiturate - propofol

• dissociative agents - ketamine

• steroids - alfaxalone

Describe the mechanism of actions of inhalation anesthetic agents

• Anesthetics work by:

  • Expanding the lipid bilayer (critical volume)

    • Drugs that are lipid soluble go into the lipid bilayer - expands it and makes it thicker, affecting the function/integrity of the cell. 

  • Fluidization of the lipid bilayer

• Cutoff effect

  • Enantiomer

  • As chains get longer, drugs become more potent - until a certain number of carbons. At this #, it stops working

  • Halothane, isoflurane, and desflurane exist as racemic mixtures of enantiomers

  • (+) enantiomer is ~50% more potent than (-)

• An improved correlation was found between anesthetic potency and amphipathic (hydrophobic and hydrophilic) solvents; such as the lipid bilayer with phospho-lipoproteins

• Franks and Lieb (1980) reported the effect of several anesthetics on the bioluminescence function of the protein luciferase, isolated from the bilayer

• Anesthetics work by interacting with PROTEINS

Identify the components of general anesthesia

1. General anesthesia is a drug-induced reversible condition that includes unconsciousness (hypnosis), amnesia (memory loss), and immobility

   1. These effects are dose-dependent (amnesia>>hypnosis>>immobility>>)

Describe amnesia

• Memory loss

• Amnestic effects appears to occur at hippocampus, amygdala - involved in learning and memory in humans

• Bilateral resection of these induces anterograde amnesia

Describe hypnosis

• Hypnotic effects less clear: thalamus, cortex, and brainstem

• Consciousness is a complex state which involves arousal (wakefulness) and awareness

• Keep monitor between 40 and 60.

Describe immobility

• Immobility is largely produced by inhibition of spinal reflex pathways

• Antognini (1993) isolated cerebral and spinal circulation in goats and demonstrated that immobility was largely dependent on spinal cord.

  • Separated vascular system of goat = like a 3-way stopcock. To make the blood go either to the head or the spinal cord. 

  • Inject propofol and assess brain perfusion

  • Turns out = if you make blood go to spinal cord - goat will not move.

  • If blood goes to brain, you need 3x as much to make the goat not move. 

  • Movement does not mean patient is awake!!

Describe anesthetic inhibitory pathways including GABA receptors

• Inhibitory pathways

  • GABAa is the most important inhibitory neurotransmitter

  • GABAa - activated channels increase Cl- conductance and hyperpolarize the cell.

  • Anesthetics mainly potentiate the effects of GABA (gabaergic)

  • They increase the affinity of GABA to GABAa

  • They increase frequency of opening, or time that remains open, and increase Cl- conductance

  • Glycine receptors are also potentiated by inhalational anesthetics

  • Do NOT work by releasing more GABA, just increase affinity

Describe how anesthetics affect excitatory pathways

• Excitatory pathways

  • Glutamate is the major excitatory neurotransmitter

  • Classified based on agonists:

    • NMDA

    • KA

    • AMPA

  • NMDA receptors might be important in the development of chronic pain, allodynia, and hyperalgesia.

  • Glutamate release is decreased in the presence of clinical concentrations of inhalational anesthetics (presynaptic effect)

  • N2O and Xenon (and ketamine) can inhibit the postsynaptic response to glutamate on NMDA receptors

Volatile anesthetics (isoflurane, sevoflurane) are predominantly __________ agents (postsynaptic; inhibitory path) and also inhibit the release of (presynaptic; excitatory path)

Gabaergic, glutamate

Gasses such as N2O and xenon (and ketamine) are predominantly _______ antagonists (postsynaptic; excitatory path)

NMDA

True/false: alveolar concentration of inhalational anesthetics can be easily measured and it represents effector-site concentration

true.

Vapor vs Gas

• Gasses exist in gaseous form at room temperature and sea level pressure

• Vapor is the gaseous form of an agent that at room temperature and sea level is a liquid

True/false: the saturated vapor pressure does not have an impact on how much vapor you can give to a patient

False

Vapors: you can give as much as the saturated vapor pressure allows

(maximal concentrations at room temperature increased with Saturated vapor pressure)

What is saturated vapor pressure?

• maximal partial pressure reached by vapor. Depends on agent and temperature

What is MAC?

MAC = Minimum alveolar concentration. It is the concentration at which 50% of individuals do not purposefully move in response to a defined stimulus (this does NOT include reflexes)

MAC awake = 50% awake, 50% unconscious

MAC no movement = needed during surgery

MACbar = blunts response.

True/false: MAC is reproducible throughout species

true

MAC limitations

• MAC determination is quantal; either anesthetized or not

• MAC depends on the end-point measured (hypnosis, movement, etc.) there are as many MACs as end-points

• Remember that MAC represents the point of no movement, not the point of no pain and hypnosis

• It is still the most popular and robust measure of potency of anesthetics

Relationship of MAC and liposolubility

Increased speed of drug as blood/gas partition coefficient is smaller

Potency: N2O> DES>SEVO>ISO>HAL>MOF

Surgical MAC is _____ x MAC

1.3-1.5

Ex. Iso: MAC% is 1.3 = meaning that 1.3% stops 50% of dogs from moving. 1.5 x MAC = stops 90% of dogs

MAC sparing effects of other drugs

• MAC sparing effects of other drugs

  • Sedatives, hypnotics, opioids, NMDA antagonists, alpha 2 agonists ALL reduce MAC

  • There are synergistic effects with some analgesics

  • This is used to our advantage in balanced anesthesia practice

How does temperature, age and thyroid function affect MAC?

• Hypothermia decreases MAC by 5% per each 1C

• Age decreases MAC in people

• Hypothyroid decreases MAC (12%) in dogs

How do vaporizers work in delivering MAC?

Ex. Sevoflurane

• MAC of sevoflurane is 2.5%

• Sevoflurane produces 21% at saturated vapor pressure (160mmHg)

• The vaporizer mixes carrier gas (O2) with sevoflurane-saturated gas (21%) so that the output is diluted to clinically useful concentrations (in this case - 2.5%)

How does temperature affect vaporizers?

it doesn’t!

How are inhalants administered, and what determines the pressure in blood (and in turn CNS)

• Carrier gas (usually O2) goes through the vaporizer

• Fresh gas (gas + sevoflurane) enters the breathing circuit. Connected to the tracheal tube and lungs

• Sevoflurane reaches the alveoli and diffuses into the blood (uptake)

• Alveolar partial pressure determines blood and CNS pressure - and the effect

• Actions are due to pressure NOT concentration

• Conveniently, we use %, but it is partial pressure of a gas (anesthetic) that determines its effect

• Alveolar partial pressure of anesthetic will determine pressure in blood and in turn the CNS

• Inhalational anesthetics move across barriers (phases) according to the pressure gradient

• Equilibrium (no more net movement) occurs when partial pressures in both phases equilibrate

• Hence, partial pressure in blood and brain will always be lower (or at the most, equal) than that in the alveoli

  • When pressures are equilibrated between blood and gas, concentrations will be different. Ex. blood/gas = 3.5 = this means that at equal pressures, the concentration in the blood is 3.5x more than in the alveoli. This determines how quickly an animal falls asleep. The lower the blood/gas ratio the FASTER

The more soluble in blood a drug is (higher blood/gas) the ______ uptake by pulmonary circulation and the _____ the induction

The greater the uptake, the ____ the rise in alveolar partial pressure

greater

slower

for these drugs, the blood acts like a sponge

The greater the uptake, the slower the rise in alveolar partial pressure (alveolar pressure drops as the drug is uptaken into the sponge that blood is)

Alveoli, Blood and Brain: Partial pressure of inhaled drugs if highest in which?

Alveoli, then blood, then brain.

The most important route of elimination is the

lungs

How do inhalation anesthetics affect the CNS?

• Dose dependent depression of the CNS

• EEG becomes flat (isoelectric) at >2.0 MAC

• Anesthetic agents increase cerebral blood flow (vasodilation) and intracranial pressure is affected in dose-dependent way

• They all decrease cerebral metabolic rate of oxygen (CMRO2)

• Low oxygen consumption with increased blood flow is called uncoupling

Inhalational anesthetics - what is uncoupling?

Low oxygen consumption with increased blood flow

How do inhalational anesthetics affect the cardiovascular system

• Dose-dependent myocardial depression

• Isoflurane and sevoflurane are vasodilators

• They reduce afterload and produce hypotension. They have a smaller negative inotropic effect

• Halothane reduces CO and ABP by depressing myocardial contractility

  • 2.0MAC causes a 50% decrease in CO and ABP

  • Halothane blunts baroreceptor function

  • Halothane sensitizes the heart to catecholamine (triggers arrhythmias)

How do inhalational anesthetics affect the respiratory system?

• Volatile agents produce dose-dependent respiratory depression

• A reduction in tidal volume is usually followed by a reduction in respiratory rate

• As a result, hypoventilation (hypercapnia) occurs

• Apneic between 2-3MAC

• Species differences - horses retain  a lot of CO2 (fail to excrete)

• Even subanesthetic doses blunt the response to hypoxia and hypercarbia

• Think of the impact after extubation

• Inhalational agents are bronchodilators

true/false: halothane produces hepatotoxicity

true

• Type 1 5-30% mild (linked to poor perfusion)

• Type 2 1/30K cases fatal, immune mediated

True/false: Sevoflurane produces compound A as it reacts with soda lime. Compound A has shown nephrotoxicity

true!!!!

Qualities of an ideal injectable anesthetic

• Water soluble - ability to be used

  • Lipid solubility - fast onset, rapid recovery

• Long shelf-life

• Stable when exposed to heat and light

• Potent, concentrated (small volume to produce anesthesia)

• Large safety margin

• Short duration of action

• No cumulative effects

• Metabolized into non-toxic metabolites

• Well characterized withdrawal times (food animals)

• Analgesia

• Muscle relaxation

• Minimal CV/R side effects

MOA and indications/Contraindications for use of Barbiturates

• MOA: GABAa receptor agonists

• Indications for use

  • CNS: CNS depression, reduction of CMRO2, decrease ICP

  • R: some preservation of laryngeal function - ok for laryngeal exam

  • Rapid induction

  • good muscle relaxation

  • anti-convulsant

  • euthanasia solution - profound CNS depression, low therapeutic index

• Contraindications for concerns for use

  • CV: decreased SV/cont, Venodil (spleen size), ventricular bigeminy

  • R: dose dependent respiratory depression

  • repro: profound sedation of puppies, uterine blood flow decrease in ewes

  • DO NOT USE IN PREGNANT ANIMALS

  • No analgesia

  • perivascular necrosis if extravasation occurs

  • “glucose effect” - reanesthetizing action

  • species specific = greyhounds = deficient in hepatic enzyme for metabolism (careful with dose)

    • horses = must be sedated first to avoid excitement/incoordination at induction

    • Rodents = IP euthanasia = pentobarbital

Define pain and nociception and discuss how they differ

Nociception: the neural process of encoding noxious stimuli: it is the physiological process that, when carried to completion, results in pain perception. It requires nociceptor stimulation. The consequences of this stimulation may be autonomic and/or behavioral, but pain perception is not implied.

Pain: unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. However, pain severity and extent of tissue damage may not be correlated. Pain requires consciousness but NOT nociceptor stimulation.

Define adaptive pain, nociceptive pain, maladaptive pain, neuropathic pain, and nociplastic pain and discuss how they differ. Provide an example of each

1. Adaptive: “protective pain” serves a biological function - it acts as a warning and produces behavior that promotes avoidance, healing, and recovery. - usually experienced after surgery or trauma and can be controlled with analgesics.

2. Nociceptive pain: pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors

3. Inflammatory pain: caused by inflammatory mediators that stimulate chemoreceptors (a type of noceceptor) so it really is a type of nociceptive pain

4. Maladaptive pain: serves no biological function and is considered to be a disease of the nervous system. Divided into nociplaststic and neuropathic pain.

   • neuropathic pain: caused by a lesion or disease of the somatosensory nervous system (compression of a nerve etc.)

   • Nociplastic pain arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory nervous system causing the pain. (fibromyalgia or phantom limb)

   • Due to neuronal plasticity and are difficult to alleviate with analgesic drugs alone.

What are the 2 types of nociceptive neurons that exist? Describe them.

A-delta

• lightly myelinated

• diameter: 2-5 microns

• conduction velocity: highly variable (5-25 m/sec)

• Fast or first pain (the pain first perceived when you touch a hot stove)

• Sharp pain

• Causes withdrawal

• Localizable pain

C

• Unmyelinated

• diameter <2 microns

• conduction velocity: slow (0.5-2.0 m/sec)

• Slow or second pain (the pain after hand withdrawal from stove)

• burning pain

• causes guarding

• diffuse pain

• more abundant in viscera

Define the physiological process involved in nociception (transduction, transmission, projection, modulation, perception)

1. Transduction: conversion of noxious stimuli into electrical activity via proteins or groups of proteins called transducers.

   • Transducers are categorized as

     • Chemotransducers - polymodal

     • thermotransducers

     • mechanotransducers

2. Transmission: propagation of an action potential along peripheral nociceptive neurons and into the CNS

   • sufficient transducer activation drives membrane potential above action potential threshold = generator potential. Leads to action potential.

3. Projection

   • Nociceptive neurons synapse in laminae I and II are where most nociceptive neurons synapse.

4. Modulation

   • modification of nociception in the spinal cord dorsal horn by descending excitatory or inhibitory pathways originating in the PAG of the mesencephalon which receives input from higher structures. PAG communicates with rostral ventromedial medulla and pontine.medullar noradrenergic (NA) nuclei. There are ON neurons (pronociceptive) or OFF neurons (antinociceptive)

5. Perception

   • Sensory-discriminitive component (neurons protect thalamus to primary somatosensory cortex)

   • Motivational-affective component

   • cognitive evaluative component

Describe the anatomical pathway of a noxious stimulus from the periphery to the somatosensory cortex

Noxious stimuli to the dorsal horn of the spinal cord using first order neurons. Interneurons in the dorsal horn. Then to second order neurons with cell bodies in the spinal cord dorsal horn. Project to the thalamus in the spinothalamic tract. In the thalamus, they snaps with third order neurons that project to the cerebral cortex = PERCEPTION

The cell bodies of the first-order nociceptive neurons carrying noxious signals into the CNS from the head are located in the trigeminal ganglia and they synapse with second order neurons in the spinal nucleus of V, which decussate and project to the thalamus in the trigeminothalamic tract.

Describe the anatomical path of a noxious stimulus from the periphery to the four major brainstem termination sites, and discuss the function of each at the four sites

Some second order neurons do not travel directly to the thalamus but to four medullary (brainstem) structures

1. periaqueductal grey = MODULATION

2. reticular formation = arousal/attention/consciousness and projects to cortex via thalamus

3. noradrenergic cell group including locus coeruleus (NACG) = stimulates the central nervous system and communicates with the hypothalamus and amygdala (limbic system)

4. parabrachial nucleus

Name at least two drugs that can be administered clinically to interfere with each of the physiological processes involved in nociception and their mechanisms of action

1. Transduction

   • Glucocorticoids - inhibit phospholipase A

   • NSAIDS - COX inhibitors

   • Prostaglandin receptor antagonists

   • Opioids

   • Lidocaine - anti-inflammatory effects

   • diphenhydramine - histamine receptor antagonist

   • Capsaicin and analogs

2. Transmission

   • Local anesthetics = voltage gates Na channel inhibition

   • Alpha 2 agonists

   • Buprenorphine

   • Ketamine

3. Projection

   • opioids

   • A2 agonists

   • cannabidol

   • Ketamine

   • Gabapentin and pregabalin

4. Perception

   • opioids

   • a2 agonists

   • cannabinol

5. Modulation

   • opioids

   • a2 agonists

   • cannabidiol

   • ketamine

   • antidepressants and tramadol

Define algoplasticity and how it manifests clinically

Algoplasticity is defined as change in the properties or functions of neurons involved in nociception and pain that outlast the stimulus that caused them (also known as sensitization) NMDA receptors play an important role!

Discuss the role of the N-methyl D-asparate (NMDA) receptor in algoplasticity

In health, NMDA receptors in the spinal cord dorsal horn are inactive, plugged by a magnesium ion. Persistent noxious stimulation increases glutamate release from first order neurons, which binds to AMPA receptors. Second order neurons are depolarized for a longer period, which allows the magnesium to exit the NMDA receptor channel. Ca+ increases in the second order neuron = CRITICAL. All changes are called “long-term potentiation”

You can treat with an NMDA receptor antagonist - ketamine

3 types of receptors that bind allogenic (pain producing) substances

1. ionotropic receptors - most rapid and direct. Binding causes conformational change that leads to action potential generation.

2. metabotropic receptors - slower, but still fast. Binds ligand and triggers intracellular signaling cascade that leads to opening of ion channel.

3. receptors for neurotrophins and cytokines - have associated protein kinases that catalyze protein phosphorylation.

What are the most abundant cell types in the spinal cord dorsal horn?

interneurons - excitatory or inhibitory

4 features of algoplasticity

1. hyperalgesia

2. allodynia

3. spontaneous neuronal activity

4. increased receptive field size

Define Opium, opiate, and opioid

1. opium: the juice of the opium poppy

2. opiates: a group of about 20 natural alkaloids (morphine, codeine) purified from opium

3. opioid: refers to any substance that binds the opioid receptors and produces at least some agonist activity. (fentanyl)

THUS - all opiates are opioid, but not all opioids are opiates.

List the three clinically important opioid receptors and name the one primarily responsible for analgesia (as well as adverse effects)

1. Mu - most analgesic effects and most side effects

2. Delta

3. Kappa

Define full (pure) agonist, partial agonist and agonist/antagonist

Agonists = elicit maximal receptor activation and produce increasing analgesia with increasing dose.

1. morphine - less lipophilic than fentanyl, enters CNS more slowly - slower onset of action. Histamine release

2. hydromorphone - semi-synthetic, no histamine release

3. methadone - synthetic opioid, also NMDA receptor antagonist and alpha 2 agonist.

4. fentanyl - very lipophilic and takes effect faster than morphine. Often used in critical patients.

Agonist-antagonist

1. butorphanol = competitive partial mu receptor antagonist that exerts analgesic effects by acting as a kappa receptor agonist.

   • side effects = ceiling effect, increasing doses do not produce additional side effects.

   • can be used to antagonize effects of full mu agonists

Partial Agonists

1. buprenorphine: semi-synthetic opioid that binds tightly to and dissociates slowly from the mu receptor. difficult to antagonize

Antagonist = naloxone.