Anesthesia

What is the purpose of anesthesia?

to numb pain and /or induce unconsciousness for medical procedures

How is anesthesia done?

by blocking nerve signals at the level of the CNS (general) or PNS (local)

What are the four main steps of general anesthesia?

1) premedication: reduce anxiety, inhibit pain, etc

2) induction: rapidly and smoothly produce state of unconsciousness

3) maintenance: keep patient unconscious as long as required

4) recovery: minimal or no delirium or struggling during emergence from anesthetic

What are the main drug types used in premedication?

• sedatives/anxiolytics/neuroleptics (calm patient/reduce anxiety, inhibit movement, sleepy)

• analgesics (minimize pain)

• muscle relaxants (reduce muscle tone)

• anticholinergics (to inhibit excess salivation caused by drugs)

What do sedatives inhibit?

irritability and excitment (also makes you sleepy)

What do anxiolytics “minor tranquilizers” inhibit?

apprehension and fear (does NOT induce sleepy)

What do neuroleptics “major tranquilizers”/antipsychotics result in?

apathy, supress agitation related movement, may cause sleepiness

What are the benefits of using sedative/anxiolytics drugs before surgery?

• easier surgical preparation

• reduction of anesthetic dose

• smoother recovery

What are the three classes of sedatives and anxiolytics drugs used as premedications?

• Phenothiazines (ex: Chlorpromazine)

• Alpha-2 agonists (ex: Dexmedetomidine)

• Benzodiazepines (ex: Midazolam)

What is the mechanism of action of Phenothiazines ex: Chlorpromazine?

Blocks dopamine D2 receptors in the brain → sedation, reduced agitation

What are the clinical effects of Chlorpromazine?

• neuroleptic (major tranquilizer) and sedative

• profound reduction of fear, anxiety

• reduction of activity and response to stimuli

• muscle relaxation

What are the clinical indications for Chlorpromazine?

• for reduction of agitation before surgery

• schizophrenia

What are the potential dangers/side effects of using phenothiazines (ex: chlorpromazine)?

blocks other receptors (like alpha 1) → side effects (vasodilation, hypotension)

chlorpromazine has largerly been replaced by which drugs for pre-anesthetics in human medicine?

alpha 2 agonists and benzodiazepines

In vet med, … is used as a pre-anesthetic and major tranquilizer for agitated canine, feline or equine patients

acepromazine

What are the clinic effects of alpha-2 agonists (ex: dexmedetomidine)?

• sedation

• analgesia

• muscle relaxation

What are the clinical indiciations of dexmedetomidine?

for sedation of adults prior/during surgery procedures

What is the mechanism of action for Dexmedetomidine?

Selective alpha 2 receptor agonist

In presynaptic CNS nerurons alpha 2 OPENS K+ channels (efflux) and SUPPRESSES Ca2+ influx → hyperpolarization and inhibition of NT release

The inhibition of NT release in these pathways are related to ….

decreased wakefulness → sedation

decreased pain signal → analgesia

decreased SNS outflow → hypotension

decreased motor activity → muscle relaxation

Describe the difference of effect when activated for alpha 2 A and B?

A (CNS) - decreased SNS outflow → low HR and low BP

B (PNS) - vasoconstriction

Why is it important that Dexmedetomidine are injected slowly at low-moderate dosages?

If injected rapidly or at high dosages → alpha 1 and 2B on blood vessels become activated and cause transient hypertension/vasconstriction

When dexmedetomidine is injected correctly, what receptor is activated and what is the result?

slower activation of pre-synaptic alpha 2a receptors in CNS, which inhibits NT release → inhibits SNS outflow → eventual BP drop

What are the most common side effects of Demedetomidine?

hypotension, bradycardia, heart block (by inhibition of SNS outflow from CNS via alpha2a receptor stimulation)

effects highly variable from patient to patient

Both Diazepam and Midazolam are types of benzodiazepines - what is main the difference between the two?

Midazolam has shorter duration of action

What is the clinical effects of Midazolam?

• reduction of anxiety

• drowsiness/fatigue

• muscle relaxation

• amnesia

• anti-convulsant effects

What are the clinical indications of benzodiazepines?

• relief of anxiety and tension in patients about to undergo a surgical procedure (and to reduce recall of the procedure)

What is the mechanism of action of Midazolam?

facilitates binding of GABA to its receptor through an ALLOSTERIC binding site → open ligand gates Cl channel → hyperpolarization → inhibition

Why are benzodiazepines considered sage when administered alone?

they have little effect on CV and respiratory systems at typical dosages

What drug can reverse effects of benzodiazepines?

Flumazenil - competitive inhibitor of the benzo binding site

What are potential adverse effects of benzodiazepines?

dose-dependent respiratory depression (usually when given with another CNS depressant)

Why are opioids given as pre-medication with general anesthetics?

To reduce pain signal generation, preventing activation of the RAS and avoiding the need for dangerously high doses of anesthetics.

Why not just increase anesthetic dose?

High doses → suppress everything
→ respiration + cardiovascular function ↓ (dangerous)

Seed pod juice of opium poppy is dried and powdered to make →

opium

Opium contains …

morphine, codeine, hundreds of other chemicals

What is the natural compoenent of opium called?

opiate

What is any opiate or synthetic derivative called?

opioid

Opioid receptors are present in …

pain pathways and most other organ systems

Mammals produce several endogenous opioids (like endorphins) stimulates …

opioid receptor types

Opioids drugs amplify …

a natural system

Opioid drugs are used for:

1) analgesia

2) sedation

3) cough suppression

4) treatment of diarrhea

What three opioid receptors mediate analgesia?

• Mu

• Delta

• Kappa

What opioid receptor produces dysphoria?

sigma

What are opioid drug examples?

morphine

codeine

heroin

fentanyl

hydrocodone

hydromorphone

oxycodone

What is the mechanism of action of opioids?

stimulate pre/post synaptic opioid receptors in the CNS

presynaptic: inhibit opening of Ca2+ channels → inhibits release of NT

postsynaptic: opens K+ channels → inhibits depolarization

inhibits neurotransmission in pain pathways but also respiratory centre, cough centre, some ANS pathways, others

What is the effect of MOR stimulation?

• analgesia (intense)

• euphoria

• miosis

• respiratory depression

What is the effect of DOR stimulation?

• analgesia (similar to MOR)

• respiratory depression (not as bad as MOR)

What is the effect of KOR stimulation?

• analgesia (moderate and primarily visceral)

• negligible respiratory depressive effects

What is the effect of Sigma stimulation?

• dysphoria (intense feeling of unease)

• hallucinations

• respiratory and vasomotor stimulation

• stimulated by opioids and non opioids (ex: ketamine)

Which opioids are full mu agonists?

Fentanyl, morphine

Which drug is a full kappa agonist and a partial mu agonist, acting like a competitive antagonist to full mu opioids like fentanyl?

Pentazocine

Sometimes combining drugs like pentazocine and fentanyl can result in…

weaker analgesia than with fentanyl alone

Why are most opioids administered parenterally?

phase I and II metabolism with high first pass effect

Why does certain people respond better to codeine than others?

Its a prodrug and metabolized to morphine

some people have normal CYP2D6 activity → lower morphine

some people have ultrarapid metabolizer CYP2D6 activity → high morphine

What are the general physiological effects of full mu agonists? how long does it last?

1. sedation

2. analgesic

lasts 2-6 hours

What are the effects of full mu agonists on the cardivascular system?

• little effect when dosed normally

• morphine can cause histamine release → vasodilation → hypotension

What is the effect of full mu agonists on the respiratory system?

• dose dependent depression → can cause death from OD

• more intense effect when combined with general anesthetic

• suppress cough reflex

What is the effect of full mu agonists on GI system?

• increase segmentation, but reduce propulsion in large bowel → dehydration → constipation

• bile duct sphincter constriction → increase gall bladder preasure → bilary colic

• nausea and vomiting

What is the effect og full mu agonists on the urinary system?

bladder sphincter tone increased, detrusor muscle tone increased → uregency to urinate, but difficult

Full mu agonists can be used to treat?

moderate-severe pain

sedation

Kappa agonists can be used to?

manage mild-moderate pain

Codeine can be used as?

anti-tussive

Loperamine can be used as an ?

anti-diarrheal

Fentanyl

• full mu agonist

• profound pain relief

• most common opioid

• constipation is common

• chronic use: patch

What are the uses of Naloxone?

• opioid overdose

• reverse sedation resulting from combo of sedative + opioid

• circulatory shock due to endogenous opioids

What is Carfentanil used for?

analgesic potency 10000x that of morphine

What is Etorphine used for?

• 1000x that of morphine

• used for wildlife

• renders large animals ataxic within seconds

What are two examples of opioids used for diarrhea?

Loperamide (Imodium) and diphenoxylate (Lomotil)

Why are some opioids used as anti-diarrheal drugs?

They reduce propulsive gut motility and secretions, and constrict anal sphincter leading to: stool remains in large colon longer, more water reabsorbed from stool, potent constipation effect

What is the goald of induction agents? How long do they last?

to render patient unconscious rapidly → patient then connected to machine that delivers inhaled anesthetic

short duration (1-3 minutes)

Why not just administer a long-lasting injectable general anesthetic if they wear off quickly?

• higher risk as we cannot remove injectable anesthetic

• if overdosed we have to wait for metabolism and excretion to occur → may take too long → higher risk of death/CNS depression

However in an emergency if a patient stops breahting due to inhaled anesthetic overdose we can …

Switch to manual ventilation → rapidly reduces concentration of inhalant anesthetic

What are the four stages of anesthesia?

1. Stage of analgesia (amnesia, euphoria, semi-conscious)

2. Stage of excitement (struggling, irregular breahting, vomiting, urination, defacation, semiconscious) WANT TO AVOID

3. Stage of surgical anesthesia (unconscious, regular breathing, movements cease) SWEET SPOT

4. Stage of medullary depression (breathing stops → death) WANT TO AVOID

Why bother with the induction agent and give inhalant instead?

• inhalants work too slowly (patients may experience stage 2 and struggle)

• injectables transition patients from conscious to unconscious state smoothly (more likely to skip stage II)

What are the properties of an ideal induction agent?

• compatible with other agents and IV fluids

• painless on administration

• high potency and efficacy

• minimal CVS and respiratory effects or abdominal organ toxicity

• inhibition of the gag reflex (makes intubating easier)

• rapid onset

• rapid metabolism (lowers grogginess when recovering)

A common feature in most induction agents are the intensitu of adverse effects (ex: respiratory depression and hypotension) are proportinal to …

rate of administration

(the faster the drug is given → worse the side effects)

What was used in the old approach of IV anesthetics? why was this a problem?

• used long-acting barbiturates (ex: pentobarbital)

• 1+ rapid injections

• cause unconsciousness ~10 minutes

• high fatality rate

What is the newer approach for IV injectable anesthetics?

• ultra short acting non barbiturates (ex: propofol)

What is CRI and what’s its purpose in veterinary medicine?

constant rate infusion - unconsciousness maintaine by administering a short acting IV anesthetic by CRI without using inhalant

What are the three types of injectable general anesthetics?

• Barbiturates

• Propofol

• Phencyclidines (ex: Ketamine)

What is the mechanism of action of barbiturates?

inhibit dissociated of GABA from its receptor → increase duration of GABA receptor opening → hyperpolarization → inhibits action potentials

also blocks NMDA and Na+ channels → further suppresses action potentials

What are 3 problems with barbiturates?

1. at high doses can open GABA channels in the absence of GABA → intense CNS depression (low therapeutic index)

2. undergo slow metabolism by CP450 enzymes → patients feel groggy during recovery (can also accumulate with repeated doses)

3. a partial dose (less than half calculated dose) → intense CNS excitation (violent-seizure like activity) - Need to give at least half the dose

What is propofol and why is it more popular than barbiturates?

sedative and general anesthetic

it is less effective at activating GABAa receptors in the absence of GABA (safer)

metabolized faster than barbiturates → smooth recovery

partial doses do not cause excitation → can be titrated (e: ¼ doses) → enhances safety less likely to OD

What is the mechanism of action of propofol?

facilitates effect of GABA at GABAa receptors → inhibits action potentials

What are the main adverse effects of propofol?

• dose dependent depression of respiration and BP

  • apnea if injected rapidly

  • hypotension is more common than other induction drugs

What is the main clinical uses of propofol?

• induction prior to transfer to an inhaled anesthetic

  • smooth onset (`10-30 s)

  • used in short procedures without inhalant needed

  • can be used an an IV infusion in place of inhalant

What type of drug is Phenylclidine (Ketamine) considered?

Dissociative anesthetic

What is Ketamine derived from?

PCP (phenylcyclidine)

Dissociative anesthesia is a dream like state of pseudo-unconscious which results in what?

• eyes open

• swallow reflex intact

• hear normally

• intense muscle rigitidy

• hallucinogenic

• disconnected from surrounding and pain

What is the mechanism of action of phenylcyclidine (Ketamine)?

NMDA recpetor block

also:

• inhibits GABA receptors (CNS (increased SNS ) and CVS (increased HR and BP) overstimulation)

• stimulates sigma opioid receptors → dysphoria

What are the CNS effects of phenylcyclidine?

• pseudo unconscious

• some analgesia

• hypo/hyperthermia (from muscle rigidity)

• amnesia

• changes in mentation (mood, vivid dreasm, hallucinations)

When given as a premedication which drug can abolish the emergence delirium caused by Ketamine producing a smoother recovery?

benzodiazepines

What is goal of maintenance anesthesia?

to keep patient in an unconscious state as long as required via inhalant general anesthetic

What does “Balanced anasthesia” mean?

Instead of using one drug at a high dose, modern anesthesia uses a combination of different drugs at lower doses (much safer)

What are the anesthetic goals during maintenance?

1) stage III surgical anesthesia

2) adequate analgesa during procedures

3) physiologic homeostasis (ex: hemodynamic stability, oxygenation, ventilation, temperature)

To be both safe and effective, general anesthetics must inhibit …while maintaining …

cerebrocortical activity

brainstem function (CV and respiratory system regulation)

Why is the cerebral cortex targeted more easily than the brainstem in anesthesia?

The cerebral cortex is more sensitive to anesthetics, so it is suppressed at lower doses than the brainstem.

What determines the safety of a general anesthetic?

The degree to which respiratory and cardiovascular function are impaired at doses required to achieve unconsciousness.

What defines effective general anesthesia?

Reversible inhibition of higher brain function (cortex) while maintaining vital brainstem functions.

What are the characteristics of an ideal anesthetic?

• produce unconsciousness while maintain brainsteam function

• negligible visceral toxicity

• non flammable

• odorless

• compatible with machine

• chemically stable without preservatives

• potent