General Anesthetics

What is general anesthesia?

Controlled, reversible state of loss of sensation and conciousess

What is analgesia

Decrease awareness of pain

Stages of general anesthesia

I. Analgesia

II. Disinhibition/Excitement

III. Surgical Anesthesia (GOAL)

IV. Medullary Depression: we do not want our patients to reach this stage

What is the goal in general anesthesia?

III. Surgical Anesthesia

Unconscious, no pain reflexes

Blood pressure and respiration are regular

Monitor: Reflexes, vital signs, EEG, respiratory and circulatory responses to surgical stimulation

Examples of inhaled anesthetics

Gas: Nitric Oxide

Volatile Liquids: Isoflurane, Desflurane, Sevoflurane, Enflurane, Methoxyflurane, Halothane

IV anesthetics examples

Barbiturates: Thiopental, Methohexital

Benzodiazepines: Diazepam, lorazepam, midazolam

Propofol, Etomidate, Ketamine ← different MOAs

Opioids: Morphine, fentanyl, sufentanil, alfentanil, remifentanil

Anesthetics Goal

General depression of neuronal activity

Anesthetics MOA

Increase opening of GABAa ligand-gated ion channels

• All inhaled anesthetics, barbiturates, benzodiazepines, etomidate, propofol

• Exceptions: Ketamine and Opioids

What type of channel is GABAa

Ligand-gated ion channel

Influx of Cl- causes hyperpolarization → Inhibatory

Ketamine MOA

Antagonizes the N-methyl-D-aspartate (NMDA) receptor activation of glutamate

Block receptor; Block Na from coming in, no depolarization occurs

Opioids MOA

Activation of opioid g-protein receptors

Net effect is inhibitory

T/F Ketamine binds to GABA receptors to inhibit it

FALSE Ketamine antagonizes the N-methyl-D-aspartate NMDA receptor activation to inhibit glutamate

T/F GABA is the major excitatory NT in the brain

FALSE: GABA is a major inhibitory NT

What kind of channel is GABAa

Chloride Ion Channel

Allows Cl to enter the cell and result in a hyperpolarization

Where do anesthetic drugs bind to?

Anesthetic drugs bind to specific sites on a and b subunits on the allosteric site (NOT the same as endogenous GABA)

What drugs potentiate GABA action

These needs endogenous GABA

Benzodiazepines (increase frequency of channel opening) REQUIRE GABA regardless of concentrations

Barbiturates do not require at high doses (Duration; they make the channel open for longer) - etomidate, propofol

Major difference between benzodiazepines and barbiturates MOA

Benzodiazepines increase frequency via allosteric site

Barbiturates increase the duration. Examples include etomidate,propofol

T/F All anesthetics directly activate GABAa receptor channel opening at high concentrations

All EXCEPT benzodiazepines

Benzodiazepines NEED GABA to work to bind to the allosteric site

For all others, at high concentrations, you may not need GABA to act at the allosteric site. Benzodiazepines cannot directly activate GABA at high concentrations

However regardless, all prefer to have GABA present at normal concentrations

How can we induce selective effects with anesthetics?

Neuronal pathways are differentially sensitive to anesthetics

Example: The dorsal horn neurons (pain) are the most sensitive

What are the first neurons that respond to anesthetic doses?

Dorsal horn neurons (pain) most sensitive

• Stage I analgesia and conscious sedation

What is the least sensitive neuronal pathway?

Respiratory and vasomotor centers of medulla neurons: Least sensitive

• Stage IV cardio-respiratory collapse

What explains the excitatory phase in Stage II

Small inhibitory neurons are inhibited

Thus these result in effects in Stage II:

II.Disinhibition/Excitement

• Delirious, amnesia, enhanced reflexes

• Irregular respiration

• Vomiting, incontinence

What neuronal pathways explain step III?

We want to quickly achieve stage 3 while also keeping them at stage 3

Ascending pathways of reticular activating system: mediate sleep/awake cycle, spinal reflex activity

• Stage III: Loss of consciousness and muscle relaxation

• Surgical Anesthesia

Administration Route

lungs — blood — brain

What determines response for inhaled anesthetics?

CNS Concentration determines response

low gas partition coefficient

Affects the rate of equilibration in blood

low:gas partition coefficient = low solubility in the blood

this means that a drug with a low blood:gas partition coefficient leads to FASTER CNS action (prefers the gaseous form; blood is a barrier)

If it is not soluble (low) it wants to get our of the blood into the brain for more CNS effect

onet of action for nitrous oxide

Low blood:gas partition coefficient

Low blood solubility

*remember, low blood solubility → faster CNS action

characteristics of nitrous oxide, desflurane, sevoflurane: blood solubility

Low solubility → fast acting

Low blood = hate blood = more gas = more action in the brain

characteristics of halothane, methoxyflurane: blood solubility

High solubility → slow acting

Wants to stay in the blood → not gas → little CNS crossing

What is partial pressure

Fraction of total gas inhaled

Affects maximal effect reached

what does a higher ventilation rate translate to

higher alveolar uptake

Opioids cause lower ventilation

what does a higher pulmonary blood flow translate to

Higher blood flow → gas’s pressure rises at a slower rate → slower onset

the partial pressure of gas concentration (amount per volume) would take longer to increase and this can slow down the transfer of the anesthetic drug from the lungs into the blood → can slow the onset of action

how are halothane and methoxyflurane metabolized?

metabolized by the liver and produces hepato-toxic metabolites

how are isoflurane and desflurane metabolized?

liver enzymes

what is a major route of elimination for inhaled anesthetics?

clearance by lungs is the major route of elimination

the rate of recovery from anesthesia using agents with a ___ blood solubility is faster than that of anesthetics with a ___ blood solubility

The rate of recovery from anesthesia using agents with low blood solubility is faster than that of anesthetics with high blood solubility

Drugs with a low solubility are eliminated at a ___ rate

Drugs with a low solubility are eliminated at a fast rate

desflurane and sevoflurane have a shorter recovery time

What is potency of inhaled anesthetics measured by?

Minimum alveolar anesthetic concentration (MAC) at which 50% of patients do not move in response to a standardized painful stimulus unit of anesthetic dose

50% of pts will not feel the pain

The lower the EC50; the ____ potency

The higher the potency (EC50 is the amount needed to yield the desired effect)

Effective dose for general anesthetics is

1.5 MAC

I will have an effect combination if I have at least 1.5 MAC to be efficacious

The lower MAC; what is potency

Higher potency

What groups have a lower MAC?

Lower in elderly and infants and when combined with other IV anesthetics, opioids or sedatives

Why isnt N2O efficacious

1 MAC of N2O > 100% ; BUT 100% N2O < 1MAC

Even if you give 100% of N2O you will never reach the 1.5 efficacious MAC

T/F MACs are a unit specific to drugs and cannot be readily added together

FALSE

MACs are additive;

You can add

0.75% of halothane + 1.0% sevoflurane (0.5 MAC sevoflurane) = 1.5 MAC Inhaled anesthetic

What aspect of the chart deals with potency and efficacy?

Minimal Alveolar Concentration (MAC)

Shows the percentage required to reach 1 MAC

What aspect of the chart shows speed and onset of action?

Blood:Gas Partition Coefficient

The lower solubility = WHAT? speed

The higher solubility = WHAT speed?

Low solubility = fast onset (hates the blood; wants to be gas = go into brain)

Higher solubility = slow onset (stays in the blood)

what effect do anesthetic drugs have on the braim?

Can increase cerebral blood flow via decreasing vascular resistance

• Can lead to an increase in intracranial pressure

What is the worse anesthetic for increasing intracranial pressure?

Halothane should NOT BE USED in Pts with High Intracranial Pressure

Least with nitrous oxide (N2O)

Effects of inhaled anesthetics on metabolic rate

Decrease metabolic rate in the brain

what does enflurane do to the brain

induces seizure-like EEG activity; contraindicated in pts with history of seizure

what effect do anesthetics have on the cardiovascular system?

Decrease in mean arterial pressure + General depression of cardiac function

• Reduce cardiac output: halothane, enflurane

• Sevoflurane: peripheral vasodilation (decrease blood pressure)

• Decreased blood flow to liver and kidney

Halothane: bradycardia via vagal stimulation

Desflurane, isoflurane: decreased heart rate

Myocardial depression: all, esp. enflurane and halothane

Halothane sensitizes the myocardium to catecholamines (epinephrine)

• Arrhythmias in pts taking sympathomimetics

These make sense; we don’t want these to be SUPER active but we have to make sure we don’t make any existing comorbidities worse

what effects do inhaled anesthetics have on respiratory system?

All except N2O → decrease respiratory volume and increase respiratory rate → overall lower ventilation

All are general respiratory depressants

• Most: isoflurane, enflurane

• Least: N2O

All depress mucociliary function in airways

• Increase infections

Most cause bronchodilation

• Esp. Halothane, sevoflurane

Desflurane can cause airway irritation

• Bronchospasm, coughing, breath-holding

Effects of inhaled anesthetics on the kidney

decrease GFR and renal blood flow

effects of inhaled anesthetics in the liver

decrease hepatic blood flow

effect of inhaled anesthetics on uterus

potentially relax uterine smooth muscle

malignant hyperthermia

rare genetic disorder, sensitivity to inhaled anesthetics

Mutations in ryanodine receptors; responsible for the release of calcium from intracellular organelles

• caused by increase in free calcium concentration in skeletal muscle cells

• Severe muscle rigidity, hyperthermia, tachycardia, hypertension

Treated with dantrolene to decrease Ca, stabilize temperature and electrolytes

examples of barbiturates

thiopental, methohexital

barbiturates moa

• barbiturates bind and increase the duration of GABAa channel openings in reponse to GABA binding

HIGH lipid solubility → low blood gas coefficient (want to leave when they get to the blood) —> cross BBB

• Directly cause channel opening at high concentrations

Barbiturates would prefer GABA to be present in the channel, BUT at a high concentration; they could activate the receptor on their own

Clinical use for barbiturates

Fast acting and short acting: Induction of stage III

• Rapidly cross BBB

• Redistribute to other tissues, eliminated via hepatic metabolism

Good for induction (quickly)

Fast recovery (methohexital > thiopental)

• Respiratory depressant, myocardial depressant

  • leads to a decrease in arterial blood pressure and cardiac output (not good for pts with cardiac dysfunction)

• Decrease cerebral metabolism and cerebral blood flow

  • Good for patients with brain swelling or high intracranial pressure

What is an clinical advantage and disadvantage for IV barbiturates

Advantage: decrease cerebral metabolism and cerebral blood flow; good for patients with brain swelling or high intracranial pressure

Disadvantage: Respiratory depressant, myocardial depressant, decrease arterial blood pressure and cardiac output (not good for patients with cardiac dysfunction)

• can also reduce liver function temporarily

examples of benzodiazepines

lorazepam, diazepam, midazolam

Benzodiazepines MOA

Potentiate GABAergic inhibition in brain regions

• increase the frequency of GABAa channel opening in response to GABA

DOES NOT ACTIVATE GABAa CHANNEL IN THE ABSENCE OF GABA

difference between barbiturates vs benzodiazepines MOA

Barbiturates increase the duration of GABAa channel

Benzodiazepines increase the frequency of GABAa channel (allosteric site)

• does NOT activate GABAa channel in the absence of GABA

T/F at high concentrations, benzodiazepines can directly activate GABAa receptors

FALSE; benzodiazepines require the prior binding of GABA to GABAa receptors

onset of action of benzodiazepines vs barbiturates

Benzodiazepines have a slower onset of action than barbiturates

Characteristics of benzodiazepines in clinical use

Slower onset than barbiturates: Midazolam effects are slower than thiopental but has a longer duration of action.

Midazolam > diazepam > lorazepam

Does NOT reach surgical levels of anesthesia alone

• significant sedation and amnesia

High doses may result in very long recovery from anesthesia, post operative respiratory depression

what can be used to accelerate recovery from sedative effects of benzodiazepines?

flumazenil (antagonist)

Propofol MOA

Potentiate GABA action, directly activate GABAa receptor channel opening

Propofol clinical use

Popular, replacing barbiturates as induction agents

• Rapid onset of action: similar barbiturates

• Rapid recovery: faster than barbiturates

• Comfortable recovery: better than barbiturates (anti-emetic)

Commonly used for For surgery, part of a cocktail induction and maintenance

• Used alone for outpatient surgery procedures

  • ADR: prolonged sedation in critical care patients

ADR for propofol

• Respiratory depressant: similar to thiopental

• Decrease in systemic blood pressure: via vasodilation

• Cardiovascular effects (hypotension): worse than etomidate or thiopental (barbiturates)

• Pain (common, at injection site/water insoluble)

CLEARANCE: Liver and other mechanisms

Etomidate MOA

potential GABA action, directly activate GABAa receptor channel opening

• imidazole derivative

Etomidate clinical use

• Used for induction: rapid onset, rapid recovery

• No analgesic effects: given with opioids to block intubation response

• Causes minimal cardiovascular and respiratory depression

  • no change in HR, little hypotensive effect

Toxicity: Pain on injection, post-operative N&V

• Prolonged infusion can cause hypotension and electrolyte imbalance

No analgesic effect

MOA of ketamine

Blocks excitatory NMDA glutamate receptors

• Can cause dissociative anesthesia: catatonia (loss of movement), amnesia, analgesia, may retain consciousness

what is ketamine used for

• analgesia

• stimulated the cardiovascular system

• increase HR, BP, output (good for pts with weak cardiac function)

• Increases cerebral blood flow

  • should not be used in patients with elevated intracranial pressure

ketamine toxicity

decreases respiratory rate

post-operative emergence reactions: disorientation and hallucinations

• inhibited with prior benzodiazepine (etomidate)

• NOT USED in the elderly (low cardiovascular activity)

• Children (less sensitive psychic effects)

Opiates MOA

full agonists at the u opioid GPCRs

opiates clinical use

moderate general anesthesia

• Morphine/Fentanyl combined with N2O benzodiazepines

• Pts with low circulatory reserve

Premedication and induction agents or as an adjunct for other anesthetics

• alfentanil and remifentanil: short duration of action

• Remifentanil has fastest metabolism; fastest recovery

  • ambulatory procedures

• Opioids useful for spinal and epidural applications: post-operative analgesia

• Outpatient procedures as fast recovery and short acting

• Cocktail of balanced anesthesia

• Conscious sedation: minor procedures

opioids ADR

impaired ventilation due to rigidity of the chest wall

prolonged postoperative respiratory depression —> reversed with naloxone

The primary mechanism for most general anesthetics is to:

A. Activate GABA_A

B. Inhibit GABA_A

C. Activate GABA_B

D. Inhibit GABA_B

A) Activate GABA_A receptors

downstream effect is inhibition bc GABA is inhibitory

In inhaled anesthetics, faster onset of action is predicted by

A. High blood solubility
B. Low blood solubility
C. High MAC
D. Low MAC

B) Low blood solubility

Low blood solubility = more for the gas = easier to get to the brain OR low blood solubility = hates water = lipophilic

Onset deals with Solubility and Speed and path to the brain

MAC deals with efficacy and potency (similar to EC50)

In inhaled anesthetics, maximal efficacy is predicted by_________.
A. High blood solubility
B. Low blood solubility
C. High MAC
D. Low MAC

D) low MAC

MAC deals with efficacy and potency (similar to EC50) → Minimum alveolar anesthetic concentration; low possible dose for same efficacy

Low blood solubility = more for the gas = easier to get to the brain OR low blood solubility = hates water = lipophilic

Onset deals with Solubility and Speed

Which of the following would be a reasonable level of inhaled anesthesia for major surgery?
A. Pure nitrous oxide
B. Pure halothane
C. 10% isoflurane
D. 2% sevoflurane + 3% desflurane
E. 3% halothane + 1% sevoflurane

D. 2% sevoflurane + 3% desflurane

This would give 2% Sevoflurane = 1 MAC (2.0% is needed for 1 MAC) and 3% desflurane = 0.5 MAC (6-7% is needed for 1 MAC)

The MAC in percent is the percent need to achieve 1 MAC

Which drug causes the least effect on blood pressure and respiration?
A. Halothane
B. Enflurane
C. Sevoflurane
D. Desflurane
E. Nitrous oxide

E. Nitrous Oxide

Safest overall with the lowest MAC

What kind of receptors are glutamate receptors?

Major excitatory NT in the CNS; when glutamate binds to its receptors? The sodium channels open up; Ligand gated CATION channels