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PHAR2005 > General Anaesthetics. Mechanism of Action of Ethanol. > Flashcards

General Anaesthetics. Mechanism of Action of Ethanol. Flashcards

1
Q

Which scientists first observed the anaesthetic effects of ether ?
When did GA become generally accepted ?

A

Priestley (1776) and Davy (1796), and Faraday (1816)
noted the anaesthetic effects of ether.
They became generally accepted when Queen Victoria
used chloroform during the birth of her 7th child.

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2
Q

What are GAs used for ?
What is their TI ?
What does this imply ?

A
  • Drugs in ubiquitous clinical use
  • Surgery, dentistry and intensive care
  • Narrow dose safety margins : TI ~ 4
  • Side effects range from mild to fatal
  • Highly trained anaesthetists and expensive monitoring equipment.
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3
Q

What are the 4 stages of anaesthesia ?

A

STAGE 1 : Analgesia (not all anaesthetics are
analgesic at sub-anaesthetic concentrations)
STAGE 2 : Excitement or delirium (ethanol!)
STAGE 3 : Surgical anaesthesia
loss of consciousness : 4 planes
- The eyes roll, then become fixed
- Corneal and laryngeal reflexes are lost
- The pupils dilate and light reflex is lost
- Intercostal paralysis and shallow abdominal respiration occur
STAGE 4 : Respiratory paralysis – Death – patient has severe brainstem depression

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4
Q

When was ether first used as an anaesthetic ?

What about chloroform ?

A

Ether first used as anaesthetic 1842

Chloroform first used 1847

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5
Q

What are the 2 main types of anaesthetics ?

A

a. Inhalation anaesthetics absorbed through lungs
gases or volatile liquids
b. Intravenous anaesthetics developed for induction of anaesthesia e.g. thiopentone, propofol, etomidate - increasingly used for short-duration operations and procedures e.g. propofol

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6
Q

Where do GAs bind ?
What is the common feature of all GAs ?
Which compound has lots of features in common w/ GAs ?

A

Specific “anaesthetic” receptors do not exist.
No features common to all anaesthetics apart from
lipid solubility.
Ethanol has many features in common with anaesthetics !

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7
Q

Name 4 structural factors that increase GA potency.

A

1) unsaturation
2) halogen substitution (Cl, Br, F)
3) ether group (C-O-C)
4) no hydrophilic groups (-OH, -NH2)

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8
Q

Name 6 gas GAs you know.

A 
(Diethyl ether)
(Chloroform)
Isoflurane
Haloflurane
(Cyclopropane)
Nitrous Oxide
Sevofluorane
Xenon
() = not is use anymore
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9
Q

What is the Meyer-Overton rule ?

A

GA potency is proportional to oil : water partition coefficient

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10
Q

What was the first theory concerning GA mechanism of action ?
How was it proven incorrect ?

A

First theory = anaesthetics are dissolving in lipid
bilayer and distorting it => incorrect
There are some enantiomers , e.g. Etomidate, where one is an anaesthetic and the other is not, despite identical lipid solubility

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11
Q

Which domains of proteins do GAs bind to ?

How does alcohol chain length affect potency ?

A

Franks & Lieb (1980s) showed anaesthetics bind to hydrophobic domains of proteins. (Their experiments were on firefly luciferase enzyme).
Long chain alcohols increase in potency up to a cut-off point of decanol. Dodecanol is much less potent. This defines the size of the binding pocket within the protein.

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12
Q

How do GAs affect neuronal fct ?

A

CNS : synaptic function is most sensitive to the effect of
anaesthetics - ion channels, pumps and receptors likely to be involved
Pathways normally involved in sleep may be most sensitive.
Brainstem synapses not so sensitive - respiratory depression

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13
Q

What are the molecular targtes of GAs ?

Which GAs are exceptions to this rule ?

A

Anaesthetics must be shown to modulate protein targets in lipid-free environments at clinically used concentrations
Neuronal ion channels are the most plausible targets
GABA-AR currents are potentiated by many GAs
Apparent affinity for GABA is increased
But…
nitrous oxide and xenon do not enhance GABA-AR function

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14
Q

Which GAs enhance the effects of GABA ?

What other effects do these molecules also have ?

A

Halothane, thiopentone, etomidate and propofol.
Also increase current through two-pore (leak) K channels,
which hyperpolarises neurons.
Also enhance the effect of glycine on glycine receptors (spinal cord) (immobility?)

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15
Q

How does xenon affect NMDARs ?

A

Xenon inhibits the Gly binding site (Gly = co-agonist for NMDAR) on NMDAR.

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16
Q

Name 4 inhalation GAs in common use and 4 not/no longer in use.

A 
In common use : 
- Halothane ?
- Enflurane
- Isoflurane
- Nitrous oxide            
Not/no longer in use : 
- Ether
- Cyclopropane
- Methoxyflurane
- Chloroform
17
Q

What is MAC ?

How is it measured ?

A 
MAC = the concentration in the lungs that is needed to prevent movement (motor response) in 50% of subjects in response to surgical (pain) stimulus
Alveolar concentration (partial pressure) is measured as end-tidal anaesthetic concentration.
This can be measured continuously – infrared spectroscope/mass spect
18
Q

What is the concentration of GA in the tissues compared to the lungs ? t

A 
The partial pressure (P) in lungs once stable will be the same in the tissue :
Equilibrium P(CNS) = P(blood) = P(alveoli) = P(blood)= P(CNS)
19
Q

What are the units of MAC ?

A

mmHg (% of atmospheric pressure, i.e. 760mmHg)

20
Q

What are the MACs of :

  • Isoflurane
  • Seveflurane
  • Desflurane
  • Nitrous oxide
A

Isoflurane => 1.15% (of 760mmHg)
Seveflurane => 7.05%
Desflurane => 7.25%
Nitrous oxide => 110.00%

21
Q

What are the factors influencing speed of induction and recovery of a GA ?

A

Blood : gas partition coefficient i.e. solubility in blood
λb/g
Oil : gas partition coefficient i.e. solubility in fat λO/G
High solubility in blood λb/g > 1 –> more agent in blood and less in gas phase –> need to dissolve more to gas to get certain partial pressure
If reverse blood λb/g < 1 less agent in blood more in gas phase
Poor solubility in blood –> quicker to reach equilibrium alveolar levels and in brain :
- onset quicker
-offset quicker
High lipid solubility :
- slower recovery
- accumulates in fat (reservoir)
- hangover

22
Q

What is the definition of MAC ?

A

Minimum Alveolar Concentration [MAC] = concentration in air giving safe level of anaesthesia in 50% of patients (lack of response to a painful stimulus)

23
Q

What is the minimum proportion of inspired O2 in inspired air ?

A

minimum O2 in inspired air is 15% = 114 mmHg

24
Q

Why is N2O not suitable alone for surgical anaesthesia ?

How is it therefore used ? - to what purpose ?

A

N2O : MAC = 101% atm = 767.6 mmHg
Minimum O2 inspired air is 15% = 114mmHg N2O is not suitable alone for surgical anaesthesia
- it is used in mixtures with other anaesthetics
- 50% N2O /air used for analgesia in childbirth

25
Q

What is the relationship between GA potency and MAC ?

What is MAC analogous to in classical pharmacology ?

A

GA potency is inversely proportional to MAC.

MAC is analogous to EC50.

26
Q

How is GA blood concentration at equilibrium calculated ?

What is the blood concentration at equilibrium of isoflurane ?

A

Blood concentration at equilibrium = MAC x solubility in blood
Isoflurane : Isoflurane 310 μM

27
Q

What properties should the ideal GA have in terms of MAC and blood solubility ?

A

Ideally a general anaesthetic should have a low MAC (high potency) and a low blood solubility (rapid onset and offset).

28
Q

How large is the safety margin for inhalation anaesthetics ?

A

Very low –> overdose causes death

29
Q

What are the adverse effects of halothane of the CV system ?

Which GA is therefore prefered ?

A
  • cardiac arrhythmias
  • blood pressure lowered
  • respiratory depression
    Replaced by isoflurane.
30
Q

What are the general adverse effects of GAs ?
What specific adverse effects are associated with :
- halothane
- N2O
- enflurane

A
  • Generally : nausea/hangover
  • Halothane : liver damage esp. with multiple exposure
  • H2O : megaloblastic anaemia-rare
  • Enflurane : epilepsy-like seizures
31
Q

Propofol, thiopental and etomidate are 3 IV anaesthetics.

What are the specific characteristics of each ?

A

1) Propofol :
Fast onset and recovery - CV and respiratory depression
Administered by continuous slow intravenous infusion - computer controlled - to avoid overdose risk
- very little abuse potential (as given i.v.).
- irritant at site of injection - pain
2) Thiopental
Fast onset slow recovery high lipid solubility
CV and respiratory depression
3) Etomidate
Fast onset + fast recovery
Excitatory effect during induction –> increase nausea
- Adrenocortical suppression

32
Q

Name an IV dissociative anaesthetic you know.

What ar its advantages and disadvantages ?

A

Ketamine analogue of phencyclidine :
DISADVANTAGES
- recovery slow
- hallucinations, less in children –> used in paediatric surgery, and as paediatric sedative after trauma
- widely used in veterinary practice
- widely abused (bladder damage on chronic use)
- produce incomplete anaesthesia: (dissociation from surroundings, light sleep), for use when co-operation needed
ADVANTAGES
A very good analgesic :
- lethal overdose rare can be used in combat zones or acute trauma outside hospital setting (e.g. London bombings)
- also orally active (can be used orally as analgesic)

33
Q

What kind of an anaesthetic is bupivocaine ?
What is it’s effect ?
What is it generally administered with ?
What is it used for ?

A

Bupivocaine = an injectable, epidural anaesthetic (local anaesthetic)
- long duration of action (usually given with narcotic analgesic e.g. Fentanyl)
- only gives pain control below site of epidural
Uses:
a. Childbirth
b. Minor surgery or lower limb surgery (e.g. hip replacement)
c. When co-operation needed
d. Pain control e.g. post-operative

34
Q

Which kinds of drugs are used perioperatively ?

A

1) Premedication :
- analgesic, anxiolytic, anti-emetic, anti-muscarinic
2) Induction :
- i.v .anaesthetic e.g.propofol
3) Maintenance
- inhalation anaesthetic- advantage that level of anaesthesia can be constantly titrated
- TIVA (Total intravenous anaesthetic - remifentanil μ-opioid agonist - rapid onset and peak effect, and short duration of action - rapidly metabolized by hydrolysis + propofol)
4) Muscle relaxant reduce plane of anaesthesia needed
(e. g. neuromuscular blocking drugs)
5) Local anaesthetic = for surface anaesthesia lignocaine

35
Q 
Cremophor EL (polyethoxylated castor oil) was previously available to treat anaphylactic reactions. However, this formulation was withdrawn from the market and  subsequently reformulated as an emulsion of a soya oil/propofol mixture.
What are the contents of the new mixture ?
A

The currently available preparation is :

  • 1% propofol, 10% soybean oil
  • 1.2% purified egg phospholipid as an emulsifier
  • 2.25% glycerol as a tonicity-adjusting agent
  • sodium hydroxide to adjust the pH

PHAR2005 (24 decks)

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