General Anaesthetics. Mechanism of Action of Ethanol. Flashcards
Which scientists first observed the anaesthetic effects of ether ?
When did GA become generally accepted ?
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.
What are GAs used for ?
What is their TI ?
What does this imply ?
- 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.
What are the 4 stages of anaesthesia ?
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
When was ether first used as an anaesthetic ?
What about chloroform ?
Ether first used as anaesthetic 1842
Chloroform first used 1847
What are the 2 main types of anaesthetics ?
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
Where do GAs bind ?
What is the common feature of all GAs ?
Which compound has lots of features in common w/ GAs ?
Specific “anaesthetic” receptors do not exist.
No features common to all anaesthetics apart from
lipid solubility.
Ethanol has many features in common with anaesthetics !
Name 4 structural factors that increase GA potency.
1) unsaturation
2) halogen substitution (Cl, Br, F)
3) ether group (C-O-C)
4) no hydrophilic groups (-OH, -NH2)
Name 6 gas GAs you know.
(Diethyl ether) (Chloroform) Isoflurane Haloflurane (Cyclopropane) Nitrous Oxide Sevofluorane Xenon () = not is use anymore
What is the Meyer-Overton rule ?
GA potency is proportional to oil : water partition coefficient
What was the first theory concerning GA mechanism of action ?
How was it proven incorrect ?
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
Which domains of proteins do GAs bind to ?
How does alcohol chain length affect potency ?
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.
How do GAs affect neuronal fct ?
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
What are the molecular targtes of GAs ?
Which GAs are exceptions to this rule ?
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
Which GAs enhance the effects of GABA ?
What other effects do these molecules also have ?
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?)
How does xenon affect NMDARs ?
Xenon inhibits the Gly binding site (Gly = co-agonist for NMDAR) on NMDAR.
Name 4 inhalation GAs in common use and 4 not/no longer in use.
In common use : - Halothane ? - Enflurane - Isoflurane - Nitrous oxide Not/no longer in use : - Ether - Cyclopropane - Methoxyflurane - Chloroform
What is MAC ?
How is it measured ?
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
What is the concentration of GA in the tissues compared to the lungs ? t
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)
What are the units of MAC ?
mmHg (% of atmospheric pressure, i.e. 760mmHg)
What are the MACs of :
- Isoflurane
- Seveflurane
- Desflurane
- Nitrous oxide
Isoflurane => 1.15% (of 760mmHg)
Seveflurane => 7.05%
Desflurane => 7.25%
Nitrous oxide => 110.00%
What are the factors influencing speed of induction and recovery of a GA ?
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
What is the definition of MAC ?
Minimum Alveolar Concentration [MAC] = concentration in air giving safe level of anaesthesia in 50% of patients (lack of response to a painful stimulus)
What is the minimum proportion of inspired O2 in inspired air ?
minimum O2 in inspired air is 15% = 114 mmHg
Why is N2O not suitable alone for surgical anaesthesia ?
How is it therefore used ? - to what purpose ?
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
What is the relationship between GA potency and MAC ?
What is MAC analogous to in classical pharmacology ?
GA potency is inversely proportional to MAC.
MAC is analogous to EC50.
How is GA blood concentration at equilibrium calculated ?
What is the blood concentration at equilibrium of isoflurane ?
Blood concentration at equilibrium = MAC x solubility in blood
Isoflurane : Isoflurane 310 μM
What properties should the ideal GA have in terms of MAC and blood solubility ?
Ideally a general anaesthetic should have a low MAC (high potency) and a low blood solubility (rapid onset and offset).
How large is the safety margin for inhalation anaesthetics ?
Very low –> overdose causes death
What are the adverse effects of halothane of the CV system ?
Which GA is therefore prefered ?
- cardiac arrhythmias
- blood pressure lowered
- respiratory depression
Replaced by isoflurane.
What are the general adverse effects of GAs ?
What specific adverse effects are associated with :
- halothane
- N2O
- enflurane
- Generally : nausea/hangover
- Halothane : liver damage esp. with multiple exposure
- H2O : megaloblastic anaemia-rare
- Enflurane : epilepsy-like seizures
Propofol, thiopental and etomidate are 3 IV anaesthetics.
What are the specific characteristics of each ?
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
Name an IV dissociative anaesthetic you know.
What ar its advantages and disadvantages ?
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)
What kind of an anaesthetic is bupivocaine ?
What is it’s effect ?
What is it generally administered with ?
What is it used for ?
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
Which kinds of drugs are used perioperatively ?
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
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 ?
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
