Anaesthetics

Prof G Woodhall
 Lecture Outline-Learning Objectives.
• To provide a very general overview (taster) of
anaesthesia from a pharmacological perspective.
• To provide a comparison of general, regional and
local anaesthesia.
• To provide an overview of the concepts and
terminology used to describe anaesthetic potency.
• To integrate molecular, cellular and systems level
target sites to the discussion.
• I am NOT going to give you dosing information.
A definition

Anaethesia from Greek:

an – lack of

aisthsis – feeling
Basic Principles of Anaesthesia

Anaesthesia - abolition of sensation

Analgesia - abolition of pain
‘Triad of General Anesthesia’
need for unconsciousness
need for analgesia
need for muscle relaxation
Why bother?

Consider the world without anaesthics…

A reproduction from a woodcut from Hans Von Gersdorff's
Feldtbuch der Wundtarzney, Strassburg, J. Schott, 1517, this is
reputed to be the first known picture of an amputation. The four
figures are the patient, the operator and his assistant, and probably
a priest. (Courtesy of the American College of Surgeons).
 A true story…

One of the most thorough descriptions of preanaesthetic surgery can be found in a 12-page letter written by English
author Fanny Burney to her sister Esther in March 1812, after surviving a mastectomy in 1811. For pain and induration
in her breast, she sought the opinions of several respected medical and surgical consultants and was devastated
when they concluded she had a life-threatening cancer: "[I]n time I was formally condemned to an operation by all
three."

When the fateful day arrived, her only premedication was a "wine cordial," and she courageously submitted to the
team of seven physicians who had arrived at her home in Paris. She tried to ignore the entire closet they filled with
compresses and bandages, and one tactfully "inquired whether I had cried or screamed at the birth of [my son]
Alexander ... what terrible inferences were here to be drawn." She lay on her bed, and although her face was covered
with a light handkerchief, she could see the surgeon outline his intended incision with a forefinger and "the glitter" of
his knife. "When the dreadful steel was plunged into the breast, cutting through veins, arteries, flesh, nerves, I needed
no injunction not to restrain my cries. I began a scream that lasted unintermittingly during the whole time of the
incision, and I almost marvel that it rings not in my ears still! So excruciating was the agony."

A second incision was made, and when the knife was withdrawn, "I concluded the operation over. Oh no! Presently the
terrible cutting was renewed and worse than ever...." Even when the tissue was severed from her body, "yet again all
was not over," I then felt the knife rackling against the breastbone, scraping it! This performed, while I remained in
utterly speechless torture...." When it was over, she was carried virtually lifeless from the bed but did recall looking up
at her surgeon who was "pale nearly as myself, his face streaked with blood and its expression depicting grief,
apprehension, and almost horror."
 History of anaesthesia in 10⅓ lines

Chinese – acupuncture
Hindu – henbane, wine and hemp
Ancient Greek Discorides coined term anaesthsia for effects of drinking
mandrake
Early Arab writing – inhalation via the ‘soporific sponge’. Sponge soaked in
a dissolved solution of opium, mandragora, hemlock juice
Manual methods –compression, bleeding, smack on head
1800 Humphry Davy N2O
1818 Davy's student Michael Faraday (1791-1867) determined that
inhalation of ether had the same effect
1842 Crawford Long 1st operation under GA
1844 Robert Liston 1st AMPUTATION under GA (ether)
2005 Jeanna Giese kept in GA coma for 8 days, tapered over 31 days in
total with few ill effects
 Anaesthetic Techniques.
These Can Be Combined.
Inhalational
or ‘volatile’
General
Anaesthesia Intravenous
Local

Regional

Conscious sedation: use of small amounts of anaesthetic or benzodiazepines

to produce a ‘sleepy-like’ state. (Maintain verbal contact but feel comfortable)
 Anaesthesia From a Practical Viewpoint.
• Premedication (Hypnotic-benzodiazepine).
• Induction (usually intravenous but may be inhalational).
• Intraoperative analgesia (usually an opioid).
• Muscle paralysis-facilitate intubation/ventilation/stillness.
• Maintenance (intravenous and/or inhalational).
• Reversal of muscle paralysis and recovery which includes
postoperative analgesia (opioid/NSAID/paracetamol).
• Provision for PONV.
• POINT: during anaesthesia many (interacting) pharmacological
agents “on board” requiring excellent pharmacological knowledge
and skill to manage.
 Despite Polypharmacology
Anaesthesia Is Very Safe.
• Deaths caused by anaesthesia are very rare.
– In UK ~5/1,000,000 anaesthetics given.
– (In 1940s ~640/1,000,000)
• Side effects covered later
Inhalational or ‘Volatile’ General
Anaesthesia.
 General Anaesthetics Difficult To
Classify-VAST Range Of Structures.

Gases-Volatiles-Delivered via lungs

• Intravenous
• Propofol
• Barbiturates
• Etomidate
• Ketamine
Guedel’s signs:
Stage 1: analgesia and consciousness
Stage 2: unconscious, breathing erratic
but delirium could occur, leading to an
excitement phase.
Stage 3: surgical anaesthesia, with four
levels describing increasing depth until
breathing weak.
Stage 4: respiratory paralysis and
death.

Anaesthesia is a combination of;

• Analgesia
• Hypnosis (loss of
consciousness)
• Depression of spinal reflexes
•Muscle relaxation
(insensibility and immobility)
End-Point Is Concentration Dependent. For
Volatiles We Use MAC To Describe Potency.
MAC and Volatile Anaesthetic Potency.
• What is potency ? (M&R year 1).
• Volatile anaesthetic potency is described by MAC or
Minimum Alveolar Concentration.
– [Alveolar] (at 1atm) at which 50% of subjects fail to move to
surgical stimulus (unpremedicated breathing O2/air)
– At equilibrium [alveolar] = [spinal cord]
– MAC, MAC-BAR (Autonomic Response), MACawake
• Anatomical substrate for MAC is spinal cord
– In animal models if section cord (i.e., remove connection to
the brain) MAC is unchanged.
 Factors Affecting Induction and
Recovery.
Partition coefficients (solubility)
• Blood:Gas partition (in the blood)
– Low value fast induction and recovery e.g., desflurane
• Oil:Gas partition (in fat)
– Determines potency and slow accumulation due to
partition into fat (e.g, halothane)
 What Affects MAC ?
• Age (High in infants lower in elderly)
• Hyperthermia (increased); hypothermia
(decreased)
• Pregnancy (increased)
• Alcoholism (increased)
• Central stimulants (increased)
• Other anaesthetics and sedatives
(decreased)
• Opioids (decreased)
 MAC and effects of Nitrous Oxide.
In Oxygen In 50-60% N2O
Halothane 0.75% 0.29%
Isoflurane 1.15% 0.59%
Sevoflurane 1.85% 0.57%
Desflurane 6.00% 3.00%
N2O 105% --
Nitrous Oxide is very often added to other
volatile agents (reduced dosing).
(30-60 year olds)
Molecular Target: Meyer-Overton (like)
Anaes Potency Correlates Lipid Sol and GABAA
activity.

Potency and Lipid Sol Potency and GABAA interaction

Common ‘Anaesthetic’ Theme
GABAA Receptors.
• GABAA receptors critical target
• Major inhibitory transmitter
• LGIC (Cl- conductance)
• Potentiate GABA activity
• Anxiolysis
• Sedation
• Anaesthesia
•With the exception of Xe,N2O and
ketamine all anaesthetics potentiate
GABAA mediated Cl- conductance to
depress CNS activity.
• NMDA receptors probable other
Molecular-Cellular Target.
In the brain consciousness is
(simplistically) a balance
between excitation
(Glutamate) and inhibition
(GABA).

Anaesthetics modulate this

balance.
 Systems Target: Brain Circuitry.
• Reticular formation (hindbrain, midbrain and thalamus)
depressed. Connectivity lost.
• Reticular system often called “activating system” due to
ability to increase arousal.
• Thalamus transmits and modifies sensory information.
• Hippocampus depressed (memory).
• Brainstem depressed (respiratory and some CVS).
• Spinal cord-depress dorsal horn (analgesia) and motor
neuronal activity (MAC).
 Targets: Putting it all together in a ‘whole’ human
GABAA receptors activated in human brain during anaesthesia.

In test tube Isoflurane

potentiates benzodiazepine
binding.
Intravenous General Anaesthesia.

Propofol
 Main Intravenous Anaesthetics.
• Propofol (rapid), Barbiturates (rapid), Ketamine
(slower).
• Given intravenously for ‘induction’.
• Can be used as sole anaesthetic in TIVA (Total
IntraVenous Anaesthesia).
• Target sites as for inhalational.
• With exception of Ketamine (NMDA) all potentiate
GABAA.
• Systems target as for inhalational.
 How Do We Describe Intravenous
Anaesthetic Potency ?
• Plasma concentration to achieve a specific end
point (loss of eyelash reflex or a BIS value or…..).
• For induction in mixed anaesthesia – Bolus to end
point then switch to volatile.
• TIVA uses a defined PK based algorithm to infuse
at a rate to maintain set point. Preceded by a
bolus.
Local and Regional Anaesthesia.

Dentistry
Obstetrics
Regional surgery (patient awake)
Post-op (wound pain)
Chronic pain management (PHN)
 Local Anaesthetics: Lidocaine,
Bupivacaine, Ropivacaine and Procaine.
Characteristics
• Lipid solubility – potency
(higher greater potency)
• Dissociation constant
(pKa)
– time of onset. Lower pKa
faster onset
• Chemical link –
metabolism
• Protein binding – duration
Bupivacaine Infiltration For
Wound Analgesia.
• Cocaine archetypal
• Esters-shorter acting
• Amides-longer acting
• Block is USE Dependent
• Block small myelinated
(afferent) nerves

in preferance hence
nociceptive and symp block
• Adrenaline ↑ duration
Bupivacaine an amide so more stable-longer lasting. Slow onset (pKa 8.2).
 Comparison of Lidocaine, Bupivacaine,
Ropivacaine and Procaine.
Potency Speed Metab
*O:B pKa Linker Duration
Protein Bind
Lidocaine 43 7.8 Amide 64%
Bupivacaine 346 8.2 Amide 95%
Ropivacaine 115 8.2 Amide 94%
Procaine 1.7 8.9 Ester 6
*O:B, Octanol:Buffer partition coefficient is an index of lipid solubility

Compared to Procaine, Bupivacaine is more potent with a longer

duration of action. Procaine is esterase metabolised and has a
slower onset time but not much in it.
 Regional Anaesthesia.
• As the name suggests selectively anaesthetising a part
of the body.
• Often described as a ‘block’ of a nerve and hence the
patient remains awake.
• Uses local anaesthetic and or an opioid.
• Upper extremity (e.g.,); interscalene, supraclavicular,
infraclavicular, axillary.
• Lower extremity (e.g.,) ; femoral, sciatic, popliteal,
saphenous.
• Extradural / Intrathecal / Combined (labour).
 Main Anaesthetic Side Effects.
(from the very common 1:10 category for GA)
• Too many agent specific effects to list and remember
polypharmacology !
• General anaesthesia
– PONV (opioids)
– CVS – hypotension
– PO Cog Dysfunc (increases with increasing age)
– Chest infection
– Postoperative urinary retention (POUR)
• Local and regional
– Depends on the agent used and usually result from systemic spread (Locals are Na+
channel blockers so cardiovascular toxicity)
• Increased general concern re: allergic reactions/anaphylaxis
Anaesthetic of the Future: Xenon
• Rare gas extracted from air
• Very expensive to produce
• Close to ideal anesthetic
• Low blood and tissue solubility
• (rapid induction/recovery)
• Potent
• Not metabolized
• Nonflammable
• Minimal side effects
 Summary.
• Anaesthesia good example of polypharmacology.
• Anaesthesia: General, regional or local.
• Vast array of agents for general; volatile or i.v.
• Main molecular targets of interest are;
– GABA transmission.
– NMDA glutamate receptors.
– Voltage gated Na+ channels (locals).
• This has been a very brief overview. Most of the
exceptions to all pharmacological rules can be found in
anaesthesia !