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Transcript of 2nd Year Special
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The Chemistry of Pain
Anaesthetics
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The Chemistry of Pain
Christened by Oliver Wendell Holmes
Greek:
an without
esthesia - sensibility
Anaesthesia:
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Outline
Basic Physiology of the Nervous System
History of Anaesthetics - Early methods
- N2O, ether, chloroform
Local Anaesthetics - Intravenous
General An
aesthetics - Inh
alation/vol
atile
- Intravenous
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Anatomy of the a nerve cell
Sensory neurons:
Messages to CNS
Motor neurons: Messagesfrom CNS
Interneurons: Messages
within CNS
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Signal propagation
Negative resting potential(-65mV), positive outside the
cell due to Na+
Na+ enters cell, alters
potential, influx of Na+
intocell (Na+ gate opens)
Positive membrane potential,
K+ moves out (K+ gate
opens)
Na+/K+ pump resets resting
potential (active transport)
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Synapse
Action potential, release of neurotransmitters, binds to receptors,initiate or inhibit action potential
Acetylcholine, norepinephrine, dopamine (Parkinsons), GABA(tetani), etc.
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History
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History
Herodotus (c.484 BC)- hemp induced stupor
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaults
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaultsApuleius (5th century)
- wine
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaultsApuleius (5th century)
- wine
Arnold of Villanova (13th century)
- mixture of opium, mandragora
and henbane
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaultsApuleius (5th century)
- wine
Arnold of Villanova (13th century)
- mixture of opium, mandragora
and henbane
Incas
- coca
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaultsApuleius (5th century)
- wine
Arnold of Villanova (13th century)
- mixture of opium, mandragora
and henbane
Incas
- coca
Chinese
- acupuncture (endogeneous opiods)
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History
Herodotus (c.484 BC)- hemp induced stupor
Egyptians
- half-asphyxiate by strangling
Oracles of Delphi
- vapours from vaultsApuleius (5th century)
- wine
Arnold of Villanova (13th century)
- mixture of opium, mandragora
and henbane
Incas
- coca
Chinese
- acupuncture (endogeneous opiods)
Non-pharmacological
- blood letting (often fatal)
- ice
- counter irritation
(nettles)
- nerve clamping
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History - N2O
Isolated by Joseph Priestley (1772)
Icannot help flattering myself that, in time, very great
medicinal use will be made of the application of these different
kinds of airs
Exhilarating effects described by Sir Humphry Davy (~1790)
WheneverIhave breathed the gas, the delight has been
often intense and sublime.
Michael Faraday compared the pain-relieving effects of N2O
with the action of sulphuric ether (1818) Public demonstration by dentist Horace Wells (1845) - failed
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Discovered by Raymundus Lullius (13th century)
Synthesis described by Valerius Cordus (1540)
Pracelsus noted its tendency to promote sleep and how it
quiets all suffering without any harm and relieves all pain, andquenches all fevers, and prevents complications in all
disease.
Recommended and marketed for pain relief by Friedrich
Hoffmann under the name Adodyne (~1700)
First used as surgical anaesthetic by Crawford WilliamsonLong to remove a cyst from the neck ofa patient (1842)
Public demonstration by dentist William Morton (1846)
History - Ether
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History - Chloroform
Discovered by Samuel Guthrie (1831)
Named and chemically characterised by Jean-Baptiste
Dumas (1834)
First used as general anaesthetic by James Young Simpson
(1847)
Given to Queen Victoria during the birth of Prince Leopold
(1853)
Not as safe as ether first fatality in 1848
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Local Anaesthetics
= Drugs used to produce reversible loss of sensation in a
circumscribed area of the body.
Two classes: Esters and Amides
Esters: Unstable in solution, hydrolysed by esterases,
breakdownp-aminobenzoate associated with allergic
responses and hypersensitivity.
Amides: Metabolised by hep
atic
amid
ases, hypersensitivityreactions are rare.
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Local Anaesthetics
Mode ofaction:
Act in peripheral nerves decreasing the rate and degree of
depolarisation, threshold potential not reached.
Block Na+
channels. Amine bases administered as hydrochloride salts.
Equilibrium depending on pH of tissue fluid, alkaline:
BH+ + HCO3- B + H2CO3
Deprotonated species diffuses to axoplasmw
here equilibriumis established again.
BH+ blocks Na+ channel from the interior of the nerve fiber.
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Signal propagation
Negative resting potential(-65mV), positive outside the
cell due to Na+
Na+ enters cell, alters
potential, influx of Na+
intocell (Na+ gate opens)
Positive membrane potential,
K+ moves out (K+ gate
opens)
Na+/K+ pump resets resting
potential (active transport)
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Ester: Procaine (2-(diethylamino)ethyl 4-aminobenzoate)
- constricts blood vessels
- allergic responses
Amide:Lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide)
- doesnt constrict blood vessels
- used with epinephrine
Local Anaesthetics
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Local Anaesthetics
Prilocaine (2-(propylamino)-N-o-tolylpropanamide)
- Dentistry
- Often combined with lidocaine
Bupivacaine (1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide)
- Co-administered with adrenalin
- Cardiotoxic
Ropivacaine ((S)-N-(2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide)
- Less cardiotoxic
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General Anaesthetics
= Drugs with the capacity to produce a state in which surgery
can be tolerated. Provides pain relief, immobility and
unconsciousness.
Halogenated ethers, barbiturates, benzodiazepines, opoids. Meyerand Overton (~1900) correlation between
anaesthetic potency and lipophilicity.
Lipid theory: General anaesthetics act through a common
non-specific mechanism by dissolving and causing structural
changes in the lipid bilayer of nerve cells.
Franks and Lieb (1994) anaesthetics interact directly with
proteins and optical isomers differ in potency.
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General Anaesthetics
Mode ofaction:
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General Anaesthetics
GABAA receptors:
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Signal propagation
Negative resting potential(-65mV), positive outside the
cell due to Na+
Na+ enters cell, alters
potential, influx of Na+
intocell (Na+ gate opens)
Positive membrane potential,
K+ moves out (K+ gate
opens)
Na+/K+ pump resets resting
potential (active transport)
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General Anaesthetics - Volatiles
Lipid soluble
Low blood/gas solubility
Non-toxic
Not metabolised
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General Anaesthetics - Volatiles
Isoflurane (2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane)
- Administered with air/O2
- Maintainanaesthesi
a
- Irritable
Desflurane (2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane)
- React with CO2, detectable CO
- Maintainanaesthesi
a
- Irritable
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General Anaesthetics - Volatiles
Sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane)
- Administered with N2O and O2
- Induction- Sweet smelling, less irritable
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General Anaesthetics - Non-opoid
Barbitur
ates:
Methohexital (5-allyl-5-(hex-3-yn-2-yl)-1-methylpyrimidine-
2,4,6(1H,3H,5H)-trione)
- Short-acting
- Inducea
nd ma
inta
ina
na
esthesia
- Oral surgery
- Not analgesic
Thiopental (5-ethyl-2-mercapto-5-(pentan-2-yl)pyrimidine-
4,6(1H,5H)-dione)
- Slow elimination- Induce anaesthesia
- Used in lethal injections along with
pancuronium bromide and KCl
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General Anaesthetics - Non-opoid
Benzodi
azepines:
Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-
imidazo[1,5-][1,4]benzodiazepine)- Induce anaesthesia
- Used in combination with other
anaesthetics
- Not analgesic
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General Anaesthetics - Non-opoid
Others:
Etomidate (ethyl 1-((R)-1-phenylethyl)-1H-imidazole-5-
carboxylate)
- Ester hydrolysis
- Rapid induction
- Low cardiovascular risk
Propofol (2,6-diisopropylphenol)
- Short-acting
- Induce and maintain anaesthesia
- Not analgesic
- Hypotention
- Pain on injection (pretreat with lidocaine)
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General Anaesthetics - Non-opoid
Others:
Ketamine ((S)-2-(2-chlorophenyl)-2-(methylamino)-
cyclohexanone)
- Induce and maintain anaesthesia
- Analgesic
- Muscle relaxant
- Increase heart rate and blood pressure
- Hallucinations not primary anaesthetic
- Cataleptic state if used alone
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General Anaesthetics - Opoid
Can produce unconsciousness but unreliable
Used with non-opoid and inhalation anaesthetics to relief pain
Fentanyl analogues
Fentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylpropionamide)
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General Anaesthetics - Opoid
Analogues:
Alfentanil Remifentanil Sufentanil
Carfentanil
- 10 000 x more analgesic than
morphine
- 100 x more potent than fentanyl
- tranquiliser, immobilise elephants
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Conclusion
Methods to cope with surgical pain explored and
performed throughout history.
Breakthroughs came with the discovery of N2O, ether
and chloroform.
Exact mechanism ofaction of current anaesthetics notfully understood.
Various anaesthetic agents used in combination to
achieve desired surgical state.
Mortons Grave: Inventor andRevealer of Anaesthetic
Inhalation, Before Whom, in All Time, SurgeryWas
Agony, ByWhom Pain in Surgery was Averted and
Annulled, Since Whom Science Has Control of Pain
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Sleep tight
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References www.wikipedia.org
www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookNERV.html
www.nda.ox.ac.uk/wfsa/html/u04/u04_014.htm
www.general-anaesthesia.com
Rudolph, U. and Antkowiak, B. Nature Reviews Neuroscience,
2004, 5, 709. Hemmings, H.C. et al. Trends in PharmacologicalSciences, 2005,
26, 503.
Orser, B.A. Scientific American, June 2007.
Walser, A. et al. J. Org. Chem. 1978, 43, 936.
Bieniarz, C. et al. Organic Process Research and Development,2000, 4, 581.
Brunner, H. Chirality, 2001, 13, 420.
www.erowid.org/archive/rhodium/chemistry/pcp/ketamine.html
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Midazolam