2nd Year Special

8/6/2019 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


Egyptians

- half-asphyxiate by strangling

Oracles of Delphi

- vapours from vaults


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History


Egyptians


Oracles of Delphi

- vapours from vaultsApuleius (5th century)

- wine


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History


Egyptians


Oracles of Delphi


- wine

Arnold of Villanova (13th century)

- mixture of opium, mandragora

and henbane


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History


Egyptians


Oracles of Delphi


- wine



and henbane

Incas

- coca


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History


Egyptians


Oracles of Delphi


- wine



and henbane

Incas

- coca

Chinese

- acupuncture (endogeneous opiods)


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History


Egyptians


Oracles of Delphi


- wine



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


cell due to Na+






opens)




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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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Mode ofaction:


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GABAA receptors:


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Signal propagation


cell due to Na+






opens)




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General Anaesthetics - Volatiles

Lipid soluble

Low blood/gas solubility

Non-toxic

Not metabolised


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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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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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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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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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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

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