Local Anaesthetics: Structure & Chemistry

local anaesthetic agent

drug when given topically or parenterally to a local area produces a state of local anaesthesia

how do anaesthetics produce anaesthetic effect?

blocking nerve conduction in a localised area

clinical uses of local anaesthetics

dentistry, minor surgery, creams, throat spray, OTC products (strepsils/lozanges)

mechanism of local anaesthetics

block voltage gated sodium channels, preventing sodium influx and depolarisation of channel, resulting in no action potential and no pain signal

how do local anaesthetics work?

Block nerves that transmit sensation of pain from local area to brain

Act on cell membranes of the nerve cells

Transmission of signal along neuron due to changes in potential difference across membrane

are local anaesthetics reversible?

yes

types of local anaesthetics

esters, amides

examples of ester anaesthetics

cocaine, procaine

Examples of amide anaesthetics

lidocaine, bupivacaine

ester anaesthetics

unstable, rapidly hydrolysed, short duration of action

ester anaesthetics are hydrolysed by

pseudocholinesterase

hydrolysis of ester anaesthetics

p-aminobenzoic acid, an immune system activator

ester anaesthetics have a

higher allergy risk

amide anaesthetics

more stable, lower allergy risk, metabolised hepatically (liver), longer duration

all local anaesthetics have a risk of

cardiac arrest

example of topical anaesthetic

lidocaine hydrochloride

structural requirements of anaesthetics

lipophilic aromatic ring, hydrophilic tertiary amine, ester/amide chain linkage

best activity occurs when

lipophilicity and hydrophilicity are balanced

too lipophilic

toxic

too hydrophilic

poor membrane penetration

lipophilic aromatic ring

allows for membrane penetration

ester/amide linkage

determine stability of compound and metabolism

hydrophilic tertiary amine

ionisable to for water soluble salts, cationic form binds to sodium channel

benzoic acid ester

cocaine, important structure component for anaesthetic effects

what structure of cocaine is essential for anaesthetic effect

benzoate ester

n-methyl removal from cocaine

toxicity increases

quaternized nitrogen atom

anaesthetic activity lost

cocaine double ring structure

not necessary for anaesthetic effect

simplified piperidine structures

similar local anaesthetic effect to cocaine, low toxicity, stable in aqueous mediums

hydrolysed products of cocaine

no potency as anaesthetics, aqueous solutions not stable

discovery of modern local anaesthetics

tropane structure

benzocaine

benzoate ester synthesised in 1890

procaine

local anaesthetic, sufficiently water soluble and can be injected

how was procaine developed?

simplification of cocaine structure

mechanism of procaine

Act by blocking external entry into Na+ ion channels, preventing influx of Na + ions into neurons, binds to proteins forming channel and distorts structure completely to prevent conductance of sodium ions

advantages of procaine

does not have severe local and systemic toxicities of cocaine, less addictive

local anaesthetics exist in

equilibrium

uncharged anaesthetic

lipophilic, crosses membrane barrier via hydrophobic pathway

charged anaesthetic

hydrophilic, binds receptors and blocks sodium influx/conductance via entering sodium channel from hydrophilic pathway

local anaesthetics that are amines are

weak bases

where was cocaine previously used?

dentistry, ophthalmology

procaine disturbs

membrane structure

lidocaine

injected as a dental anaesthetic, minor surgery

topically to relieve itching, burning, inflammation

amine

basic, can be ionised at physiological pH

at what physiological pH are molecules ionised

7.4

neutral molecules

diffuse into lipid membrane more easily, anaesthetic enters in neutral form

charged form of anaesthetic

binds to receptor site

inflammation

produces acidic pH of extracellular fluid, increases ionisation of basic anaesthetics, more charged molecules means less neutral molecules to reach neurons and act on ion channels

more ionised drug

occurs at acidic pH, less membrane penetration results in reduced anaesthetic effect

higher pKa

lower concentration of uncharged base, and slower the diffusion into the nerve cells, longer onset duration

pKa of benzocaine

2.5-3.2, only used topically

hydrophilic centre

basic, ionised, water soluble

lipophilic centre

aromatic rinf, lipid soluble, cross non-polar lipid membrane

link groups contain

hydrocarbon chain

what was the first local anaesthetic and when?

cocaine, 1884

cocaine limitations

instability, toxicity, addiction

tropane ring

not a required structure

lidocaine (2)

amide, pKa 7.9, fast onset, moderate duration

bupivacaine

highly lipophilic, longer acting, higher cardiotoxicity

ropivacaine

long acting, s enantiomer only (less cardiotoxic)

articaine

thiophene ring increases lipophilicity, potent, ester side chain (rapid metabolism by esterases)

metabolism of esters

rapid hydrolysis by plamsa esterases, allergy risk

amides metabolism

hepatic metabolism

lidocaine metabolism

multiple conjugates

Articaine metabolism

ester rapidly hydrolysed to articaninic acid and glucoronidation occurs

lipophilic portion

aromatic group attached to carbonyl/amide series

intermediate chain

1-3 carbons linked to aromatic ring

amides

more resistant to metabolic hydrolysis, longer lasting, can increase systemic toxicity

Hydrophilic Portion

tertiary alkyl amine, able to form water soluble salts

binding of procaine to receptor site

hydrogen bonding, VDW, electrostatic interactions, permanent dipoles

racemates

equal amounts of R and S enantiomers

where are sodium ion channels found?

peripheral nervous system, bypass debilitating side affects associated with non-specific drugs

when was lidocaine synthesised?

1948

general anaesthesia

patients are unconscious and sensation free

Regional anaesthesia

numbs are of body (epidural)

sedation

patients drowsy and relaxed but not unconscious