Local Anaesthetics I

8/3/2019 Local Anaesthetics I

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Local Anaesthetics - 1

Neuropharmacology – BIOL 20782

Dr. Liz FitzgeraldTel. x55495

Email. [email protected]



To prevent pain within a localised area of thebody, e.g. nerve endings of the teeth, cornea,skin

Exert main effects on PNS

Provide relief from prolonged severe pain

Enable minor operative procedures to becarried out

Investigative pharmacology

Local Anaesthetics



Epidural/spinalIntravenous regional

Some examples of uses……

Corneal surgery



Mode of action

Reversible depression of nerve conduction

Block voltage-gated sodium channels

(VGSCs) that underlie the generation ofAPs along nerve axons



Some History…

Coca leaves – psychotropic effects + numbing effectson mouth and tongue, used by South American Indiansfor 1000s yrs.

Cocaine – isolated 1860, proposed as a local anaesthetic

(LA) for surgical use. Use in reversible cornealanaesthesia reported 1884. Introduced as LA indentistry and general surgery.

Procaine – synthetic substitute discovered 1905.

http://cocaine.org/cocatooth.htm



Basic structure

- lipophilic end (aromatic ring,left)

- hydrophilic end (secondary/tertiary amine group, right)

- connected by intermediate

chain (ester or amide , shaded).

Benzocaine is an exception,lacking a side-chain amino

group.

Table 44.1 – new Rang



LA compounds must penetratethe nerve sheath and axonmembrane to reach the inner

(cytoplasmic) end of the sodiumchannel (where the LA bindingsite is located).



pH-dependence of LA action(Tissue penetration)

Most LAs are tertiary amines and are weak bases (pK a 8to 9).

In tissue fluids, LAs are present in both ionized (BH+)

and non-ionized forms (B);

B + H+ BH+

their relative proportions being dependent on pH of thesolution and pK a of the individual drug.



Extracellular Intracellular

ionised BH + - NOT membrane permeant

non-ionised B – membrane permeant

Fig. 44.2 – new Rang

Non-ionised B diffuses through the nerve sheath into the axon,where it partially ionises again. As ionised BH + , LA binds to itstarget, the sodium channel.



LA activity is…..

- increased at alkaline pH – when the proportion of

BH + is low

-decreased at acid pH – when the proportion of BH + is high

pH dependence is clinically important because inflamedtissues are often acidic and therefore, somewhatresistant to LAs.

LA activity (speed of onset)is strongly pH-dependent




Quaternary amine LAs (fully ionized) – injected inside nerve axon

Uncharged molecules, e.g. Benzocaine – dissolve in membrane

Rates of tissue penetration differ but ionized/non-ionized LAs

work in the same way, by binding to VGSC.



Tissue penetration of LAs

Good Cocaine

Lidocaine (lignocaine)

Moderate Tetracaine (methacaine)BupivacainePrilocaine

Poor Procaine



LA action on neuronal action potentials

Regenerative inward Na+ current(voltage-gated sodiumchannels (VGSCs), initiates

the AP.

LAs block the initiation andpropagation of action potentials

by blocking VGSCs andpreventing voltage-dependentincrease in Na+ conductance,gNa.



Many LAs exhibit use (frequency)-dependent block of VGSCs

Depth of block increases with action potential frequencybecause LA molecules….

- gain access more readily to open channels

than resting or inactivated channels

- have higher binding affinity for inactivated channels than for resting channels





VGSCs exist in at least 3 different functionalstates –

resting activated inactivated

resting = closed state that prevails at normal resting potential

activated = open state favoured by brief depolarisation

inactivated = blocked state resulting from trapdoor-like occlusionof the channel by a “floppy” part of the intracellularregion of the protein.

LAs



Use (frequency)-dependent block

LA-binding increases with increasingfrequency of APs due to increasedrate at which LAs can access channels(more open channels)+ increased numbers of inactivated

(LA-sensitive) channels generated.

frequency of action potentials number of channels in active/inactive states probability of channels being blocked + nos.of LA-sensitive channels in inactive state.

Thus, block builds up over time .





Access to open channelsHydrophilic vs. Hydrophobic pathways


Fig 44.2 –

new Rang et al !!!!!



……….the more channels are opened, the greater the blockbecomes since LAs gain access more readily to open

channels

Quaternary LAs (QX-314; fully ionised)- work ONLY when injected inside

the membrane

not used clinically - channels must be cycled through their open state severaltimes before block appears

Tertiary LAs (partially ionised)

- Block can develop even when channels not opennon-ionised form of LA can enter channel either

1) directly from membrane phase (hydrophobic pathway )2) via the open channel gate (hydrophilic pathway )



LA

1 2 3 4

56

I II III IVNH2

extracellular

intracellular

SODIUM CHANNEL

subunit

++

++

Na+

Na+

IFM motif – inactivationparticle

Receptor for inactivationparticle



Structures involved in channel gating

- +vely charged S4 segments act as the “voltage sensor” (blue; may exhibit outward and/or rotary movement toopen the “activation gate”.

- Intracellular III-IV loop (red) involved in “inactivationgating” – within this region, a triplet sequence ofhydrophobic residues (IFM; isoleucine, phenylalanine,methionine) is proposed as part of the inactivationparticle that plugs the channel pore inactivation.

- S4-S5 linker in domains III & IV – receptor for theIFM triplet (pink).

- S6 segments (domains I, III, IV) contain “LA receptors” .



Mutations in IS6 and IIIS6 primarily affect LA potency for inactivatedchannels (suggests movement of S6 during channel inactivation).

Mutations in IS6 and IIIS6 also affect activation.

“Activation/inactivation gates” possibly located near cytoplasmicends of S6 segments constriction site for opening/closing channels



Nociceptive inputtransmitted from peripheryto dorsal horn via A and Cfibres (somatic pain).

Modulated in dorsal hornand sent to hypothalamus,to brain stem cerebral

cortex.

Major Neural Pathways involved in Nociception

Nociception - A physiological

modality (sense) normallyperceived as pain.



Differential sensitivity of nerves to LAs

small-diameter >> large diameter

(small myelinated > small non-myelinated > large myelinated)

A – pain and T o (small, myelinated )

C – pain and T o (small, non-myelinated )B – autonomic preganglionic (small myelinated )

A – proprioception (large, myelinated )

A – touch and pressure (“ ”) (A – Motor (“ “))

Thus, nociceptive and sympathetic transmission are

blocked first.



Table 44.1 –

new Rang



Duration of Action

Depends on amount of tissue/plasma protein bindingof LA

Higher % protein-bound LA longer duration

of action Examples: Lidocaine ~ 65% protein-bound

Bupivacaine ~ 95% Procaine ~ 6%

BUT Protein-binding also affects duration of UNWANTED effects of LAs!!!



Effects of Local Anaesthetics

1. Local - include nerve block and direct effects onvascular smooth muscle.

2. Regional - loss of sensation (pain, T o, touch) andvasomotor tone in the region supplied byblocked nerves.

3. Systemic - occurring because of absorption orintravenous administration (UNWANTEDEFFECTS).



Local/Regional side-effects

Neurotoxicity due to allergic reaction Excess fluid pressure on nerve

Severing nerve fibres/support tissue Injection site haematoma – pressure on nerve Injection site infection

Symptoms resolve within a few weeks



Systemic effects of LAs (UNWANTED)

central nervous system (CNS)

cardiovascular system



Effects on CNS

Mixture of stimulant and depressant effects depending on

local tissue concentration of LA

Low concs – depression inhibitory neurones cerebralexcitation (restlessness/tremor) generalised

convulsions

High concs - depression of brain functions coma,respiratory arrest & death

• Procaine – particularly liable to CNS effects no longer used,superceded by lidocaine & prilocaine .

• Cocaine – produces euphoria at doses well below those that causeother CNS effects.



Myocardial depression :-

- decreased mycardial contractility, indirect result ofreduced sodium conductance decreased [Ca2+]i reduced force of contraction bradycardia .

- antiarrhythmic effect of some LAs (lidocaine), clinically

useful (e.g. after acute myocardial infarction).

Vasodilation :-- direct effects on vascular smooth muscle + inhibitionof sympathetic nervous system. Mainly affects arterioles

Effects on cardiovascular system



Effects on vascular smooth muscle vary…

REGIONAL vasodilation, caused by block ofsympathetic nerves

LOCAL e.g. Cocaine – vasoconstrictorProcaine – vasodilator

Most amide LAs cause vasoconstriction at lowconcentrations & vasodilation at higher concentrations.

Vasoconstriction at clinical doses:-Prilocaine > Lidocaine > Bupivacaine

myocardial depression + vasodilation reduced BP (hypotension may be sudden and life threatening)



*Cocaine is an exception……

it inhibits NA reuptake sympathetic activity

Tachycardia ( heart rate) cardiac outputvasoconstriction

arterial pressure



Vasoconstrictors and LA action

• prolong anaesthetic action

• reduce systemic distribution (plasma levels)

• reduce dose

ADRENALINE/NORADRENALINE- adrenoceptors(ARs) constrict blood vessels; ARs raise heartrate and induce arrhythmias

FELYPRESSIN - less effective, constrict bloodvessels; coronary vasoconstriction; no effect onheart



Pharmacokinetic aspects

Ester-linked LAs : - Most, e.g. tetracaine (amethacaine), rapidly hydrolysedby plasma cholinesterase. Plasma half-life short (1-2 h).

Amide-linked LAs : - e.g. lidocaine, prilocaine, metabolised in the liver byN-dealkylation rather than cleavage of the amide bond,metabolites often pharmacologically active.

*Benzocaine (lacks side-chain amino group). Very lowsolubility, slowly released, produces long-lasting surfaceanaesthesia.



Esters – allergic reactionsSensitivity to ester metabolite, PABA (para-amino-benzoic acid)

Cocaine – potent vasoconstrictor problems in patients

Already taking vasoconstrictors, e.g. monoamine oxidaseInhibs.

Amides – e.g. prilocaine

Metabolised to O-toluidine

methaemaglobinaemiareduced haemaglobin available for O2 transportPotentially life-threatening



LAs and foetal effects

Esters – Metabolised rapidly, minimal effects on foetus

Little LA in maternal circulation to crossplacenta

Amides – More likely to cross placenta, e.g. lidocaine

(only ~ 65% protein-bound)

If foetus compromised, envt. Acidotic more foetal LAin IONISED form (membrane impermeant)↓ ability to return to maternal circulation

Foetal toxicity



Table

44.2 in

NewRang



LAs vary in their potency, duration of action, toxicity,ability to penetrate mucous membranes

Lidocaine (Lignocaine) – most widely used LA.Acts > rapidly, > stable than most LAs.Duration of action approx. 90 min.

Prilocaine – similar to Lidocaine but, > extensivelymetabolised + < toxic at equivalent dose.

Bupivacaine – Slow onset (< 30 min), v. long duration ofaction (8 h); continual epidural block during labour

Benzocaine – neutral, water-insoluble, low potency;surface anaesthesia only (mouth, pharynx)

Tetracaine (amethocaine)/cocaine, more toxic agents, restricted use



Preparations:- Solutions for injection, spray,creams, gels

LAs combined with additives to enhance effects

Other LAs

Adrenaline/felypressin (1/200,000) - vasoconstrictors

Bicarbonate - pH local envt. faster onset

Glucose – baricity of bupivacaine so > CSF morecontrolled spread LA in intrathecal space



Ideal properties

• reversible• good therapeutic index (toxic/effective

doses)

• short onset

• suitable duration

• no local irritation even on repeatedapplication

• no side effects• no potential to induce allergy

• apply to any site

• cheap, stable, soluble

Documents

Local Anaesthetics I