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Anaesthetics > Local anaesthetics > Flashcards

Local anaesthetics Flashcards

1
Q

Chemistry

A

Analogues of cocaine
Hydrophobic group (aromatic) and ionisable group (e.g. amine)
Linked by ester/amide bond
Weak base (exist as B and BH+)

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2
Q

Permanently charged LA

A

QX-314 and QX-222
Useful for experiments - mechanism of action of local anaesthetics
Analogues of lidocaine

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3
Q

Widely used LA

A

Procaine, lidocaine, bupivacaine, amethocaine, tetracaine

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4
Q

Procaine

A 
Potency = 1
Duration = short
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5
Q

Tetracaine

A 
Potency = 16 
Duration = long
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6
Q

Lidocaine

A

Potency = 4
Duration = med
Amine
pKa = 7.9

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7
Q

Bupivacaine

A

Potency = 16
Duration = long
Epidural

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8
Q

Amethocaine

A

Cream when take blood

Eye drop after cataract surgery

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9
Q

Mechanism of action

A 
Block initiation and propagation of action potentials - block voltage gated Na+ channels
Binding site in channel pore 
Threshold potential not reached 
Lose sensation  
Bind reversibly
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10
Q

Physiological pain circuits

A

Harmful stimuli sensed by specialised nerve fibres:
Unmyelinated C, thinly myelinated Aδ (both narrow)
Physiochemical properties convert to electrical by transient receptor potential (TRP) + purinergic channels
Electrical activity amplify by Na+ channels = action potentials

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11
Q

pH

A

LA = Weak base (exist as B and BH+)

Ratio between ionised and non-ionised drug in tissue depends on pH and pKa of drug

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12
Q

Henderson-Hasselbalch equation (pH)

A

pKa-pH = log[BH+]/[B]

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13
Q

Equilibrium (pH)

A

Want most drug outside cell = unionised - travel through membrane
Want most drug in cell = ionised - block channel
Achieve w/ diff. pH in and out

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14
Q

Factors influencing the activity of LA

A

pKa, pH, lipid solubility, intermediate chaine, protein binding

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15
Q

Factors influencing the activity of LA: pKa

A

pKa: ph when no. ionised drug = no. unionised (equilibrium)

More unionised present for given pH = faster onset action

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16
Q

Factors influencing the activity of LA: pH

A

Lower pH = lower potency
In acidic conditions - more ionised, less LA can cross lipid bilayer and block V-G Na+ channel
Worse reduction of pain in infected tissues (e.g. abscesses) - highly acidic, all LA ionised, not cross membrane

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17
Q

Factors influencing the activity of LA: Lipid solubility

A

More lipid soluble = higher potency = faster onset action = longer duration
More drug cross lipid bilayer of neuronal membrane, create store of drug in axoplasm

18
Q

Factors influencing the activity of LA: Intermediate chain

A

Longer = higher potency

E.g. bipuvacaine has longer chain than lidocaine, more potent

19
Q

Factors influencing the activity of LA: protein binding

A

Higher degree of protein binding = longer duration

20
Q

Model for LA block

A

QX-314 and QX-222 = permanently charged
Not cross membrane
Only block when introduce to cytosol
Bind cumulatively w/ depolarising pulse = use-dependent block
Not unbind at rest = open channel block
Block is voltage dependent - negative holding pulse can remove block

21
Q

LA pathways to access blocking site

A

Access blocking site in Na+ channel pore

Hydrophilic or hydrophobic

22
Q

Hydrophilic pathway

A

Clinically useful LA = highly lipophilic (cross membranes)
LA solutions = acidic (from HCl salts), increase drug solubility, mostly charged form
Inject - buffering system in tissue increase pH of solution, establish equilibrium, increase uncharged form, can cross cell membrane
LA interconvert to BH+ in cytosol - block channel from intracellular side
Block and recovery - need open channels

23
Q

Hydrophobic pathway

A

Experiment:
Hydrophilic analogue of lidocaine (GEA-968) - low lipid solubility
Show diff. route for drug access
Uncharged (B) gain direct access to channel through membrane
Hydrophobic LA - bind/unbind/leak out when channel closed
Low extracellular pH - slow leakage LA, extracellular H+ access LA in pore at rest
Leak from closed channels depend on lipid solubility of LA
Crystal structure of V-G Na+ channel - show side portals give hydrophobic access to central cavity

24
Q

Other channels blocked by LA

A

LA = +ve charge - enter many cation channels, block cation currents
Nicotinic acetylcholine receptor
Ryanodine receptor
K+ channels

25
Q

Other clinical uses of LA

A

Anti-arrhythmic properties: If associate and dissociate before next HB, useful for treat arrhythmias (lidocaine)
Block Na+ channels in heart

26
Q

Tetrodotoxin (TTX)

A

Not LA
More specific and potent blocker Na+ channels
Enter extracellularly
Not easy cross nerve sheath/ perineuronal tissues surrounding bundles of neurons

27
Q

Metabolism

A

Esters: Procaine, tetracaine
Rapidly metabolised in blood by plasma cholinesterases/ liver esterase’s
Amides: lidocaine, bupivacaine
Widely distribute by circulation, only metabolise by liver enzymes, longer half-life/ duration

28
Q

Factors influencing absorption

A

Dose, site of injection, drug-tissue binding, presence of vasoconstriction agents (loss LA from site of local application into circulation, prolong effect and reduce circulation of LA if vasoconstricting agent given)

29
Q

Toxic action/ side effects

A

Result escape XS LA into systemic circulation

Toxicity more likely w/ impaired liver function (reduced break down of LA)

30
Q

CNS toxicity

A

Light headed, leading to convulsions, respiratory depression, coma
Brain - block inhibitory neurons = excitatory symptoms (trembling, tingle round mouth, fits, coma)

31
Q

Cardiovascular toxicity

A

myocardial depression - reduce HR, SV
Vasodilation
Reduce BP

32
Q

Administration

A

Surface application (nose, mouth, cornea, brachial tree, urinary tract)
Direct injection into tissue for minor/ oral surgery (w/ vasoconstrictor e.g. adrenaline/felypressin)
*Can’t predict from injection how much reach spec. location
Injection close to nerve trunk - brachial plexus, intercostal/dental nerves (increase rate of systemic absorption)
Regional anaesthesia for limb surgery
Spinal anaesthesia - act on spinal roots and spinal cord
Epidural anaesthesia - act on spinal roots

33
Q

Intravenous regional anaesthesia

A

Drug inject intravenously
Distal to pressure cuff on limb
Used prilocaine in past - lowest risk of cardiac toxicity, short acting
Now - nerve block

34
Q

Spinal anaesthesia

A

Inject into subarachnoid space
Below outer membranes covering spinal chord
Between 2nd and 5th lumbar vertebrae
Major surgery (e.g. Caesarean section)

35
Q

Epidural anaesthesia

A

Inject into epidural space
Outside dura matter
Direct action on nerve roots + spinal cord following diffusion across dura
Use in obstetrics

36
Q

Sequence of blockade

A

Pain - general sensory - motor
Sequential block of different types of nerve fibre as exposed to LA
Small diameter axons more sensitive than large
Myelinated more sensitive than non

37
Q

Nociceptor-specific anaesthesia

A

Current LA - block pain + tactile input + motor signals
Prefer - pain selective block
Target small unmyelinated C-fibres, selectively express TRPV1 channel, activated by capsaicin (in chilli)

38
Q

Pharmacodynamics

A

What a drug does to the body

39
Q

Pharmacokinetics

A

What the body does to a drug (metabolism)

40
Q

Use-dependent block

A

LA drug bind Bettie to inactivated channel
Must first activate (neuron fired) to become inactivated
More neuron fired = more inactive channels = more binding LA

Anaesthetics (1 decks)

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