HD22&25 Local Anaesthetic Flashcards
describe the ideal LA?
- Specific and reversible action
- Non-irritant
- Produces no permanent damage
- No systemic toxicity
- Active topically and by injection
- Rapid onset
- Suitable duration of action
- Chemically stable and sterilisable
- Combinable with other agents
- Non-allergic
- Non-addictive
What would be the therapeutic ratio of the ideal LA?
High therapeutic ratio (difference in dose between the effect that would give you the dose you want and the dose that would cause toxic effects) = want it to be high
LA is not specific, what will affect transmission in any excitable tissue. What are the 3 excitable tissues
- CNS
- Cardiac
- Motor
What are the uses of LA in dentistry (4)?
- Operative pain management
- Post-operative pain management - give LA while in GA so when wake aren’t in pain
- Diagnosis – pulp sensibility tests (in the past), now used for atypical pain or to identify which tooth is causing the pain if a number are carious
- Haemostasis – reduce bleeding during procedures
A chemical roadblock between the tooth and the brain
TRUE OR FALSE
true
Explain the theory of membrane expansion as the way LA works:
• The LA diffuses into cell membrane, cuasing it to expant. Therefore membrane is less permeable to Na and changes in polarisation do not occur.
what happens normally during membrane potential?
Sodium channel has 2 gates
• At rest – m gate closed/ h gate open
• Depolarisation – m gate opens which allows sodium to move inside cell + ve inside
• Repolarises – H gate closes which stops sodium moving into nerve cell membrane
• Potassium diffuses back out – electrochemical gradient shifts back (+ outside)
• Now in refractory period – cannot fire another impulse
What is the specific receptor theory of LA ?
- Receptor on inside of H gate – LA attaches to receptor holding the gate closed
- This holds it in the refractory period so that no more impulses can be fired
what are the 3 components of LA molecule?
- Aromatic group (lipophilic)
- Intermediate chain (ester or amide link)
- Substituted amino terminal (hydrophilic)
What part of the LA molecule allows:
spatial separation of lipid and water-soluble components
Intermediate chain
What part of the LA molecule allows:
classification of LA into 2 major groups:
- Esters
- Amides
Intermediate chain
What 2 major groups can LA belong to (determined by Intermediate chain ):
Esters
- Amides
What 2 major groups can LA belong to (determined by Intermediate chain ):
2) Which are at greater risk of an allergic reaction?
Esters
- Amides
2) esters
Name the amide LAs:
- Lidocaine
- Prilocaine
- Mepivacaine
- Articaine
- Bupivacaine
- Levobupivacaine
- Ropivacaine
Name the esters LAs:
which of these is a topical anaesthetic?
- Benzocaine – topical anaesthetic
- Amethocaine
- Procaine
The binding site of LA is intracellular , what is the significance of this?
2) What is required for specific binding to any receptor by LA?
1) • Therefore LA needs to be lipophilic and uncharged to cross the cell membrane
2) • Specific binding to any receptor to achieve LA requires a charged molecule
• Therefore the LA needs to be in a charged form
• How can LA be uncharged (lipophilic) and charged at the same time?
2) What does this achieve?
• LAs are weak bases
• In solution the LA molecule will exist as both -
- Uncharged base
- Charged cation
2) - Lipid soluble to enter cells to work
- Charged form for specific binding once in cell
which is the more effective LA once injected, the one with a higher proportion of uncharged molecule or lower?
- The quicker the LA enters the cell the more effective it is and the quicker it acts
- Therefore, LA with a high proportion of uncharged molecules after injection are most effective
what is ionisation?
ratio of charged to uncharged
what governs ionisation?
- pH – can be controlled usually
* pKa (dissociation constant) – set within each LA (cannot change)
what is the affect on LA uptake when the pH around the neurone is low?
2) what tissues have a lower pH?
• Lower pH - less uncharged molecules present (difficult to cross membrane as not uncharged)
2)infected tissues
what affect does pKa have on the onset of action of LA?
2) list the pKa of these from high to low:
lidocaine
bupivacaine
procaine
articaine
1) the lower the pKa the better
2) procaine -9.1
bupivacaine- 8.1
articaine- 7.8
lidocaine- 7.9
For more ionisation does pH need to be high or low?
2) for pKa ?
1) high
2) low
What chemico-physical properties influence the onset of LA?
- Ionisation (pH and pKa) - onset
* Partition coefficient - onset
What chemico-physical properties influence the duration of action of LA?
- Protein binding – duration of action
* Vasodilator ability – duration of action
what does the partition coefficient measure?
2) what does a higher partition coefficient mean?
3) what does this means in terms of LA with a high partition coefficient in the body?
measures lipid solubility
2) more lipid soluble
3) • Therefore crosses nerve sheath quicker
• Therefore higher partition coefficient the faster the onset of action
why is lidocaine the gold standard?
its partition coefficient is 3 while for procaine it is 0.6
Proteins bind to drugs. bound portion acts as what and has what role?
• Bound portion acts as a reservoir from which free drug can be released to replace what has been used/metabolised
Give half-lifes:
lidocaine 64%
bupivacaine 96%
lidocaine- half life 90 mins
bupivacaine- half life 160 mins
Give protein binding percentages:
lidocaine- half life 90 mins
bupivacaine- half life 160 mins
lidocaine 64%
bupivacaine 96%
Most LAs are vasodilators, what is the exception?
2) what is the significance of this?
cocaine
2) vasoconstrictor added to conteract this
What is inside an LA cartridge?
- Anaesthetic agent
- Vasoconstrictor
- Reducing agent (only present if vasoconstrictor is – prevents it breaking down)
- Ringer’s solution – forms bulk of cartridge, which all this shit dissolves in
- Preservative
what are the benefits of vasoconstrictor in LA?
- More profound anaesthesia
- Longer lasting anaesthesia – prevents dilation of vessels which would wash it away
- Better haemostasis
what vasoconstrictors are used in the UK?
Vasoconstrictors used in the UK
• Adrenaline (epinephrine) – a catecholamine
• Felypressin (octapressin) – a synthetic peptide
what can adrenaline affect?
- Blood vessels
- Heart
- Lungs
- Metabolism
- Wound healing
where are the following receptors found:
1) Alpha adrenoreceptors:
2) Beta adrenoreceptors:
- Skin and mucous membrane
2) - Skeletal muscle and liver
what is the vascular affect of adrenaline acting on beta adrenoreceptors?
- Vasodilation
- Reduced diastolic BP
- Fainting with high doses
what is the vascular affect of adrenaline acting on
alpha adrenoreceptors:?
vasoconstriction
what is the metabolic affect of adrenaline acting on
1) alpha
2) beta adrenoreceptors?
- Alpha adrenoreceptor inhibition of insulin release → increase blood glucose
- Beta adrenoreceptor activation of sodium-potassium pump → potassium pumped intracellular → decrease plasma potassium (hypokalaemia)
1) what are the direct cardiac effects of adrenaline?
2) what are the indirect cardiac effects of adrenaline?
1) Direct effect • Activation of beta-adrenoreceptors • Increases rate and force of contraction • Increases cardiac output 2) Secondary to metabolic changes
what are the pulmonary effects of adrenaline? what receptors are involved?
- Stimulation beta-adrenoreceptors
- Bronchiolar relaxation
- Theoretical in LA doses
what vasoconstrictor is involved in wound healing?
- Decreased oxygen tension in tissues
* Increased fibrinolysis – decreased stability of blood clots
Why is it so important to aspirate?
- 1:80 000 = 12.5g/mL
- 2.2mL contains 27.5g
- 0.00825micrograms in blood system naturally occurs in BV therefore MUST aspirate
What does felypression cause?
2) How is it not as good as adrenaline?
3) why is it given?
- Coronary artery vasoconstriction
- Oxytocic action on uterus
2) poorer control of haemorrhage of adrenaline
3) given if can’t tolerate adrenaline
what is the number of micrograms of these in 2.2mL:
1) adrenaline
2) felypressin
1) 27.5
2) 1.2
rate LA ends up in blood stream depends on:
Vasodilatory ability
Protein binding capacity – higher it is, slower enters bloodstream
• Once in circulation LA partially bound to _____1_____and __2___
• Unbound portion free to enter any ____3___
Not inhibited by barriers to ___4___, therefore will cross ___5___ and ___6__
1) plasma proteins
2) proteins
3) liver
4) diffusion
5) BBB
6) placenta
highly perfused organs will receive higher levels of LA… including:
brain, liver , kidneys
metabolism of esters in blood is rapid , what enzyme metabolises this?
pseudocholinesterase
what reaction occurs to esters in liver?
hydrolysis
Are the metabolites of esters active?
no
What is the major metabolite of ester vasoconstrictors?
para-aminobenzoic acid (PABA)
People who lack psuedocholinesterase, what are they at risk of?
• 1 in 2800 lack pseudocholinesterase – sux apnoea (muscle relaxant) and risk of ester overdose
What is sux apnoea
permanently paralysed as body cannot metabolise drug, as don’t have the enzyme
What are ester allergies usually allergic to?
para-aminobenzoic acid (PABA)
Compare the metabolism of amides to esters?
• More complex than esters, therefore longer half life
what is the primmary site of metabolism of amides?
liver
What reactions (and order) for metabolism of amides?
o Dealkylation o Hydrolysis o Hydroxylation o Further dealkylation o Conjugation
What properties can metabolites possess?
• Metabolites can possess LA and sedative properties
prilocaineis partly metabolised where?
lung
articaine undergoes hydrolysis where and by what enzyme?
• Articaine also undergoes hydrolysis in plasma by pseudocholinesterase (liver and blood)
Where is lidocaine excreted?
- Via kidney
* <3% excreted unchanged in urine
How long does it take adrenaline to appear in plasma/ systemic circulation?
• Appears in systemic circulation rapidly – peak plasma levels couple of mins after intra oral injection
What enzyme is involved in the methylation of adrenaline?
2) where is transported for deamination?
3) what is it conjugated with?
4) wat is it excreted in?
5) What % is excreted unchanged in urine?
1) COMT
2) deamination
3) sulphate
4) urine
5) 1%
What enzymes are involved in adrenaline excretion?
COMT
MAO
ADH
