LA Flashcards
Define LA
Loss of sensation ins specific area of the body by depression of excitation in nerve endings or an inhibitor of the conduction process in peripheral nerves
List some qualities of the ideal LA (12)
Specific and reversible Non-irritant produces no permeant damage no systemic toxicity high therapeutic ratio active topically and by injection Rapid onset suitable duration of action Chemically stable and sterilisable Combine with other agents Non-allergic Non-additive
Of the 12 qualities of an ideal LA, what is the hardest to achieve?
Specificity
What is the consequence of the lack of specificity of LAs?
It will affect transmission of any excitable tissue they come into contact with e.g. CNS, cardiac, motor system
List 4 uses of LA in dentistry?
Operative pain management
Post-operative pain management
Diagnosis
Haemostasis
How can LA be used in diagnosis?
If tooth ache cannot be localised can give infiltrations adjacent to each tooth and see which one gets rid of the pain
Why is LA not commonly used for diagnosis of tooth ache anymore?
Pulp sensibility testing is available (EPT, ethyl chloride)
How is LA used for haemostasis?
Uses the adrenaline within the LA to cause vasoconstriction of the BV in that area - reduce bleeding
Name the 2 theories of LA action?
Membrane expasnion therory
Specific receptor theory
Describe generally how LA works?
Blocks/inhibits sensory signals from tooth to brain
Describe an action potential
Resting potential - the inside of the cell is negative compared to the outside fo the cell. 3K+ out for 1Na+ in
Depolarisation - voltage gated sodium ion channels open due to electronic stimulus - Na+ move into the cell and the inside of the cell becomes positive compared to the outside of the cell. If the membrane potential reaches the threshold potential the maximum response will be elicited.
Repolarisation - once the action potential has occurred voltage gated Na+ channels close. the positive charge in the cell causes voltage gated K+ channel to open, K+ move down electrochemical gradient out of the cell. Membrane returns to resting potential. depolarisation tends to overshoot - making the inside of the cell more negative = hyperpolarisation = refractory period where another AP cannot occur
What part of an action potential is targeted by LA?
Voltage gated NA+ channels
Name the gates within voltage gated Na+ channels?
M gate and H gate
Make and halt
Describe the membrane potential and positioning of the voltage gated Na+ channel at rest
Inside of the cell -ve compared to outside
M gate closed, H gate open
How does the voltage gated Na+ channel change during depolarisation?
M gate opens, Na+ flood in - inside of cell = +ve
How does voltage gated Na+ channel change during repolarisation?
H gate closes
This stops Na+ moving into the cell
The inside fo the cell is +ve - this opens voltage gated K+ channels and K+ moves out of the cell making the inside -ve
Describe membrane expansion theory
La enters the nerve cell membrane, this causes the membrane to expand, this blocks the Na+ channels and stops Na+ entering the cells, this stops depolarisation = no AP
Describe specific receptor theory
Specific receipt int he H gate of the VG Na+ channel.
LA bind to this receptor
Stops the H gate opening - keeps Na+ channel closed - hold the cell in the refractory period - no AP can be fired
In what subunit does NA pass through the VG Na+ channel?
alpha
Describe the position of the M gate on the VG Na+ channel
Alpha subunit split into 4 domains, each contains 6 subunits
M gate is the 4th subunit
Describe the position of the H gate on the VG Na+ channel
Link of protein between domain 3 and 4 within the alpha subunit
Name the 3 parts fo an LA molecule
Aromatic group, intermediate chain, substituted amino terminal
Function of the aromatic group on LA?
Makes it lipophilic
Function of substituted amino terminal on LA?
Makes it hydrophilic
Function of intermediate chain on LA?
Allows optimal separation of lipid and water soluble components
Allows classification of LA = ester or amides depending on what chain it is
Why does LA need to lipophilic and uncharged?
LA binding is intracellular so needs to cross the membrane.
Why does LA need to be charged when in the cell?
Specific binding requires charged molecules
LA needs to be lipophilic and uncharges to cross the membrane but charged to bind to the receptor - how is this achieved?
LAs are weak bases:
in solution LA exists as uncharges base and charged cation –> lipid soluble and enter the cell, but when is gets there becomes charged
Describe how weak bases allow for passing the membrane and binding to receptor.
In solution the LA will be a mix of uncharged base and charged cation. So when injected into the body, the uncharged base portion will cross the membrane. The weak base will always want to be in equilibrium so when in the cell half of the uncharged base will dissociate into charged cations. These charged cations will bind to specific receptors on the H gate
Why is it important for LA to have a high proportion of uncharged molecules soon after injection?
Makes the LA more effective because more can pass through the membrane - enters the cell quicker = acts quicker
What term describes the ratio of uncharged to charged molecules? What 2 factors govern this?
Ionisation
pH and PKa
What is pKA?
Dissociation constant
How do pH and pKa relate to ionisation?
Lower pH = less uncharged molecules present
Lower pKa = more uncharged molecules present
Why does LA not tend to work in areas of infection?
Infected tissues have lower pH = makes the weak base have less uncharged molecules = does not enter the cell as quickly
List 4 chemico-phsycial properties that influence LA action. How do they effect the action
Ionisation (pH and pKa) - onset
Partition coefficient - onset
Protein binding - duration of action
Vasodilatror ability - duration of action
Describe partition coefficient. How does this effect LA
Measures lipid solubility
Higher partition coefficient = more lipid soluble = crosses the lipid bilayer quicker.
Higher partition coefficient = faster onset
How does protein binding effect LA?
Degree of protein binding related to duration of action.
Bound portion of drug acts as a reservoir that cannot be used until the free drug has been used up. Higher protein binding = longer action
How does vasodilator ability effect LA?
More vasodilation = LA washes away quicker so short duration
Are most LAs vasodilators or vasoconstrictors?
Vasodilators
What is in an LA cartridge?
Anaesthetic agent Vasoconstrictor Reducing agent (stop vasoconstrictor breaking down) Ringers solution (solvent the drugs are dissolved in) No longer have preservatives because of allergies
Name 2 vasoconstrictors used in LA?
Adrenaline, felypressin
List 5 factors adrenaline can effect?
Blood vessels - vasoconstriction Heart Lungs Metabolsim Wound healing
What receptors does adrenaline bind to?
Alpha and beta adrenoreceptors
Location and function of adrenaline on alpha adrenoreceptors
Skin and mucous membrane
Vasoconstriction
Location and function of adrenaline on beta adrenoreceptors
Skeletal muscle and liver
Vasodilation, reduce diastolic BP, fainting with high dose
Is peripheral vasoconstriction better for adrenaline or felypressin, what is the effect of this?
adrenaline - more haemostasis
Describe the metallic effects of adrenaline binding to alpha and beta adrenorecceptors
Alpha = inhibition of insulin release - increase blood glucose Beta = activation of sodium potassium pump - potassium pumped intracellular = decrease plasma K
How does adrenaline effect the heart?
Direct effects - adrenaline binds to beta adrenoreceptors and activates them = increases rate and force of contraction - increase cardiac output
Indirect effects - secondary to metabolic changes
How does adrenaline effect the lungs?
Stimulate beta adrenoreceptors = bronchiolar relaxation
Why are pulmonary effects not valid in dentistry?
Dose used is too low for effects
How does adrenaline effect wound healing?
Decreased oxygen tension in tissues = increased fibrinolysis = decreased stability of blood clots
What 4 processes are involved in the metabolism of a drug?
Adsorption, Distribution, Metabolism, excretion
Where does the LA need to be absorbed to be metabolised?
The blood stream
What effects the rate of absorption into the blood stream?
The drug - vasodilatory ability, protein binding capacity
Dose - volume and concentration
Route of admin
Presence of vasoconstrictor
How does the drug effect the rate of absorption?
Vasodilatory effect = enter blood quick
Higher protein binding = slower absorption
How does route of admin effect absorption?
Site- is it a vascular tissue
IV = very fast
How does vasoconstrictor effect absorption?
Slow down absorption
How does the dose effect absorption?
Increased dose/conc = slower
Once in circulation what does LA bind to?
Plasma proteins and RBC
What type of molecules can enter organs? a) protein bound LA, b) unbound LA
unbound portion
Why can LA cross blood brain barrier and placenta?
Not inhibited by barriers to diffusion
why do organs like brain, liver and kidney get higher levels of La?
Highly perfused organs
What enzyme metabolises esters?
Pseudocholinesterase
Where does metabolism of esters occur?
In the blood by pseuodocholinesterases and some hydrolysis in the liver
Name a major ester metabolite. Why has this caused esters to be less commonly used?
PABA - allergies
Why do amends have a longer half life than esters?
More complex metabolism
Where is the primary site of metboalis of amides?
Liver
Name the 5 stages of metabolism of amides?
Dealkylation Hydrolyses Hydroxylation Further dealkylation Conjugation
Are metabolites of amides active?
Yes they possess LA and sedative properties
Are metabolites of esters active?
No
Where does the majority of excretion of La occur?
Kidney
Is the absorption of adrenaline rapid or slow?
Rapid - peak plasma levels within a couple of minutes after injection
Describe the metabolism of adrenaline?
Methylation by OCMT
Transported to the liver for deamination
Conjugated by sulphate
Excreted in urine
Why does LA have unwanted side effects?
Not specific to peripheral sensory nerves so effects the CNS and CVS
How can LA cause toxicity?
Inability to metabolise
too large a dose
Intravascular injection –> aspirate
How much lidocaine/L causes toxicity in the CNS?
5mg/L
What is the maximum dose of lidocaine in Uk?
4.4mg/kg
Why can you only get 2.2ml cartridges in the Uk?
Easy to calculate maximum dose
How much lidocaine in 2.2ml cartridge?
44mg
What weight should a patient be for 1 cartridge of lidocaine?
1 cartridge = 10kg
Adults typically weight around 70kg
Children typically = 20kg
What is the max cartridge for each?
1 and 2
Why is liver disease important when giving LA?
Major site of metabolism for LA and produces plasma cholinesterase’s for metabolism
If you have an impaired liver function how does the effect your maximum LA intake?
Reduced as overdose occurs at lower dose
How does old age effect La metabolism?
Liver function decreases with age so don’t give maximum dose based on body weight
What are the signs of CNS toxicity at low dose?
Excitatory
- LA blocks inhibitory activity = involuntary muscle activity - twitches
What are the signs of CNS toxicity at high dose?
Inhibitory - Depressant effects Unconsciousness Respiratory arrest CNS becomes overwhelmed so inhibitory and excitatory is blocked
How does CVS toxicity present?
Direct or indirect action (via disinhibition of autonomic nerves)
Depressant action on heart - reduced cardiac output and circulatory collapse
List the initial symptoms of LA toxicity? For CNS and CVS
Sedation, dizzy, anxious, increased HR, BP
List the later effects of LA toxicity at high dose? For CNS and CVS
Confusion, slowed speech, drowsiness, shivering, cardiac instability
List the final effects of LA toxicity at very high dose? For CVS and CNS
Seizure
Coma
Cardiac arrest
How can you reduce toxicity risk?
Limit dose
Avoid intravascular injection - aspirate
Inject slowly
How should you treat LA overdose?
Stop procedure Get help Lie patient flat Maintain airway Administer oxygen
IS toxicity of adrenaline common?
No - made naturally in the body
List some signs of adrenaline overdose?
Fear Anxiety Restlessness Headache Trembling Sweating Weakness Dizziness Pallor Respiratory difficulties Palpitations
Treatment of adrenaline overdose
Stop procedure
Get help
Place in semi-supine or erect position - minimise increase in cerebral BP
Reassure
Administer oxygen (if not hyperventilating)
What unwanted effects of adrenaline are common?
Idiosyncratic - unpredictable effects on individual people at low dose
Drug interactions
Name 2 types of CNS drugs that interact with adrenaline?
Tricyclic antidepressants
Monoamine oxidase inhibitors
How does tricycle antidepressants affect adrenaline?
Decrease re-uptake of adrenaline into nerve cells
Effects fo adrenaline doubled - reduced dose
Name 2 types of cardiac drugs that interact with adrenaline
Beta blockers
Diuretics
How do beta blockers effect adrenaline?
Patient will have beta-adrenergic affects blocked - more alpha-adrenergic effects
adrenaline will increase systolic BP
How do diuretics effect adrenaline?
Adrenaline decreases plasma potassium, exaggerated in pats taking non-potassium diuretics = hypokalaemia
How do drug like amphetamines cannabis and cocoain interact with adrenaline?
Increases toxicity
