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ACEM Primary Written > Anaesthetics: Pharmacology - Local anaesthetics > Flashcards

Anaesthetics: Pharmacology - Local anaesthetics Flashcards

1
Q

Four examples of ester-type local anaesthetics

A
  1. Articaine
  2. Benzocaine
  3. Chloroprocaine
  4. Cocaine
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2
Q

Six examples of amide-type local anaesthetics

A
  1. Bupivacaine
  2. Levobupivacaine
  3. Mepivacaine
  4. Rupivacaine
  5. Procaine
  6. Lidocaine
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3
Q

Describe the chemical structure of local anaesthetics

A

Lipophilic group connected to ionisable group (e.g. tertiary amine) via an ester or amide
Weak bases and exist in the body as uncharged base or cation with relative proprtions of these forms determined by pKa and pH (pKa of most local anaesthetics is 7.5-9.0, so charged cationic form makes up higher % at physiologic pH)

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4
Q

Why are ester-type local anaesthetics shorter-acting?

A

More prone to hydrolysis than amide links, more unstable in solution

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5
Q

What is the difference in physiologic activity of the uncharged and cationic forms of local anaesthetics? What is the clinical relevance of this?

A

Cationic form most active at receptor site, which sits at inner vestibule of sodium channel, but limited ability to diffuse through biologic membranes
Neutral base better at diffusing across membranes

This is why local anaesthetics are less effective at sites with low pH (e.g. infected tissues) -> more charged form, less neutral base for diffusion across membranes
Also means that adding bicarbonate can increase effective concentration of nonionised form and decreased time to onset of regional block

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6
Q

Describe the absorption of local anaesthetics. What are the six factors governing systemic absorption?

A

Injected locally so diffusion is more important than systemic absorption with respect to effect, however systemic absorption still important for duration of action and toxicity

Factors affecting systemic absorption:
1. Dosage
2. Site of injection (increased systemic absorption in highly vascularised tissues, e.g. tracheal mucosa)
3. Drug-tissue binding
4. Local tissue blood flow
5. Use of vasoconstrictor
6. Physicochemical properties of drug

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7
Q

How do peak serum levels of local anaesthetic compare in intercostal vs sciatic and femoral nerve blocks?

A

Higher in intercostal than sciatic and femoral

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8
Q

How does the use of vasoconstrictor reduce systemic absorption of local anaesthetic? In what types of local anaesthetics is this particularly useful?

A

Vasoconstriction decreases blood flow and delays systemic absorption
Useful for shorter acting, less potent, less lipophilic drugs (e.g. procaine, lidocaine)
Less effective in prolonging anaesthesia in more lipid-soluble, longer acting drugs (e.g. bupivacaine)

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9
Q

What mediates the direct analgesic effect of adrenaline with its use in spinal anaesthesia?

A

a-adrenoceptor activation produces reduction in substance P and decreased sensory neuron firing

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10
Q

Describe the factors influencing CSF distribution of local anaesthetic agents

A
  1. Specific gravity of drug relative to CSF (may be hyperbaric and descend within subarachnoid space relative to CSF with upright position, isobaric and remain static, or hypobaric and ascend)
  2. Patient position
  3. Injection technique
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11
Q

Describe the distribution of esters vs amides

A

Esters: extremely short half-life, distribution not extensively studied
Amide: distribution has alpha and beta phases; alpha involves rapid distribution in blood and highly perfused organs, beta involves distribution into less well-perfused tissue (including fat) with slower linear rate of decline

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12
Q

What is the effect of lipid solubility on local anaesthetic potency, speed of onset, and duration of action? What is the effect on protein binding? Give three examples of highly lipophilic local anaesthetics

A

Increased
Bind more avidly to plasma proteins (can be displaced by other protein-binding drugs)
E.g. tetracaine, bupivacaine, rupivacaine

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13
Q

Describe the metabolism of ester local anaesthetics

A

Hydrolysed rapidly in blood by butyrylcholinesterase (pseudocholinesterase)
Very short plasma t1/2

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14
Q

Describe the metabolism of amide local anaesthetics

A

Hydrolysed by microsomal CYP450 enzymes in liver
Variable rate of metabolism

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15
Q

List the six amide anaesthetics in terms of highest to lowest rate of hepatic metabolism

A

Prilocaine > lidocaine > mepivacaine > rupivacaine = bupivacaine, levobupivacaine

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16
Q

Describe the elimination of local anaesthetics

A

All metabolites have increased water solubility and are readily excreted in urine

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17
Q

In what three settings (related to hepatic metabolism of amide local anaesthetics) can toxicity occur?

A
  1. Hepatic disease
  2. Reduced hepatic blood flow (e.g. heart failure, volatile anaesthetics especially halothane)
  3. Concomitant administration of other drugs metabolised by CYP450 enzymes
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18
Q

Describe the mechanism of action of local anaesthetics

A

Primary mechanism is Na+ channel blockade (Na+ channel opening is ordinarily responsible for nerve axon depolarisation)
Binds near intracellular end of Na+ channel, with blockade voltage- and time-dependent: binds preferentially to activated (open) and inactivated channels, with lower affinity for those in resting state

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19
Q

Describe the structure of the neuronal Na+ channel

A

Single alpha subunit with central pore
Accessory beta subunits

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20
Q

Describe the progression of changes in membrane potential and AP conduction with increasing dose of local anaesthetic

A

Increased AP threshold
Slowed impulse conduction
Decrease rate of rise of AP
Decreased AP amplitude
Finally: ability to generate AP complete abolished

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21
Q

What is the effect of frequency of axon firing, amplitude of depolarisation, and fibre diameter and myelination on local anaesthetic effect?

A

More marked local anaesthetic effect in rapidly firing axons and those with larger depolarisations (e.g. sensory fibres)
Preferentially block small fibres (distance over which they can propagate AP is shorter)
For myelinated fibres, at least 2 (preferably 3) successive nodes must be blocked to halt impulse propagation (the thicker the fibre, the farther apart the nodes tend to be - conferring increased resistance to blockade)

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22
Q

Describe four type A fibre types in terms of their function, diameter, degree of myelination, conduction velocity, and sensitivity to local anaesthetic blockade

A

A-alpha: proprioception and motor function, 12-20um, heavy myelination, conduction 70-120m/s, + sensitivity to blockade
A-beta: touch and pressure function, 5-12um, heavy myelination, conduction 30-70m/s, ++ sensitivity to blockade
A-gamma: muscle spindle function, 3-6um, heavy myelination, conduction 15-30m/s, ++ sensitivity to blockade
A-delta: pain and temperature function, 2-5um, heavy myelination, conduction 5-25m/s, +++ sensitivity to blockade

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23
Q

Describe type B fibres in terms of their function, diameter, degree of myelination, conduction velocity, and sensitivity to local anaesthetic blockade

A

Function: preganglionic autonomic
Diameter: <3um
Myelination: light
Conduction velocity: 3-15m/s
Sensitivity to blockade: ++++

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24
Q

Describe two type C fibre types in terms of their function, diameter, degree of myelination, conduction velocity, and sensitivity to local anaesthetic blockade

A

Dorsal root: pain, 0.4-1.2um, unmyelinated, 0.5-2.3m/s, ++++ blockade
Sympathetic: postganglionic, 0.3-1.3um, unmyelinated, 0.7-2.3m/s, ++++ blockade

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25
Q

How does block occur in a predictable manner in spinal anaesthesia?

A

Loss of cold sensation two spinal cord segments above analgesia for pinprick, which is in turn two segments rostral to loss of light touch
(Peripheral blocks have anatomic considerations that make onset more variable)

26
Q

Four systemic effects of local anaesthetic toxicity

A
  1. CNS toxicity
  2. Cardiotoxicity
  3. Haematotoxicity
  4. Allergy
27
Q

Describe the CNS toxic effects seen with local anaesthetic

A

Early: circumoral and tongue numbness
Later: sedation, light-headedness, visual/auditory disturbances, restlessness
At higher concentrations: nystagmus, muscle twitching, progression to tonic-clonic seizure followed by CNS depression and death

28
Q

What can be used as prophylaxis for local anaesthetic mediated CNS toxicity?

A

Benzodiazepines (but does not treat and may mask cardiotoxicity)

29
Q

How are local anaesthetic induced seizures treated?

A

With benzodiazepine (e.g. midazolam) or small dose of propofol and thiopental

30
Q

Describe the mechanism of cardiotoxicity seen with local anaesthetics

A

Blockade of Na+ (and at higher concentrations Ca2+) channels: increased risk of arrhythmia
Decreased cardiac contractility and arteriolar dilation (reduced TPR) -> severe hypotension

31
Q

How can local anaesthetic induced cardiotoxicity be treated?

A

Intravenous lipid emulsion

32
Q

What are the specific cardiotoxic effects of cocaine?

A

Blocks NA reuptake to induce vasoconstriction, HTN, arrhythmias, and myocardial ischaemia

33
Q

What are the haematotoxic effects of local anaesthetics?

A

Large doses (>10mg/kg) of prilocaine used in regional anaesthesia may lead to accumulation of metabolite ortho-toluidine, which causes methaemoglobinaemia

34
Q

What type of local anaesthetic is more likely to cause allergy?

A

Ester (specifically p-aminobenzoic acid metabolites of ester local anaesthetics)
Extremely rare with amides

35
Q

What factor increases susceptibility to localised toxicity of local anaesthetics?

A

Pregnancy

36
Q

What are the two localised toxicities seen with local anaesthetics?

A
  1. Neural injury: especially with chloroprocaine and lidocaine (e.g. can cause CES with inadvertent administration of epidural dose into intrathecal space)
  2. Transient neurologic symptoms: transient pain or dysaesthesia linked to lidocaine use in spinal anaesthesia (occurs even at modest doses); negligible risk with bupivacaine, prilocaine, chloroprocaine
37
Q

Five routes of administration of local anaesthetics

A
  1. Topical (e.g. EMLA, cocaine)
  2. Local infiltration
  3. Injection into epidural or subarachnoid space surrounding spinal cord
  4. Biers block
  5. Infiltration block of autonomic sympathetic fibres
38
Q

What is EMLA?

A

Eutectic mixture of 2.5% lignocaine and 2.5% prilocaine

39
Q

One example of a short-acting local anaesthetic

A

Procaine

40
Q

Five examples of intermediate-acting local anaesthetic

A
  1. Cocaine
  2. Lidocaine
  3. Mepivacaine
  4. Articaine
  5. Prilocaine
41
Q

Three examples of long-acting local anaesthetic

A
  1. Tetracaine
  2. Bupivacaine
  3. Rupivacaine
42
Q

In what two ways can duration of action of local anaesthetic be increased?

A

Increased dose
Co-administration with vasoconstrictor

43
Q

How can speed of onset of local anaesthetic can be increased?

A

By using solutions saturated with CO2 (“carbonated”) -> CO2 passes into cells and causes intracellular acidosis -> sequestration of cationic form intracellularly

44
Q

How does tachyphylaxis result from repeated local anaesthetic dosing?

A

Local anaesthetic prepared in form of HCl salts with pH 4.0-6.0 -> extracellular acidosis -> decreased buffering capacity of tissues -> decreased drug ionisation -> decreased diffusion to site

45
Q

Unique structural feature of articaine

A

Thiophene ring rather than benzene (increases lipophilicity)

46
Q

Why is articaine a common choice for dental anaesthesia?

A

Short t1/2
Risk of paraesthesias but less than lidocaine

47
Q

Which local anaesthetic has a thiophene ring in place of a benzene ring?

A

Articaine

48
Q

Which local anaesthetics may cause methaemoglobinaemia?

A

Benzocaine
Prilocaine (via oxidising metabolite ortho-toluidine)

49
Q

What is the route of administration for benzocaine?

A

Topical only (highly lipophilic)

50
Q

When is benzocaine relatively contraindicated and when is it the agent of choice?

A

Risk of cardiotoxicity with high doses so should not be used when surgical anaesthesia needs to be achieved
Not suitable for outpatient/ambulatory surgery due to long duration of action
Agent of choice for epidural for post-operative pain management and labour analgesia

51
Q

What is the risk of toxicity with chloroprocraine?

A

Risk of TNS with large intrathecal doses

52
Q

What is the typical use for cocaine?

A

Topical anaesthesia and vasoconstriction in ENT procedures

53
Q

How does the risk of cardiotoxicity with levobupivacaine compare with bupivacaine?

A

Decreased

54
Q

What is the “standard” local anaesthetic agent against which others are compared?

A

Lidocaine

55
Q

What adverse effect is seen with lidocaine?

A

Increased risk of TNS with spinal administration

56
Q

Why is mepivacaine a poor choice of anaesthetic for epidural in labour?

A

Slowly metabolised by foetus

57
Q

Does mepivacaine tend to vasoconstrict or vasodilate?

A

Vasoconstrict

58
Q

Which amide anaesthetic has the highest clearance of all amide anaesthetics, and what is the clinical relevance of this?

A

Prilocaine
Decreased risk of systemic toxicity

59
Q

How does prilocaine compare with lidocaine in terms of duration of action and risk of TNS?

A

Longer duration of action
Less risk of TNS

60
Q

In what contexts is rupivacaine typically used?

A

High-volume peripheral nerve blocks
Epidural infusions in labour and for post-operative pain management

ACEM Primary Written (150 decks)

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