Please review the following questions before reading the answers

1. What is a Local Anaesthetic?

2. How can local anaesthetics be classified structurally?

3. How do local anaesthetics work?

4. What determines the onset time of action?

5. What determines the duration of action of a local anaesthetic?

6. What determines the potency of a local anaesthetic?

7. An anaesthetist performs an ankle block on a patient with a necrotic infected foot. His technique is without fault yet the block fails, why?

8. Is there any way of accelerating the speed of onset of blockade with a local anaesthetic?

9. What is the purpose of "carbonated lignocaine".

10. Do local anaesthetics have preferential effects on any particular types of nerve fibre?

11. Why do we rarely use ester type LAs in our practise?

12. Describe the process of local anaesthetic toxicity, from warning signs to the worst clinical scenario.

13. What are the maximum safe doses of lignocaine, bupivicaine and prilocaine?

14. What factors relate to the possibility of drug toxicity with LAs?

15. Why would one add adrenaline to a local anaesthetic? If you were to use adrenaline, which drugs would you add it to.

16. Tell me about prilocaine.

17. Tell me about amethocaine.

18. tell me about ropivicaine.

19. You meet a drug rep in the corridor. He says that he has a new local anaesthetic that would be ideal for your practice. What questions would you ask him about it.

1. What is a Local Anaesthetic?

Local anaesthetics are drugs that produce reversible depression of nerve conduction when applied to the nerve fibre. The first local anaesthetic discovered was cocaine. Subsequent synthesis of alternative agents early in the century were ester derivatives of benzoic acid. Lignocaine was synthesised in 1943 - an amide derivative of diethylamino acetic acid. Most subsequent agents introduced into practise have been of this type.

2. How can local anaesthetics be classified structurally?

The following structure is common to all local anaesthetic agents

Aromatic ->Ester or Amide portion  ->Amine portion

The two types of local anaesthetics differ with respect to their intermediate chain, which may contain an ester or an amide.

3. How do local anaesthetics work?

Local anaesthetics work by blocking sodium channels

• The agent, a weak base, is injected as hydrochloride salt in an acid solution - tertiary amine group becomes quaternary and suitable for injection (i.e. dissolves in solution).
• Following injection, the pH increases (due to the higher pH of the tissues, which is usually 7.4) and the drug dissociates, the degree of which depends on pKa, and free base is released.
• Lipid soluble free base enters the axon. Inside the axon the pH is lower ( because the environment is more acidic), and re-ionization takes place.
• The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization

4. What determines the onset time of action?

The pKa is the pH at which the drug is 50% ionized and 50% unionized. Ionized drugs are poorly lipid soluble (e.g. morphine compared to fentanyl - the former has a much slower time of onset of action).

The closer the pKa is to local tissue pH (usually 7.4), the more unionized the drug is, or, the higher the pKa, the more ionized. Because all local anaesthetics are weak bases, those with a pKa near physiological pH (7.4) will have more molecules in the unionized lipid soluble form (e.g. lignocaine) -> more rapid onset of action.

Importance:

• lower pKa -> better absorption into nerve tissue
• higher pKa -> more effective blockade within nerve

5. What determines the duration of action of a local anaesthetic?

The more highly protein bound the drug, the longer the duration of action. More highly bound drugs probably bind for longer to neuronal membrane proteins. The protein probably provides a depot for maintenance of neural blockade.

6. What determines the potency of a local anaesthetic?

Highly lipid soluble drugs readily cross membranes, the higher lipid partition coefficient, the more potent and longer DOA of the drug eg. Prilocaine 0.9, Lignocaine 2.9, Bupivicaine 28.

If tissues are infected, local pH decreases and local anaesthetics are less effective.

8. Is there any way of accelerating the speed of onset of blockade with a local anaesthetic?

Yes: alkalinisation of the solution (by adding bicarbonate)- makes it more effective. By elevating tissue pH it raises the base-cation ratio (brings the pH & pKa closer together) and increases absorption of the local anaesthetic into nerve into the nerve tissue.

9. What is the purpose of "carbonated lignocaine."

Carbonation of anaesthetic solution - add CO2 to the solution - CO2 passes into the nerve and decreases the pH inside (due to the formation of carbonic acid), thus increasing the amount of ionized LA inside, blocking more channels

10. Do local anaesthetics have preferential effects on any particular types of nerve fibre?

Yes, as a general rule of thumb, the greater the diameter of the nerve fibre, the greater the concentration of LA required to produce conduction blockade. Small unmyelinated fibres are more vunerable to blockade than large myelinated fibres.

There is a progressive loss of function, for example with epidural anaesthesia, as the dose of the LA is increased in the following order:

The clinical implication of this is the possibility of differential nerve blockade, such as the woman is able to feel the baby coming down (pressure) in the second stage of labour and is able to push the baby out (motor), thus avoiding forceps delivery.

11. Why do we rarely use ester type LAs in our practise?

12. Describe the process of local anaesthetic toxicity, from warning signs to the worst clinical scenario.

Lignocaine:

• 4m g/ml: lightheadedness, tinnitus, circumoral and tongue numbness [anticonvulsant and antiarrhythmic activity]
• 6m g/ml: visual disturbances.
• 8m g/ml: muscular twitching
• 10m g/ml: convulsions
• 12m g/ml: unconsciousness
• 15m g/ml: coma
• 20m g/ml: respiratory arrest
• 26m g/ml: cardiovascular collapse

Source Mather Drugs 18:185-205, 1979

13. What are the maximum safe doses of lignocaine, bupivicaine and prilocaine?

Bupivicaine2mg/kg

Lignocaine 3mg/kg

Prilocaine 6mg/kg

cc/cns ratio is 4 for bupivicaine, 7 for lignocaine

What is this cc/cns ratio?

This is the ratio of dosage or blood levels required to produce irreversible cardiovascular collapse to that level required to produce convulsions. The lower the ratio, the more potentially hazardous the drug is. This is the reason why we don't use bupivicaine for iv regional blocks.

How do you treat LA toxicity?

The treatment is supportive. Treat with oxygen & IPPV as necessary. Correct any acid-base or electrolyte abnormalities (acidosis and hypoxia worsen the cardiovascular toxicity of bupivicaine). Treat convulsions with phenytoin or barbiturates. The treatment for LA induced arrhythmia is Bretylium 7mg/kg or Phenytoin 5mg/lkg

14. What factors relate to the possibility of drug toxicity with LAs?

Toxicity depends on the amount of free drug in plasma ® this relates to three factors:

1. Dose given (see above).

2. Rate of injection (the effective dose given).

3. Site of injection (the greater the blood supply to the area injected the greater the systemic absorption). Sites of absorption from greatest to least:

interpleural > intercostal > pudendal > caudal > epidural > brachial plexus > infiltration

Adrenaline is a local vasoconstrictor. Reduced blood supply has three advantages:

1. Less bleeding at the site [local infiltration].

2. Less systemic absorption, and consequently lower toxicity and possibility of giving a higher dose.

3. Prolonged duration of action.

It is conventional to use adrenaline only with short acting agents such as lignocaine, as it has little effect on the duration of action of longer acting drugs.

If asked whether you use adrenaline, I would be inclined to say no: you would use a longer acting agent, as excessive vasoconstriction could cause ischaemia.

16. Tell me about Prilocaine.

Prilocaine is equipotent with lignocaine, but its duration of action is longer and it is less toxic. This makes it an ideal agent for intravenous regional anaesthesia. However it should be noted that prilocaine undergoes rapid hepatic metabolism to o-toluidine, which causes methaemoglobinaemia. Consequently this is not used for epidural anaesthesia in labour (fetal haemoglobin is more sensitive than it's adult counterpart). Methaemoglobinaemia is treated with methylene blue i.v.

17. Tell me about Amethocaine.

Amethocaine is an ester an is generally used for topical anaesthesia in eye surgery or placement of iv cannulae. It should be used with care as it is an ester and is rather toxic as it is very slowly hydrolysed by pseudocholinesterase. Traditionally this drug was very poplar in the USA for spinal anaesthesia.

18. Tell me about Ropivicaine.

Ropivicaine is a long acting agent which closely resembles bupivicaine in its chemical structure, protein binding, pKa and clinical uses. It is unusual for a LA as it is prepared as an s-isomer rather than as a racemic mixture; this conveys certain advantages. Bupivicaine, prilocaine and mepivicaine have an asymmetrical carbon atom and consequently have two stereoisomers with different pharmacological properties.

The stereoisomer specificity of ropivicaine confers two advantages:

1. Less toxicity as this isomer binds less to cardiac tissue.

2. Greater specificity for sensory nerves > motor nerves.

19. You meet a drug rep in the corridor. He says that he has a new local anaesthetic that would be ideal for your practice. What questions would you ask him about it?

You would enquire about the following:

• Ester or amide? [short or long acting - allergic potential]
• For topical or regional use?
• pKa - onset of action
• Protein binding - duration of action.
• Lipid solubility coefficient - potency.
• CC/CNS ratio as an indication of toxicity.
• Safe for iv anaesthesia - maximum safe dose.
• Racemic mixture? Stereospecific.
• Does it cause methaemoglobinaemia

Is it safe for epidural use (ion trapping does not occur - as in mepivicaine).