Local Anaesthetics and Antidysrhythmic Drugs

Question 1

Define local anaesthetics

Answer 1

Substances that reversibly block the generation and conduction of the action potential

Question 2

What was the first local anaesthetic to be discovered ?

Answer 2

COCAINE

Question 3

Name two analogues of cocaine that were searched for due to the toxic and addictive properties of cocaine

Answer 3

1. PROCAINE (novocaine)

2. LIDOCAINE (xylocaine)

Question 4

Describe the common structure of local anaesthetics

Answer 4

1. Aromatic group
2. Intermediate chain
   (either an ester or amide bond)
3. Tertiary or secondary amino group

Question 5

What are the three ways that local anaesthetics are administered?

Answer 5

INTRADERMAL

SUBCUTANEOUS

INTRATHECAL

Question 6

What two channels are responsible for the action potential, what type of channel are they, and what is the activation time for each?

Answer 6

NA+ CHANNELS:
allow Na+ influx - depolarisation
[Na+] is low inside and high outside

K+ CHANNELS:
allow K+ efflux - repolarisation
[K+] is high inside and low outside

Both are VOLTAGE-DEPENDENT:

 - membrane depolarisation causes channels to open
 - transition from closed-open is known as activation

Na+ channel activation is rapid, followed by inactivation

K+ channel activation is delayed

Question 7

What is the pH of most local anaesthetics?

Answer 7

WEAK BASES:
administered as water soluble hydrochlorides (B.HCl);

after injection, the (B) is liberated by the relatively alkaline pH of tissue fluids

Question 8

In which form would a local anaesthetic be found in tissue fluid?

Answer 8

BOTH ionised (BH+) and non-ionised (B)

Question 9

Where do local anaesthetics bind on Na+ channels??

Answer 9

The binding site for local anaesthetics on Na+ channels is on the ALPHA SUBUNIT

These sites are located in the inner cavity of the pore of the sodium channel

Question 10

What is the basic function of local anaesthetics?

Answer 10

Local anaesthetics prevent the generation and conduction of action potentials down afferent nerve fibres (neurones associated with pain)

Question 11

Outline the mechanism of action of local anaesthetics.

Answer 11

Typically, action potentials travel along neurones by allowing Na+ in and K+ out.

Unionised LA (B) are able to penetrate the membrane of nerve cells. The space inside the neuron is slightly acidic, causing the LA to become ionised.

The ionised LA binds to sodium channels and ultimately prevents Na+ from entering the nerve cell, thereby preventing the propagation of an action potential down the neuron.

Question 12

What differentiates local anaesthetics?

Answer 12

POTENCY:
lipid solubility determines anaesthetic potency; highly lipophilic molecules easily penetrate nerve cell membranes

CONDUCTION BLOCK DURATION:
pKa is pH at which 50% of the agent exists in the ionic and 50% in the non-ionic form;

lower pKa = greater fraction of molecules exist in uncharged form

Question 13

Describe the physiological characteristics of the action of local anaesthetics.

Answer 13

ALL fibres can be blocked.

THIN fibres are more easily blocked than thin ones.

SMALL, MYELINATED fibres are more readily blocked than non-myelinated ones.

The degree of block at a given [LA] depends upon the recent frequency of nerve activity - use-dependence of block

Small diameter C and A-delta pain fibres fire at a high frequence and are blocked eariler and sooner with low [LA] than are the A-alpha fibres

pain > cold > warmth > touch > pressure > motor

Question 14

What are the differences in the metabolism of local anaesthetics?

Answer 14

AMINO ESTERS:
relatively unstable in solution and are rapidly hydrolysed in the body by plasma cholinesterase

Examples: PROCAINE, TETRACINE

AMINO AMIDES:
stable in solution, are slowly metabolised by hepatic amidases

Examples: LIDOCAINE, PRILOCAINE