pharmacology of local anesthetics

1. Local anesthetic
DR.IBRAHIM HASSAAN, MBCHB,MSC,EDAIC
14/04/2023

2. local anesthetics classification
According to the nature of the link chain between an aromatic group & an amine group, local
anesthetics either esters or amides.

3. local anesthetics classification

4. LA work by blocking sodium channels
along the axonal membrane
Open sodium channel block
– Unionized lipid-soluble drug passes through the phospholipid membrane. Inside the axoplasm the
drug is protonated, i.e., becomes ionized and binds to the internal surface of a sodium channel.
This prevents the channel from opening.
Local anesthetics bind more avidly to sodium channels that are inactivated or open, and so they are
more likely to affect nerves that have a rapid firing rate.
Closed sodium channel block (membrane expansion theory)
– The un-ionised local anesthetic dissolves in the neuronal membrane resulting in swelling of the
neuronal membrane and consequent physical inactivation of neuronal sodium channels preventing
depolarization of the neuron.

5. Differential block
Different nerve fibres are affected by local anaesthetics at different rates. This may be related to
the size of the nerve. Small sensory nerves are usually blocked before large motor nerves.
Frequency-dependence may play a role in this differential block. LA can enter the axoplasm
while the sodium channel is in the open state, during depolarization.
This happens at higher frequencies in smaller fibres, which get blocked more rapidly and easily.
Larger motor fibres, by contrast, operate at lower frequencies so block occurs more slowly.

6. significance of the pKa
The onset of action is closely related to the pKa of the drug.
The pKa is the pH at which the ionized and unionized forms of that LA are in equilibrium, i.e.,
50% is ionized and 50% is unionized.
All LAs are weak bases and exist mainly in the ionized form at normal physiological pH.
a higher pKa =The onset of action is slower.
a lower pKa =The onset of action is faster.
This also explains why LAs are less effective in infected and therefore more acidic tissues.
At physiological pH (7.4), bupivacaine (pKa 8.1) is 15% un-ionised.
Lignocaine (pKa 7.9) is 25% un-ionised (faster onset)

7. lipid solubility
The more lipid soluble the drug, the greater its potency, e.g. bupivacaine is seven times more
lipid soluble than lignocaine and therefore more potent.

8. factors govern the duration of action?
Protein bound
bupivacaine is 95% protein bound (longer duration of action)
Lignocaine is 65% protein bound.
Addition of vasoconstrictors
Adrenaline.

10. Bupivacaine vs lignocaine Ropivacaine

11. Ropivacaine
-concentrations of 0.2/0.75/1.0% equivalent to 2.0, 7.5, and 10 mg/ml, respectively.
-It is not available in combination with a vasoconstrictor, as this does not alter its tissue uptake or the
duration of action
- administered topically, by infiltration, or epidurally; the drug is not currently intended for use in spinal
anaesthesia
- Sensory blockade is similar in time course to that produced by bupivacaine; motor blockade is slower in
onset and shorter in duration than that after an equivalent dose of bupivacaine.
-Alkalinization of 0.75% ropivacaine significantly increases the duration of action of epidural blockade

12. Local anesthetic toxicity
1 Recognition
2 Immediate management
3 Treatment
4 Follow-up

13. Local anesthetic toxicity

14. Intralipid
soybean oil emulsion
Has therapeutic effect of intravenous infusion of lipid emulsion in refractory systemic local
anesthetic toxicity.
The exact mechanism behind lipid rescue is debated
The sequestration hypothesis (“lipid sink”)
It is currently thought that the main actions involve sequestration of lipophilic local anesthetics
and a bolstering of fatty acid metabolism in cardiomyocytes.
Its antidote effect of lipid infusion for other lipophilic medications, including calcium channel
blockers, β blockers, and tricyclic antidepressants.