1. Pharmacology of local anesthetics
Dr S. Parthasarathy MD DA DNB PhD FICA , Dip software based statistics

2. History
Local anesthesia was accomplished by having the operator chew coca leaves and apply the mascerated pulp to the skin and wound edges while using a tumi knife to bore through the bone.

4. Cocaine – brachial plexus
Animal epidural
Freud , koller
Reviews on cocaine

5. Other drugs ??
Pethidine ??
Phenergan ??
LA properties !!

7. Basic structure Three parts Lipophilic aromatic ring Hydrophilic amine
Intermediate chain
Ester or amide chain

8. Esters – amides Cocaine Procaine Chlroprocaine Tetracaine Lignocaine
Mepivacaine
Prilocaine
Etidocaine
Bupivacaine
Ropivacaine

10. Esters Metabolism by pseudocholinesterase Short action usually
PABA – possible allergic reactions
Cocaine is hydrolyzed in the liver

11. Amide with ester bond – hydrolysis for inactivation
Articaine
Amide with ester bond – hydrolysis for inactivation

12. Aromatic ring – lipophilic
Lipophilic means membrane liking – potency of the molecule Hydrophobic or lipophilic More – more potent

14. What does it mean ?? Procaine – 4 % solution Lignocaine - 2 % solution
Bupivacaine – 0.5 % solution
Aromatic ring – substitution – lipophilicity
Molecular weight !!

16. Pharmacokinetics
Onset

17. NH4+ B
BH +

18. Local anesthetics are weak bases
Means they are hydrogen acceptors
NH3 ( tertiary amine ) will become NH4 +
Unionized Vs ionized
Unionized is lipophilic hence it has to be made as hydrochloride salts to make it as solution

19. Base = unionized = lipophilic part = membrane liking
This part has to be more if the drug has to have a fast onset

20. Henderson hasselbach equation
pKa – pH = log [BH+] / [B]
pKa = pH + log [BH+] / [B]
Both are equal pH = pKa
If pKa is low , the lipid soluble portion is more

25. Onset =other factors Site Lipophilicity Strength of a solution
Very potent

26. Explanation – physiological pH
But if the pH is itself is low
Acidic tissue
Base is further less – no action in pus and inflamed tissue

27. If we add sodium bicarbonate
Lipid soluble form will be more in the syringe
If we add more NaHCO3 – precipitation
Not water soluble !!

28. Carbonation Local anesthetics are made as HCl salts at a pH of 3-6
We don’t want that
Make it as carbonate salt – higher pH
Carbondioxide later = acidic inside = action inside

29. Duration

30. Protein binding
bupi
tetrac
Lig

31. But high protein binding is one of the projected reasons for increased toxic effect of bupivacaine

32. Vasodilation
when used without vasopressors, lidocaine shortens its own duration by dilating local vasculature, whereas mepivacaine and bupivacaine do not.
Lignocaine vasodilates and shortens

33. The duration of action of the drug is also related to its structure,
length of the intermediate chain joining the aromatic and amine groups.

34. Onset – pKa , but lipophilic and concentration also
Potency – lipophilicity
Duration =- protein binding and vascular actions

35. Order of ease of blockade
Preganglionic –
Pain – Temperature –
Touch – Proprioception (pressure) –
Motor.
Why ??
Size and myelination !!

37. Autonomic
Sensory
Motor
But dentist -

38. Chiral drugs – asymmetric carbon atom
Mepivacaine, bupivacaine, ropivacaine, and levobupivacaine have been developed as a pure S enantiomers.
less neurotoxicity and cardiotoxicity than racemic mixtures or the R enantiomers of local anesthetics,
perhaps reflecting decreased potency at sodium ion channels

39. An asymmetric carbon atom (chiral carbon) is a carbon atom that is attached to four different types of atoms or groups of atoms.

40. Sodium channel

41. Minimum concentration for blocking nerve fiber conduction is called Cm
Nodes of ranvier
3 nodes –
6 mm of fiber to be blocked

43. sensory anesthesia sufficient for skin incision usually cannot be obtained without motor impairment,
But if we have an LA , blocks pain but not others great
Bupi and ropi – more sensory but etidocaine – more motor – differential blockade

45. States of sodium channel
Local anesthetics bind to sodium channels in open position
from inside , block sodium entry ,
prevent depolarization – conductance
Inactivated state
Later resting state
Use dependent block !!

47. Other actions Vasculature Anti arrhythmic action
CNS action e,g. blunting intubation response
Neuropathic pain

48. Distribution Lung extraction Skeletal muscle – maximum concentration
Metabolized and excreted in the urine
A unique systemic side effect associated with a specific local anesthetic is the development of methemoglobinemia after the administration of large doses of prilocaine

49. Amide local anesthetics
N-dealkylation of the tertiary amine (e.g. lignocaine) produces a more water soluble secondary amine and renders it more susceptible to amide hydrolysis.

50. Local anesthetics may be combined in an effort to produce a rapid onset (chloroprocaine) and prolonged duration (bupivacaine) of action.
The toxicity of combinations of local anesthetic drugs is additive rather than synergistic.

51. Emla
(a eutectic mixture of 2.5 % lidocaine and 2.5 % prilocaine) is a topical local anesthetic that penetrates intact skin and reaches an anesthetic depth of up to 5 mm.
The onset of effect is approximately 1 h.
When the effect takes place, the vessels in the skin show vasoconstriction initially, followed by vasodilation when higher concentrations are reached
IV access in children

52. Summary Local – history – cocaine Three portions Esters and amides
Onset , duration and potency
Metabolism and excretion
Nerve fibre size, myelination and sensitivity
Sodium channel