Local anesthetics are drugs that when given topically or parenterally to a localized area, produce a state of local anesthesia by reversibly blocking the nerve conduction that transmit the feeling of pain from this area to the brain.
As their action is reversible, so after their use, it is followed by complete recovery in nerve functions with no risk of structural damage to nerve fiberes of the cells.
Procaine: First synthetic local anesthetic (LA) but it has slowonset, shortduration of action and causes allergy.
Lidocaine: First modern LA. It is the most widely used LA today but it causes vasodilatation at the site of application ⇒ duration of action, increases ↑ heart rate and palpitation. So, it is taken with epinephrine ⇒ vasoconstriction ⇒ absorption and ↑ duration of action.
Mepivacaine and Prilocaine: They vasodilatation effect so, used without epinephrine for hypertensive patients.
Mechanism of Action: They prevent the conduction and formation of action potential by either fully or partially blocking the sodium Na+ ion channels ⇒ no significant change in the membrane potential ⇒ conduction of action potential along the neuron would be prevented.
N.B.: Action potential = the ability of nerve cells to be excited.
Characteristics for an Ideal LA :
It should produce reversible block of sensory nerve fibres with minimal effect on the motor fibres.
It should have rapid onset with sufficient duration of action without systemic toxicities.
It should be non-irritating to tissues.
It should be effective upon injection or local action.
Structure-Activity Relationships (SAR):
According to Lofgren’s classification, the LA has 3-parts:
A) Liphophilic Portion (Aryl Group):
The lipophilic portion of the molecule is essential for L.A. activity because it is responsible for penetration into the cell membrane.
1- Electron-donating group on ortho or para positions ⇒↑ anesthetic activity. e.g.:
pAmino group (NH2) in procaine and butacaine.
p-Butylamino group in tetracaine.
p-Propanoxy group in proparacaine.
2- Electron-withdrawing group (NO2, CO, CN) ⇒ anesthetic activity.
3- o,oDimethyl substitution ⇒ protection against amide or ester hydrolysis.
4- Insertion of a methylene group (CH2) between the aromatic moiety and the carbonyl function ⇒ LA activity and ↑ anticholinergic activity due to prohibiting the formation of zwitter ion (in procaine).
B) Intermediate Chain:
The intermediate chain is responsible for the onset of action.
↑ pKa ⇒ LA activity (pKa must be 7.5-9).
Short carbon chain(- 3C) in length: ↑ length ⇒↑ pKa ⇒ LA activity.
Presence of small alkyl groups around the ester or amido ⇒ hydrolysis by esterase or amidase ⇒↑ duration of action (as in etidocaine).
Thioester ⇒ dermatitis but more active than normal esters.
Amino-amide LA ⇒ hydrolysis ⇒↑ duration of action. Also, they facilitate the formation of zwitter ion ⇒↑ anesthetic activity.
Generally, L.A. with ↑ lipid solubility and pKa values ⇒↑ onset and toxicity.
C) Hydrophilic Portion:
The hydrophilic portion is responsible for water solubility and binding to the receptor.