Pharmacology of Local Anesthesia

By Dr. Khaled Moustafa Kamel Assistant Professor College of Dentistry KAU - SA

Local Anesthetic Drugs

Most of local anesthetic drugs are tertiary amines i.e. an ammonia molecule in which each of the 3 H atoms has been replaced by an organic radicle.

H H N H
Ammonia Molecule

R H H
[Primary Amine]

R N R H [Secondary Amine]

R R N by R
All 3 H ions replaced organic radicles

[Tertiary Amine]

Classification of L.A. Drugs

I. Esters
Esters of benzoic acid:
1- Butacaine. 3- Metycaine. 2- Cocaine. 4- Kinacaine.

II. Anilide [Non-ester or Amides]

1- Lidocaine (Xylocaine).

Esters of acid:

para-amino-benzoic

1- Procaine (Novocaine). 2- Tetracaine (Pontocaine). 3- Ravocaine.

2- Carbocaine (Mepivacaine). 3- Prilocaine (Citanest). 4- Bupivacaine.

Meta-amino-benzoic acid esters:

1- Unacaine. 1- Intracaine. 2- Primacaine.

III. Quinoline
Centbucridine

Para-ethoxybezoic acid esters:

 It is assumed that the free base of these salts is the effective agent on nerve tissue. This free base is liberated from its salt by interaction with the slightly alkaline body fluids. The more the alkaline the tissue fluids are, the more rapid the free anesthetic free-base is liberated. On the other hand, if anesthetic solution is injected in acidic medium in the tissue (inflamed), the liberation of the free base is prohibited, and failure of anesthesia occurs.

I. Ester Local Anesthesia

Ester L.A. are metabolized mainly in plasma by an enzyme called Pseudocholinesterase [A hereditary trait] and partially in kidney during excretion. Allergic reaction to esters: It does not occur to the ester agents but rather to para-aminobenzoic acid (PABA) which is the major metabolic product of esters. Some patients have Atypical form of Pseudocholinesterase that results in inability to metabolize esters and therefore induce toxicity.

II. Anilides [Amides] [Non-esters]:

The metabolism of the amide local anesthetics takes place in liver. An exception is Prilocaine, where it is metabolized mainly in liver with some possibility in lung. Therefore, significant liver dysfunction or heart failure is relative contraindication to the use of amide local anesthesia.

The kidneys are the primary execratory organ for both types of local anesthesia. Impairment in renal function will result in incomplete removal of local anesthesia and their metabolites from the blood and possibility of toxic reaction.

Systemic Action of L.A. Drugs

[I] Central Nervous System CNS:

The local anesthetics can cross the bloodbrain barrier. At low (nontoxic) levels there are no CNS effects of any significance. At high (toxic or overdose) the primary clinical manifestation is Tonic-clonic convulsive episode [Excitation]. Some local anesthetics (procaine, lidocaine, prilocaine) have anticonvulsant properties, but if their blood levels is increased it also can produce seizure activity.

[1] Excitation-Depression (A) Pre-convulsive signs and symptoms

Signs:
1. 2. 3. 4. Slurred speech. Shivering. Muscular twitching. Tremor in muscles of face and distal extremities. Symptoms:
1. Numbness of tongue and circum-oral region. 2. Warm, flushed feeling of skin. 3. Pleasant dreamlike state. 4. Dizziness. 5. Visual disturbance (inability to focus). 6. Auditory disturbance (tinnitus). 7. Drowsiness. 8. Disorientation.

(B) Convulsive Phase

1. Further elevation of L.A. drug in the blood will produce clinical signs of tonic-clonic convulsive episode. 2. Seizure activity is self limiting, since cardiovascular activity is not significantly impaired and the L.A. drug undergoes biotransformation throughout the episode, this result in decreasing the blood level of L.A. and termination of the seizure activity. 3. On the contrary, there is an increase of cerebral blood flow and cerebral metabolism during local anesthetic-induced convulsions.

Increased cerebral metabolism leads to a progressive metabolic acidosis that tends to prolong the seizure activity. Further increase in L.A. blood level result in a cessation of the seizure activity [Generalized Depression], respiratory depression occurs at this time leading eventually to respiratory arrest.

[2] Analgesia
1. The second action on CNS is analgesia. 2. When L.A. drug is given IV, they increase the pain threshold producing a degree of analgesia. 3. Procaine is used for this purpose; 4 mg/kg of body weight administered over 20 minutes, but it is ineffective with acute pain. 4. Because of the narrow safety margin between procaines analgesic action and signs and symptoms of overdose on CNS, it is not commonly used nowadays.

[II] Cardiovascular System:

A. Direct Action on Myocardium: 1- It produces a depression of the myocardium and decreases the electrical excitability of the myocardium, decreases the conduction rate, and decreases the force of contraction. 2- On the other hand, there are L.A. drugs as Lidocaine and Procaine have demonstrated antidysrhythmic action. Direct Action on Peripheral Vasculature: Cocaine is the only L.A. drug that produces vasoconstriction, while all other L.A. drugs produce a peripheral vasodilatation through relaxation of the smooth muscles of blood vessels.

B.

The usual sequence of anesthetic action on CVS is:

At non-overdose level: Slight increase or no effect on BP because of increase cardiac output and heart rate as a result of enhanced sympathetic activity and there is a direct vasoconstriction of peripheral vasculature. At level approaching: Mild degree of hypotension produced by direct relaxant action on the vascular smooth muscles. At overdose level: Profound hypotension caused by decreased myocardial contractility, decrease cardiac output, and decreased peripheral resistance. At lethal level: CV collapse caused by massive peripheral vasodilatation, decreased myocardial contractility and decreased heart rate (Sinus Bradycardia).

[III] Respiratory System:

At non-overdose level: It has a direct relaxant action on bronchial smooth muscles. Overdose level: It produces respiratory arrest as a result of generalized CNS depression.

[IV] Miscellaneous Actions:

1. Neuromuscular Blockade: Many L.A. are capable of blocking neuromuscular transmission through inhibition of Na diffusion. 2. Drug Interaction: In general CNS depressants (e.g. Narcotics, Barbiturates) when used in conjugation with L.A. to potentiation of cardio-respiratory action of L.A. [e.g. Succinylcholine + Ester L.A. and Barbiturates + amides] 3. Malignant Hyperthermia: It is a pharmacogenic disorder in which a genetic variant in the individual alters the patient response to certain drug, clinically characterized by tachycardia, tachypenea, unstable BP, cyanosis, respiratory and metabolic acidosis, fever (42 C or more), muscle rigidity and death.