Local Anesthetics

Question 1

Local Anesthetic Esters

Answer 1

Cocaine
Procaine
Chloroprocaine
Tetracaine
Benzocaine

Question 2

Local Anesthetic Amines

Answer 2

Lidocaine
Prilocaine
Mepivacaine 
Ropivacaine 
Bupivacaine 
Dibucaine 

Question 3

What are local anesthetics

Answer 3

Local anesthetics:

- applied locally
- produce loss of sensation to pain 
	in a specific area of the body 
- without the loss of consciousness

Block axonal conduction in nerves when applied in appropriate concentrations.

Completely reversible action.

Question 4

Cocaine

Answer 4

an ester
hydrolyzed very rapidly in blood by pseudocholinesterase
a potent sympathomimetic and vasoconstrictor
a potent CNS stimulant
very addicting
- euphoria
- CNS stimulation
- reduced fatigue
- perceived increase in mental ability
behavioral toxicity similar to paranoid schizophrenia
fatalities from arrhythmias (ventricular fibrillation), myocardial infarction, or seizures

Question 5

Procaine (Novocaine)

Answer 5

Procaine (Novocaine®):
- the first synthetic local anesthetic drug (1898), derivative of cocaine, slow onset , short duration, less potent, higher potential to cause allergic reactions, sympathomimetic (release adrenaline) increase heart rate, feel nervous

Question 6

Chloroprocaine (Nesacaine)

Answer 6

slightly more potent with shorter duration of action than procaine

Question 7

Tetracaine (Pontocaine)

Answer 7

10 times more potent with slower onset and longer duration of action than procaine

Question 8

Benzocaine (Americaine, Ora-gel, Solarcaine)

Answer 8

does not contain the terminal hydrophilic amine group, only slightly soluble in water, slowly absorbed with prolonged duration
- only useful as a topical (surface) anesthetic

Question 9

Lidocaine (Xylocaine)

Answer 9

an amide
the first modern local anesthetic agent (1943 )
biotransformed in liver by amidases (N-dealkylation) into active form monoethylglicexylidide (MEGX) followed by hydrolysis to the inactive glycine xylidide by liver microsomal cytochrome P450)
little allergic reaction.
Excellent potency, 2 to 3 times more potent than procaine
rapid onset of action
t1/2 = 1.5-2 hours, longer duration of action when combined with epinephrine (to increase duration of action)
versatile in many clinical applications:
- surface (topical) anesthesia
- peripheral nerve block
- infiltration anesthesia
- spinal anesthesia
- epidural anesthesia
- antiarrhythmia

Question 10

Mepivacaine (Carbocaine)

Answer 10

pharmacologically similar to lidocaine
coadministration of epinephrine to prolong duration of action;
effective without a vasoconstrictor
- elderly patients
- cardiovascular disease;
- not useful in obstetrics because of prolonged metabolism in
the fetus and neonate, which increases the risk of toxicity.

Question 11

Bupivicaine (Marcaine)

Answer 11

10 times more potent than procaine

particularly long duration of action (~24 hr)

Question 12

Ropivacaine

Answer 12

duration of action similar to bupivacaine, but slightly less potent

Question 13

Mechanism of action of local anesthetics (direct sodium channel blocking theory)

Answer 13

Direct Na+ Channel blocking theory

• structure activity relationships
• active on inside of membrane
• only the ionized or charged form of the local anesthetic is active
• open-channel block (use-dependent)
• onset of action is proportional to the Na+ channel activity of the nerve being blocked.

Question 14

Mechanism of action of local anesthetics (membrane fluidity and disorganization theory)

Answer 14

• local anesthetics have been shown to increase membrane fluidity, and their anesthetic effect can be reversed under high pressure.
• need very high concentrations (mM)
• there are exceptions to the structure-activity relationships

Question 15

MOA summary

Answer 15

Local anesthetics block the inward Na+ current (Na+ influx) by blocking the voltage-gated Na+ channels in neuronal membranes that are responsible for signal propagation, the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential.

Question 16

Differential Block

Answer 16

• Preferentially block small-diameter, unmyelinated nerve fibers (c-fibers for pain and temperature stimuli) first.
  - Large-diameter, myelinated nerve fibers appear to be less susceptible and require greater doses to achieve neural blockade.
  - Overall, size factor predominates over myelination:
  small unmyelinated pain fibers > small myelinated autonomic fibers > large myelinated autonomic fibers.
  - Order of sensory loss: pain (lose first) > temperature > touch > pressure (lose last).

Question 17

Routes of Admin: infiltration

Answer 17

: Injection under the skin. Need to localize drug action. Often used with epinephrine which causes vascular constriction. Minimally effective concentration should be used to avoid toxicity.

Question 18

Spinal application

Answer 18

Injection into Subarachnoid space.
Spread of anesthetics can be controlled by
- increasing the density of the anesthetic solution (10% glucose)
- tilting the patient.
upper-abdominal surgery procedures.
Problems: autonomic blockade, sympathetic tone (hypotension).

Question 19

Caudal application

Answer 19

The anesthetic agent is introduced into the epidural space of the sacral canal.
perinea and rectal procedures

Question 20

Epidural application

Answer 20

Administered outside, but diffuses into subarachnoid space Obstetrics: labor and delivery, cesarean section.

Question 21

Factors Affect the Reaction of Local Anesthetics : lipid solubility

Answer 21

the higher lipid solubility the faster nerve penetration, block sodium channels, and the onset of action.

Question 22

Factors Affect the Reaction of Local Anesthetics : pH influence

Answer 22

log (cationic form/uncharged form) = pKa – pH
- uncharged (non-ionized) form can cross the nerve membranes
and gain access to their site of action to block the Na channels.
- All local anesthetics are weak bases with a pKa of 8 – 9.
Decrease in pH (e.g., infected tissue) shifts equilibrium toward the ionized form, delaying the penetration of the drug and thus the onset of action.

Question 23

Factors Affect the Reaction of Local Anesthetics : blood flow

Answer 23

Vasoconstrictor (epinephrine) is used to limit vasodilation activity of a local anesthetic, to delay the systemic absorption of the drug into the bloodstream and keep the anesthetic in place at a longer period and prolong the action of the drug.

Question 24

Metabolism and excretion of esters:

Answer 24

extensively and very rapidly hydrolyzed in blood by plasma pseudocholinesterase and liver esterases. Hydrolysis of esters yields paraaminobenzoic acid (PABA).

Question 25

Metabolism and excretion of amides

Answer 25

almost completely biotransformed in liver by amidases and undergo N-dealkylation followed by hydrolysis by liver microsomal cytochrome P450 (Prilocaine > etidocaine > lidocaine > mepivacaine > ropivacaine > bupivacaine and levobupivacaine).
Patients with liver diseases, concomitant use of other drugs affecting enzyme activity of P450, reduced hepatic blood flow (halothane), etc. will reduce the biotransformation of amides.

Question 26

Systemic effects on CNS

Answer 26

Moderate doses lead to CNS stimulation

Very high doses lead to CNS depression

Question 27

Systemic Cardiovascular effects

Answer 27

Direct depressant effect on the myocardium
reduces excitability
lowers contractility
prolongs the refractory period
slows conduction
vasodilation
vasoconstriction (cocaine only)

Question 28

Hypersensitivity reactions

Answer 28

Most common with the “esters”: the formation of paraaminobenzoic acid (PABA), which is known to be allergic.

Question 29

Toxicity

Answer 29

Toxicity is usually caused by systemic absorption and high concentration (dose) of the local anesthetics due to unintentional intravenously injection
- Concentration are varied (maximum dose for an individual is usually between 70mg to 500mg) according to age, weight, and health of the individual, the type of solution used and the presence of vasoconstrictor

Question 30

Cardiovascular Toxicity

Answer 30

reduced excitability, contractility, conduction,

blood vessel relaxation or constriction (Cocaine only)

Question 31

Allergic reactions can happen with ______ only

Answer 31

esters

Question 32

Neurotoxicity with local anesthetics

Answer 32

• light headedness
  
  • irritation and agitation (shivering or twitching)
  • seizures
  • numbness