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PHARMACOLOGY OF LOCAL

ANESTHESIA

Pharm Abdulai Jawo Bah


B.pharm (Hons), MSC
Pharmacology Department
COMAHS, USL
Local anaesthesia / analgesia
• Anaesthesia is the loss of consciousness and all form of
sensation.

• Local Anaesthesia is the local loss of pain, temperature,


touch, pressure and all other sensation.

• In dentistry, Only loss of pain sensation is desirable.


Local Analgesia.
• Local anesthetics produce a transient and
reversible loss of sensation (analgesia) in a
circumscribed region of the body without loss of
consciousness.

• Normally,
the process is
completely
reversible.
Pharmacology of local anesthesia

CONTENTS OF THE LOCAL ANESTHETIC


CARPULE (CARTRIDGE )

1- the anesthetic drug


2- vasoconstrictor
3- preservative
4- vehicle
5- distilled water
Pharmacology of local anesthesia

1- The anesthetic drug


Pharmacology of local anesthesia
Constituents of the anesthetic carpule

Anesthesia Plain Anesthesia


with V.C without V.C
1- Local anesthetic agent 1- Local anesthetic agent
(L.A) (L.A)

2- Vaso - Constrictor
(V.C)
3- Preservative for V.C agent
(anti-oxidant)

4- Vehicle (0.9 % NaCl ) 2- Vehicle (0.9 % NaCl )


to make solution isotonic to make solution isotonic
Pharmacology of local anesthesia

Local anesthetic agents


Pharmacology of local anesthesia

Local anesthetic agents

Ester Amide
Local anesthetics generally have a lipid-
soluble hydrophobic aromatic group and a
charged, hydrophilic amide group.
The bond between these two groups
determines the class of the drug, and may
be amide or ester.
Pharmacology of local anesthesia
Pharmacology of local anesthesia
The clinically significant
differences between esters and
amides ??
Ester Amide
Linkage Easily broken Difficult

Stability in Less More


the solution
Storing time Less More

Heat stable Less More

Autoclavable Not Yes

Allergy Produce PABA w Very rarely


produce
allergic
reaction
Pharmacology of local anesthesia

Requirements of an ideal local anesthetic drug

1) should not be irritating to the tissue to which it is applied


2) should not cause any permanent alteration of nerve structure
3) its systemic toxicity should be low
4) must be effective regardless it is injected into the tissue or applied
topically to mucous membrane
5) time of onset of anesthesia should be as short as possible
6) duration of action must be long enough to permit completion of the
procedure
7) should have potency sufficient to give complete anesthesia without
the use of harmful concentrated solutions
8) should be relatively free from producing allergic reactions
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

Uptake
Potency
Duration
Biotransformation
Excretion
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

1- Uptake

 Most L.A agents producing vasodilatation

 Vasodilatation results in:


- Increase rate of absorption
- Decrease duration of action
- Increase blood level & risk for
toxicity
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

1- Uptake

 Procaine is the most potent vasodilator

 Cocaine is the only L.A agents that produces


vasoconstriction
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

Uptake
Potency
Duration
Biotransformation
Excretion
Pharmacology of local anesthesia
Pharmacokinetics of local anesthetics

2- Potency

 The majority of local anesthetics are tertiary amines

 Few local anesthetic are secondary amines as procaine


 NH3  NR3

 Local anesthetic agent is prepared in the carpule in the


form of hydrochloride salt of tertiary amine (NR3-HCL)
The importance of the pKa of a local
anaesthetic drug.
All local anaesthetic agents are weak bases,
meaning that they exist in two forms:

- unionised (B) and


- ionised (BH+).
The importance of the pKa of a local
anaesthetic drug.
The pKa of a weak base defines the pH at which both
forms exist in equal amounts.

As the pH of the tissues differs from the pKa of the


specific drug, more of the drug exists either in its
charged or uncharged form.
The importance of the pKa of a local
anaesthetic drug.
Pka
drug

PH
tissue
The pKa of a local anaesthetic determines the
amount which exists in an ionised form at any
given pH.

At physiological pH (7.4) all local anaesthetics


are more ionised than unionised (as all the pKa
values are greater than 7.4).
As the drug must enter the cell in order to have
its effect it must pass through the lipid cell
membrane

Unionised drug will do this more readily than


ionised drug.
However the proportions vary between the drugs:

lignocaine has a pKa of 7.9 and is approximately


25% unionised at pH 7.4 .

Bupivacaine has a pKa of 8.1 and hence less of the


drug is unionised at pH 7.4 (about 15%).

why lignocaine has a faster onset of action than


bupivacaine.
Therefore the drug which is more unionised at
physiological pH will reach its target site more
quickly than the drug which is less so.

This explains why lignocaine has a faster onset of


action than bupivacaine.
Pharmacology of local anesthesia

(NR3 – HCL )
The free base (NR3) of the hydrochloride salt of tertiary amine
is liberated from its salt (HCL ) by interaction with
alkaline medium , alkaline PH , (body fluids ,
NaHCO3)

(NR3-HCL) + NaHCO3  NR3 + NaCL +H2CO3

?
In presence of
tissue infection or
inflammation
(acidic PH)
Pharmacology of local anesthesia

In presence of tissue infection or inflammation


(acidic PH)

The free base (NR3) of the hydrochloride salt of tertiary


amine (NR3 – HCL ) fail to liberated from its salt (HCL) &
failure of anesthesia occurs
(NR3-HCL) + ACIDIC PH -- (NR3-HCL)
Local anesthetics with lower pK have a more
rapid onset of action (more uncharged form
more rapid diffusion to cytoplasmic side of Na+
channel)
pK % free base Onset of anesthesia Duration
at pH 7.7 (min) (minutes)

lidocaine 7.9 25 2-4 180-600

bupivacaine 8.1 18 5-8 90-200

procaine 9.1 2 14-18 60-90


Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

Uptake
Potency
Duration
Biotransformation
Excretion
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

3- Duration

Factors affecting duration & depth of anesthetic action :

1- factors related to individual :

Individual response variation


Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

3- Duration

Factors affecting duration & depth of anesthetic action :

2- factors related to anesthetic agent :

1- lipid solubility
2-concentration & type of drug
3- +/- V.C
4- duration of exposure
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

3- Duration

Factors affecting duration & depth of anesthetic action :

3- factors related to injection technique :

1- infiltration / nerve block


2- volume of solution
3- accuracy of technique
4- anesthetic variations
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

3- Duration

Factors affecting duration & depth of anesthetic action :

4- factors related to site of injection :

1- alkalinity : affect ionization of drug & rate of liberation of


free base

2- vascularity of tissue
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

Uptake
Potency
Duration
Biotransformation
Excretion
Pharmacology of local anesthesia
4- Biotransformation ( metabolism )
Ester Amide
Metabolized in Plasma Liver

By Plasma pseudo- Microsomal


cholinesterase enzyme
enzyme
And in Liver

By Esterase enzyme

Toxicity occurs Plasma pseudo Impaired liver


in patients with cholinesterase function
enzyme deficiency Liver dysfunction
Pharmacology of local anesthesia

Biotransformation of L.A drugs

Ester group undergo biotransformation in :


- Liver by the esterase enzyme
- Plasma by cholinesterase enzyme

Amide group undergo biotransformation in:


- Liver
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

Uptake
Potency
Duration
Biotransformation
Excretion
Pharmacology of local anesthesia

Pharmacokinetics of local anesthetics

5- Excretion

Both groups of local anesthetics & their metabolites are


excreted by kidneys

Patients with renal dysfunction may be unable to eliminate


local anesthetic & their metabolites from the blood with
increase risk of toxicity
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia

Systemic actions of Local anesthetics


• Drugs temporary interrupt nerve conduction
when absorbed into it and have little or no
irritating effect when injected

• They are all synthetic compounds except


the cocaine

CVS & CNS are susceptible to L.A action


Local anaesthetic agents:
• Are drugs that block nerve
conduction when applied locally to
nerve tissues in appropriate
concentrations, acts on any part of
the nervous system, peripheral or
central and any type of nerve fibres,
sensory or motor.
Pharmacology of local anesthesia

Systemic actions of Local anesthetics

- CNS
- CVS
- RESPIRATORY SYSTEM
- DRUG INTERACTION
- MALIGNANT HYPERTHERMIA (MH)
Pharmacology of local anesthesia

Systemic actions of Local anesthetics


Effects of local anesthetics on CNS

• As is the case with CNS depressants generally (e.g.,


alcohol) local anesthetics (at toxic doses) produce a
biphasic pattern of excitation followed by depression

• The excitatory phase likely reflects the preferential


blockade of inhibitory neurons and effects can range from
mild hyperactivity to convulsions)

• The subsequent depressive phase can progress to


cardiovascular collapse and even death if unmanaged.
Pharmacology of local anesthesia

Systemic actions of Local anesthetics


Effects of local anesthetics on heart
• Local anesthetics can reduce
• myocardial excitability
• pacemaker activity

prolong the refractory period of myocardial tissue – this is the basis


of the antiarrhythmic effects of local anesthetics

• Local anesthetic-induced
• myocardial depression
• hypotension

can also be a manifestation of toxicity and can lead to


cardiovascular collapse and even death!
Pharmacology of local anesthesia

Systemic actions of Local anesthetics


Effects of local anaesthetics on respiratory system

Unaffected by L.A until overdose levels .

Overdose  respiratory arrest

Due to generalized CNS depression


Pharmacology of local anesthesia

Systemic actions of Local anesthetics


Effects of local anaesthetics on malignant
hyperthermia (MH)

Disorder in which a genetic variant in an individual


alters his response to certain drug

Tachycardia / unstable blood pressure / cyanosis /


fever (up to 42 C) / muscle rigidity / death
Functional consequences of Na+ channel blockade by
local anesthetics

• nerves: decrease or abolition of conduction


• vascular smooth muscle: vasodilatation
• heart: decreased excitability (reduced pacemaker activity,
prolongation of effective refractory period)
• central nervous system: increased excitability, followed by
generalized depression
Clinical aspects

local anesthetic toxicity (cont’d)


• allergic reactions: restricted to esters – metabolized to
allergenic p-amino benzoic acid (PABA) (∴ amides usually
preferred for nerve block)
• cardiovascular: may be due to anesthetic (cardiodepression,
hypotension) or vasoconstrictor (hypertension, tachycardia) ∴
monitor pulse/blood pressure
• CNS: excitability (agitation, increased talkativeness – may
→ convulsions) followed by CNS depression (∴
care in use of CNS depressants to treat convulsions - may
worsen depressive phase – convulsions usually well tolerated
if brain oxygenation maintained between seizures)
Pharmacology of local anesthesia

2- The vasoconstrictor
Pharmacology of vasoconstrictors

V.C commonly used in conjunction with injected


L.A are chemically similar to the sympathetic
nervous system mediators i.e :

- epinephrine &
- norepinephrine
Advantage of V.C

1- delayed absorption of anesthetic drug


2- it decrease the amount of solution needed
3-controls the rate at which the anesthetic
drug enters the circulation (decrease risk of
toxicity)
4- haemostasis
5- it causes local anaemia
What happens if you don’t use a
vasoconstrictor?
*Plain local anesthetics are vasodilators by nature

1) Blood vessels in the area dilate


2) Increase absorption of the local anesthetic into the
cardiovascular system (redistribution)
3) Higher plasma levels  increased risk of toxicity
4) Decreased depth and duration of anesthesia  diffusion
from site
5) Increased bleeding due to increased blood perfusion to the
area
Contra-Indication of V.C

Relative Absolute

1- diabetes 1- toxic goiter


2- hypertension (hyperthyroidism)
3- cardiac
4- pregnancy
Pharmacology of local anesthesia

Contra-Indication of V.C
1- diabetes : as V.C counteract the action of insulin
i.e (increase blood glucose level )

2- hypertension : as V.C raises patient’s blood pressure

3- cardiac : as V.C stimulate the heart, produce tacchycardia


& increase H.R

This is doubtful because of small amount used about 0.04 mg


if 2ml of 1: 50 000 Is used & this is about 1/5 permissible
dose that can be given to cardiac patient without ill effect
Pharmacology of local anesthesia

Contra-Indication of V.C
4- pregnancy :
because V.C causes uterine contraction & may
cause abortion

5- hyperthyroidism (toxic goiter) :


because V.C esp. adrenaline may cause thyroid
crisis & sudden death
(Prilocaine with felypressine)
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia

3- VEHICLE
Pharmacology of local anesthesia

3- VEHICLE

1- add to L.A carpule to make solution


‘isotonic’

2- 0.9 % sodium chloride


- Ringer solution (0.5% sodium chloride +
0.4 % potassium chloride)
Pharmacology of local anesthesia
Pharmacology of local anesthesia
Pharmacology of local anesthesia

4- PRESERVATIVE
4- PRESERVATIVE

1- Is added to L.A carpule to prevent the oxygenation


of the V.C

2- Na Metabisulphite is the most commonly used


preservative

3- Na Metabisulphite when oxygenated is transferred


to Na metabisulphate with a characteristic yellowish
discoloration of carpule
Pharmacology of local anesthesia

Maximum doses of L.A agents


Pharmacology of local anesthesia
Pharmacology of local anesthesia

Dilution of L.A agents


Concentration of V.C in L.A

1/ 50.000  0.02 mg/ml


1/100.000  0.01 mg/ ml
1/200,000  0.005 mg/ml
2 % lidocaine of 1/100.000 epinephrine in patient
weighted 90 kg .. What is the max permissible dose ?
Lidocaine max.dose 300 mg / normal 4.4 mg/kg

90 kg X 4.4 = 396 mg  over absolute maximum

2% lidocaine means = 20 mg/ml


(2g/100 ml = 2000 mg / 100 ml

Carpule 1.8 ml of solution


So  20 X 1.8 = 36 of lidocaine / carpule
How much lidocaine in cartridge of 2% lidocaine with
1/100.000 epinephrine

2% lidocaine = 20 mg/ml
20mg/ml X 1.8 ml / cartridge = 36 mg lidocaine/ cartridge

Epinephrine 1/100.000 = 0.01 mg/ml


0.01 mg/ml X 1.8 ml/ cartridge = 0.018 mg epinephrine / cart

Maximum epinephrine dose 0.2 mg

1 carpule of 1:100,000 = 0.018 mg


So maximum permissible dose of 2% lidocaine with
1/100.000

Maximum epinephrine dose 0.2 mg


1 carpule of 1:100,000 = 0.018 mg

0.2 / 0.018 = 11 carpules


So maximum permissible dose of 2% lidocaine with
1/100.000 in cardiac patient

Maximum epinephrine dose 0.05mg


1 carpule of 1:100,000 = 0.018 mg

0.05 / 0.018 = 2.7 carpules


1.8 ml Cartridge of 2% Lidocaine 1:100,000 epi
Maximum Epinephrine: 11 Cartridges
Maximum Anesthetic: 300 mg

1.8 ml Cartridge of 2% Lidocaine 1:200,000 epi


Maximum Epinephrine: 22 Cartridges
Maximum Anesthetic: 300 mg
Max allowed dose (mg / kg) X (weight in kg / 10) X
(1/concentration of L.A) = ml lidocaine

7 mg / kg for lidocaine with epinephrine , using 1 %


lidocaine with epinephrine for 60 kg patient

7 X 6 X 1 = 42 ml lidocaine

With epinephrine 7 mg/ kg


Without epinephrine 3 mg/ kg
How much Epinephrine in CV
patients?
Maximum Epinephrine

0.04 mg
Two cartridges of 1:100,000 epinephrine
Pharmacology of local anesthesia

Keep in mind

1- The main agent in the carpule is the L.A agent

2- the other ingredients of the local anethetic carpule


are added :
a- to potentiate the action of the L.A agent
b- to prevent deterioration of the contents
Pharmacology of local anesthesia

TOPICAL ANESTHETICS
TOPICAL ANESTHETICS

The use of topically applied L.A is an important component


of a traumatic administration of intraoral L.A

The concentration of a local anesthetic applied topically is


typically greater than that of the same local anesthetic
administered by the injection

The higher the conc facilitates diffusion of the drug thru


mucous membrane

Lidocaine (xylocaine) is the most commonly used


Clinical aspects
Applications of local anesthesia:
 nerve block: injected locally to produce regional anesthesia
(e.g., dental and other minor surgical procedures)
 topical application: to skin for analgesia (e.g., benzocaine) or
mucous membranes (for diagnostic procedures)
 spinal anesthesia: injection into CSF to produce anesthesia for
major surgery (e.g., abdomen) or childbirth
 local injection: at end of surgery to produce long-lasting post-
surgical analgesia (reduces need for narcotics)
 i.v. infusion: for control of cardiac arrhythmias (e.g., lidocaine
for ventricular arrhythmias)