Pharmcaology ppt

PHARMACOLOGY OF LOCAL ANESTHESIA

PRESENTED BYDR/ NERMINE RAMADAN MAHMOUD

Lecturer Oral & Maxillofacial surgery in OMFS department Faculty of Dentistry O6U

B.D FACULTY OF DENTISTRY, O6U , 2006

MSC ORAL & MAXILLOFACIAL SURGERY, FACULTY OF DENTISTRY, CAIRO UNIVERSITY , 2012

PHD ORAL & MAXILLOFACIAL SURGERY, FACULTY OF DENTISTRY, CAIRO UNIVERSITY, 2015

• 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 anaesthesia / 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.

CONTENTS OF THE LOCAL ANESTHETIC CARPULE (CARTRIDGE )

1- the anesthetic drug2- vasoconstrictor3- preservative4- vehicle5- distilled water

Pharmacology of local anesthesia


1- The anesthetic drug


Anesthesia with V.C

Plain Anesthesia without V.C

1- Local anesthetic agent (L.A)

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

4- Vehicle (0.9 % NaCl )to make solution isotonic

1- Local anesthetic agent (L.A)

2- Vehicle (0.9 % NaCl ) to make solution isotonic

Constituents of the anesthetic carpule


Local anesthetic agents


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.



The clinically significant differences between esters and amides ??

Ester Amide

Linkage Easily broken Difficult

Stability in the solution

Less More

Storing time Less More

Heat stable Less More

Autoclavable Not Yes

Allergy Produce PABA w produce allergic reaction

Very rarely


Requirements of an ideal local anesthetic drug

1) should not be irritating to the tissue to which it is applied2) should not cause any permanent alteration of nerve structure3) its systemic toxicity should be low4) must be effective regardless it is injected into the tissue or applied

topically to mucous membrane5) time of onset of anesthesia should be as short as possible6) 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 solutions8) should be relatively free from producing allergic reactions


Pharmacokinetics of local anesthetics

UptakePotencyDuration

BiotransformationExcretion



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



1- Uptake

Procaine is the most potent vasodilator

Cocaine is the only L.A agents that produces vasoconstriction







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 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.


Pka drug

PHtissue

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.


(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)


In presence of tissue infection or inflammation (acidic PH)

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

amine (NR3 – HCL ) fall 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 at pH 7.7

Onset of anesthesia(min)

lidocaine 7.9 25 2-4

bupivacaine 8.1 18 5-8

procaine 9.1 2 14-18

Duration(minutes)

180-600

90-200

60-90



UptakePotency

DurationBiotransformation

Excretion



3- Duration

Factors affecting duration & depth of anesthetic action :

1- factors related to individual :

Individual response variation



3- Duration


2- factors related to anesthetic agent :

1- lipid solubility2-concentration & type of drug3- +/- V.C4- duration of exposure



3- Duration


3- factors related to injection technique :

1- infiltration / nerve block2- volume of solution3- accuracy of technique4- anesthetic variations



3- Duration


4- factors related to site of injection :

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

2- vascularity of tissue






4- Biotransformation ( metabolism )

Ester Amide Metabolized in Plasma Liver

By Plasma pseudo-cholinesterase enzyme

Microsomal enzyme

And in Liver

By Esterase enzyme

Toxicity occurs in patients with

Plasma pseudo cholinesterase enzyme deficiency

Impaired liver functionLiver dysfunction


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







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




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.



- CNS- CVS- RESPIRATORY SYSTEM- DRUG INTERACTION- MALIGNANT HYPERTHERMIA (MH)



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.


Systemic actions of Local anestheticsEffects 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!



Effects of local anesthetics on respiratory system

Unaffected by L.A until overdose levels .

Overdose respiratory arrest

Due to generalized CNS depression



Effects of local anesthetics 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)


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 drug2- it decrease the amount of solution needed3-controls the rate at which the anesthetic drug enters the circulation (decrease risk of toxicity)4- haemostasis5- 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 dilate2) Increase absorption of the local anesthetic into the cardiovascular system (redistribution)3) Higher plasma levels increased risk of toxicity4) Decreased depth and duration of anesthesia diffusion from site5) Increased bleeding due to increased blood perfusion to the area

Contra-Indication of V.C

Relative Absolute

1- diabetes 1- toxic goiter2- hypertension (hyperthyroidism)3- cardiac4- pregnancy


1- diabetes : as V.C counteract the action of insulini.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




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)







3- VEHICLE


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)




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


Maximum doses of L.A agents



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/ ml1/200,000 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 solutionSo 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/ml20mg/ml X 1.8 ml / cartridge = 36 mg lidocaine/ cartridge

Epinephrine 1/100.000 = 0.01 mg/ml0.01 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 mg1 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 0.05mg1 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 epiMaximum Epinephrine: 11 CartridgesMaximum Anesthetic: 300 mg

1.8 ml Cartridge of 2% Lidocaine 1:200,000 epiMaximum Epinephrine: 22 CartridgesMaximum 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/ kgWithout epinephrine 3 mg/ kg

How much Epinephrine in CV patients?

Maximum Epinephrine

0.04 mgTwo cartridges of 1:100,000 epinephrine


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 agentb- to prevent deterioration of the contents


TOPICAL ANESTHETICS

TOPICAL ANESTHETICS

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

Education

Pharmcaology ppt