1

Local Anesthetic Agents

2

Prepared By:Rasha AL-Mobark.Haifa AL- Semeri.Alaa Mously.Maged Aggab.Fatimah Hawsawi.

3

Contents: Introduction.Historical development. Action Potential Mechanism of Action.Administration.Factors Influencing The Effectiveness of the

anesthetic action.Local anesthetic Agents.

4

Local anesthetic Blocking drugs that, when administrated locally “ block” the nerves that carry impulses in local areas of the body and the action is reversible.

5

Their method of administration is governed by such properties as toxicity, stability,

duration of action, water solubility, membrane permeability, and point of application.

6

Their systemic effects, depends on the concentration of the local anesthetic in the blood.

7

Local anesthetic are used to alleviate pain caused by a wide variety of situations, and in relieving pain in medical conditions, such as tumors growing in spine.

It is also used topically for the temporary relief of pain from insect bites, burns, and other types of surface wounds.

They are particularly effective when use on mucus membrane.

Therapeutic Uses

8

In the past people have used religious exorcism , hypnotism, acupuncture, hypothermia, nerve compression and drugs as a methods to relieve pain .

In 1882 Koller ( eye surgeon ) aware of the need for local anesthetic that could be used in the eye.

In 1884 Koller and Gaertner investigated and found that a dilute aqueous solution of cocaine hydrochloride caused local anesthesia of the cornea .

Historical development of local anesthetic

9

Koller also recommended the use of cocaine as local anesthetic in ear, nose and throat operation.

At the time, however, little was known about Its addictive properties .

By 1888 the toxic and addictive effects of cocaine were beginning to concern the medical world.

In 1900 the publication of observation that adrenal extracts

caused blood vessels to contracts so , they demonstrate that mixtures of cocaine and adrenal extracts were more effective than cocaine alone.

10

In 1904 (Led Braun) determination to design drug based on the stucture of both adrenaline and cocaine . It was

marketed as Novocaine then approved under procaine.

Adrenaline

11

2?????

Open the pipriden ring to decrease

toxicity the amine group

increase the reactivity of

the ring

Introducing amine

containing aliphatic

chains to the solubility

Procaine

12

At resting status the potential is be -70

In the initial depolarization the firing threshold rapid stimulation increase the potential to -40, here starts feeling the pain.

NA+ channels is open and increase positive in intracellular while k+ will increase in extracellular.

Action potential

13

The positive ion increase insaid the cell by increase depolarization until the potential reach to 35+ which called plateau state.

In this situation the pain stop.

Because the cell tray to back to here resting statue

Action potential

14

Action potential

15

The pain will remain constant because the reason is present.

And the impulse will transfer from cell to other Until remove of the stimulant.

Dose the pain go away after the end of action potential?

16

Local anesthetic drugs act mainly by two mechanism :

1. (voltage-gated channel).

2. (ligand-gated channels).

17

(voltage-gated channel): inhibiting sodium influx through sodium-

specific ion channels. In the neuronal cell membrane, in particular

so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an

action potential cannot arise and signal conduction is inhibited.

And therefore will not be filling pain.

18

(ligand-gated channels):

Ach Necessary to open the gate .

If given drug compete with the Ach in the receptor ,the channel will not open and therefore the action potential will not change.

And therefore will not be filling pain.

19

Main site of action is on cell membrane.

Prevention of conduction and formation of an action potential by fully or partially blocking the Na+ channel.

Blocking achieved by drug molecule causing a physical block in the channel .

Or by the drug molecule distorting the channel.

Mechanism of action of local anesthetic

20

Blocking of conduction would automatically prevent the release of neurotransmitter at the presynaptic site.

Increasing the Ca+ concentration of extracellular fluid may enhance or reduce the activity by affecting the openining of Na+ channel .

M.O.A

21

The drug must cross the membrane uncharged form before it can enter and block the ion channel .

Once inside the neuron, the action of the drug is due to its charged form .

The greater the number of channel open, the greater the block .

M.O.A

22

Hydrophilic path : Activity of L.A agent depends on it entering the channel from inside the neuron.

Hydrophopic path: L.A entering the channel

directly from the membrane .

The effect of the two pathways depends on lipid solubility of the drug.

M.O.A

23

M.O.A• Catalyzed by plasma

esterases• Or by specific liver

esterasesEster agents

• Excreted in urinePABA

• Hydrolyzed by plasma esterases• Hydrolyzed in the liver

• Metabolized by oxidation and N-alkylation in liver

Amide based

24

The delivery of L.A agents to the liver for metabolism related to their degree of binding to P.P

Amide-based bind more to P.P

The use of these agents should be avoided in patients with sever liver damage.

M.O.A

25

Plasma protein concentration may altered in many diseases .

The elimination of L.A and their metabolites from the liver depends on hepatic blood flow.

M.O.A

26

Administration of local anesthetic

27

Administration Topical or surface anesthesia :

Direct application of a local anesthetic agent to the skin or mucous membrane blocks the

sensory nerve endings, producing temporary loss of sensation in a limited area.

In the form of : liquid, spray, cream, ointment, or gel.

28

Infiltration anesthesia :• A set dose of the local anesthetic in a suitable

solvent system is injected directly into the area of the body that is to be anesthetized .

• The use of this technique may require a large concentration of anesthetic.

Administration

29

Field block anesthesia :• A solution of the local anesthetic is injected

subcutaneously at point adjacent to the area that is to be anesthetized, so that blocks the nerve transmissions to that region.

• The technique produces a larger region of anesthesia with a lower dose of the local anesthetic than is required by the infiltration technique .

30

Regional nerve block anesthesia :

•Peripheral nerve blocks are achieved by injecting anesthetic solution around a nerve root to produce anesthesia in the distribution of that nerve.

•This approach reduces the chances of the drug spreading to regions that do not require anesthesia .

31

Intravenous regional anesthesia : used to anesthetize a large region , such as a

limb . The anesthetic is injected into a suitable vein in a limb that has had its blood

flow restricted by a tourniquet .

32

Spinal anesthesia:It is carried out by injecting the anesthetic agent into the subarachnoid space in the spinal cord .Epidural anesthesia:The drug is injected into the epidural spacebetween the vertebrae and spinal cord .

This numbs the nerves leading to the uterus and the pelvic area and leads to pain relief during labor.

33

Factors Influencing The Effectiveness of The

Anesthetic Action

34

small nonmyelinated fibers > small myelinated fibers > large fibers.

In experimental work, the outer fibers in the nerve are affected first , regardless of their

nature

1 .Susceptibility of the neuron to anesthesia:

35

Local anesthetic are normally weak bases)pka 8.5 (which are only slightly soluble in water.

They are marketed as aqueous solution of their soluble salt.

Although the drug is mainly transferred through the cell membrane in its free base form.

Administration of the drug in alkaline solution does not enhance its activity. This is because the

structure of the drug is controlled by the pH of the extracellular fluid and not the PH of the

dosage form .

2 .PH of the extracellular and intracellular fluids:

36

The anesthetic action is proportional to the time that the agents in contact

with nerve fiber tissue

Adrenaline

1- the agent is confined to the site of action reducing the rate at which the blood carries it away.

2-it is also reduce the rate of absorption of a drug by allowing the metabolic rate of local anesthetic to keep

pace with the rate at which it is absorbed into blood stream .

3.vasoconstrictor:

37

1. Adrenaline ( epinephrine ).2. Noradrenaline ( norepinephrine).3.felypressin.

solution of local anesthetic often contain adrenaline or synthetic analogue such as : phenylephrine .

The main vasoconstrictors use with local anesthetics:

38

The effect of vasoconstrictor depends on the local anesthetic agent used;

adrenaline significantly prolongs the action lignocaine but has less effect with prilocaine

39

The concentration of vasoconstrictor are kept as low as possible to reduce the risk of

unwanted side effects: such as chest pain , palpitations and increase heart rate.

Consequently, restriction of blood supply can cause necrosis , a form of enforced cell death.

40

Preparations containing adrenaline should not normally used on patients with diseases

including poorly controlled diabetes, cardiovascular diseases and thyrotoxicosis

Cocaine is vasoconstrictor and so probably owes some of its effectiveness to this

property.

41

The effectiveness of the blocking action in a given concentration of a local anesthetic

agent depends on the frequency and extent to which the neuron has been recently

stimulated.

4 .Neuron stimulation

42

Structure Action

Alkaloids Agent with hypothermic

Action

Benzoic Acid and Aniline

Derivatives

Miscellaneous Compounds

Local anesthetic

agents

43

Agents with Hypothermic Action

These agents act by reducing the temperature of the area being anthesthized.

Produce intense cold through rapid evaporation and hence, an anesthetic action.

44

Most effective.Should not be used on mucous membranes or broken skin & prolonged use may cause chemical frostbite.

45

• Alkaloids are obtained from plants and trees.• The only one in general clinical use is

cocaine.• Because of its addictive properties >> Largely

restricted to use with the ear, nose, and throat.

Alkaloids

46

Tetrodotoxin and Saxitoxin are naturally occuring local anesthetic agents.

Tetrodotoxin: (is found in the tissue and organ of fish).

• Saxitoxin: (is isolated from some marine dinoflagellates).

• These compounds are highly toxic to humans

Tetrodotoxin & Saxitoxin

47

Saxitoxin Tetrodotoxin

M.O.A:

48

Most of the local anesthetic agents in current medical use are of these type.

Benzoic Acid and Anilline Derivatives

The Benzoic acid

derivatives• Are esters that were

developed from cocaine.

Aniline derivatives

• Are amide developed from iso-gramine.

49

Both types of derivative have chemical structure that normally have the general format:

Benzoic Acid and Anilline Derivatives

Hydrophilic CenterLipophilic

Center

Ester or amide Group

bridge

Either a carbocyclic

or heterocyclic

ring

2nd or 3rd amine

But 3rd more useful

Short hydrocarbon

chain or O, N, or sulfur atoms

50

Lipid solubility plays an important part in the action of local anesthetics (on their ability to penetrate the cell membrane of axon).

The hydrophilic center allows the drug to penetrate the polar outer face of the cell membrane and binding of the drug to the receptor.

Hydrophilic & lipophilic centers are in balance >>> best local anesthetic action.

51

Lipophilic Group –- Ester--Bridging Group– Hydrophilic Group(if Any)

Examples of the Ester-Based Local Anesthetic Agents

Benzocaine

Butcaine

52

Bv

Procaine hydrochloride

Oxybuprocaine hydrochloride

53

Examples of Amide-Based Local Anesthetic Agent

Lignocaine Prilocaine

hydrochloride

Lipophilic Group—Amide—Bridging Group—Hydrophilic Group(if any)

54

Mepivacaine hydrochloride

55

Several different classes of compounds exhibit some local anesthetic activity.

These compounds are usually week bases with distinct hydrophilic and lipophilic regions.

( A wide variety of compounds , including benzyl alcohol, phenol, and some antihistamines also

show some local anesthetic activity)

Miscellaneous Agents ِِِِ

56

Miscellaneous Compounds with Local Anesthetic Activity

Dyclonine hydrochloride Pramoxine

hydrochloride

57