Local Anesthetic Agents

1. Local Anesthetic Agents

2. Prepared By: • Rasha AL-Mobark. • Haifa AL- Semeri. • AlaaMously. • MagedAggab. • 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. Therapeutic Uses • 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.

8. Historical development of local anesthetic • 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 Kollerand Gaertner investigated and found that a dilute aqueous solution of cocaine hydrochloride caused local anesthesia of the cornea .

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. Introducing amine containing aliphatic chains to the solubility the amine group increase the reactivity of the ring 2????? Open the pipriden ring to decrease toxicity Procaine

12. Action potential At resting statusthe potential is be -70 In the initial depolarizationthe 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.

13. Action potential • 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

14. Action potential

15. Dose the pain go away after the end of action potential? • The pain will remain constant because the reason is present. • And the impulse will transfer from cell to other Until remove of the stimulant.

16. Local anesthetic drugs act mainly by two mechanism : • (voltage-gated channel). • (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. Mechanism of action of local anesthetic • 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.

20. M.O.A • 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 .

21. M.O.A • 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 .

22. M.O.A • 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.

23. M.O.A

24. M.O.A • 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.

25. M.O.A • Plasma protein concentration may altered in many diseases . • The elimination of L.A and their metabolites from the liver depends on hepatic blood flow.

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. Administration • 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.

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 space • between 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. 1. Susceptibility of the neuron to anesthesia : small nonmyelinated fibers > small myelinated fibers > large fibers.In experimental work, the outer fibers in the nerve are affected first , regardless of their nature

35. 2. PH of the extracellular and intracellular fluids: 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.

36. 3.vasoconstrictor: • The anesthetic action is proportional to the time that the agents in contact with nerve fiber tissue Adrenaline1-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 .

37. The main vasoconstrictors use with local anesthetics: 1. Adrenaline ( epinephrine ).2. Noradrenaline ( norepinephrine).3.felypressin. • solution of local anesthetic often contain adrenaline or synthetic analogue such as : phenylephrine.

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. 4. Neuron stimulation 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.

42. Structure Action

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 • 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.

46. Tetrodotoxin & Saxitoxin • 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

47. Saxitoxin Tetrodotoxin M.O.A:

48. Benzoic Acid and Anilline Derivatives • Most of the local anesthetic agents in current medical use are of these type.

49. Benzoic Acid and Anilline Derivatives • Both types of derivative have chemical structure that normally have the general format: Ester or amide Group bridge Hydrophilic Center Lipophilic Center Short hydrocarbon chain or O, N, or sulfur atoms 2nd or 3rd amine But 3rd more useful Either a carbocyclic or heterocyclic ring

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.