1. Local Anaesthesia and Vasoconstrictors Dr. Hassan Abdin Division of Oral & Maxillofacial Surgery

2. Local anaesthesia Anaesthesia is the loss of consciousness and all form of sensation. 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. 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. In dentistry, Only loss of pain sensation is desirable. Local Analgesia.

3. 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. 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.

4. Local anaesthesia Methods: Methods: Reducing temperature. Reducing temperature. Is used only to produce surface anaesthesia e.g. ethyl chloride spray. Is used only to produce surface anaesthesia e.g. ethyl chloride spray. Physical damage to nerve trunk e.g. nerve sectioning. Physical damage to nerve trunk e.g. nerve sectioning. Unsafe for therapeutic uses, only in Trigeminal Neuralgia. Unsafe for therapeutic uses, only in Trigeminal Neuralgia. Chemical damage to nerve trunk e.g. neurolytic agents. Chemical damage to nerve trunk e.g. neurolytic agents. Silver nitrate, Phenol - Unsafe for therapeutic use. Silver nitrate, Phenol - Unsafe for therapeutic use.

5. Local anaesthesia Methods: Cont Methods: Cont Anoxia or hypoxia resulting in lack of oxygen to nerve. Anoxia or hypoxia resulting in lack of oxygen to nerve. Unsafe as well. Unsafe as well. Stimulation of large nerve fibres, blocking the perception of smaller diameter fibres. Stimulation of large nerve fibres, blocking the perception of smaller diameter fibres. includes Acupuncture and TENS (Transcutaneous Electronic Nerve Stimulation) includes Acupuncture and TENS (Transcutaneous Electronic Nerve Stimulation) Drugs that block transmission at sensory nerve endings or along nerve fibres. Drugs that block transmission at sensory nerve endings or along nerve fibres. There action is fully reversible and without permanent damage to the tissues. There action is fully reversible and without permanent damage to the tissues.

6. Local anaesthesia Properties of Ideal local Anaesthetic: Properties of Ideal local Anaesthetic: Possess a specific and reversible action. Possess a specific and reversible action. They stabilize all excitable membrane including motor neurones They stabilize all excitable membrane including motor neurones CNS is extremely sensitive to its action. CNS is extremely sensitive to its action. Non-irritant with no permanent damage to tissues. Non-irritant with no permanent damage to tissues. No Systemic toxicity No Systemic toxicity High therapeutic ratio. High therapeutic ratio. Rapid onset and long duration Rapid onset and long duration Active Topically or by injection Active Topically or by injection

7. Local anaesthesia Chemistry: Chemistry: They are weak bases, insoluble in water They are weak bases, insoluble in water converted into soluble salts by adding Hcl for clinical use. converted into soluble salts by adding Hcl for clinical use. They are composed of three parts: They are composed of three parts: Aromatic (lipophilic) residue with acidic group R 1. Aromatic (lipophilic) residue with acidic group R 1. Intermediate aliphatic chain, which is either ester or amide link R 2. Intermediate aliphatic chain, which is either ester or amide link R 2. Terminal amino (hydrophilic) group R 3 and R 4. Terminal amino (hydrophilic) group R 3 and R 4. R 3 R 3 R 1 CO R 2 N R 4 R 4

8. Classification: Classified according to their chemical structures and the determining factor is the intermediate chain, into two groups: Classified according to their chemical structures and the determining factor is the intermediate chain, into two groups: Ester Amide Ester Amide They differ in two important respect: They differ in two important respect: Their ability to induce hypersensitivity reaction. Their ability to induce hypersensitivity reaction. Their pharmacokinetics - fate and metabolism. Their pharmacokinetics - fate and metabolism.

9. Physiochemical properties: These are very important for local anaesthetic activity. These are very important for local anaesthetic activity. Ionization: Ionization: They are weak base and exist partly in an unionized and partly in an ionized form. They are weak base and exist partly in an unionized and partly in an ionized form. The proportion depend on: The proportion depend on: the pK a or dissociation constant the pK a or dissociation constant The pH of the surrounding medium. The pH of the surrounding medium. Both ionizing and unionizing are important in producing local anaesthesia. Both ionizing and unionizing are important in producing local anaesthesia.

10. Physiochemical properties: (cont.) pK a is the pH at which the ionized and unionized form of an agent are present in equal amounts. pK a is the pH at which the ionized and unionized form of an agent are present in equal amounts. The lower the pK a, the more the unionized form, the greater the lipid solubility. The lower the pK a, the more the unionized form, the greater the lipid solubility. The higher the pK a, the more the ionized form and the slower the lipid solubility The higher the pK a, the more the ionized form and the slower the lipid solubility

11. Physiochemical properties: (cont.) Cont: Cont: Unionized form is able to cross the bi-lipid nerve membrane. Unionized form is able to cross the bi-lipid nerve membrane. The ionized form then blocks conduction. The ionized form then blocks conduction. Some of the unionized inside the cell will become ionized depending upon the pK a and the intracellular pH (lower than extracellular) Some of the unionized inside the cell will become ionized depending upon the pK a and the intracellular pH (lower than extracellular)

12. Physiochemical properties: (cont.) Cont: Cont: In general the amide type have lower pK a, and greater proportion of the drug is present in the lipid-soluble (unionized) form at the physiological pH In general the amide type have lower pK a, and greater proportion of the drug is present in the lipid-soluble (unionized) form at the physiological pH This produces faster onset of action. This produces faster onset of action. Lignocaine 1 – 2 minutes Lignocaine 1 – 2 minutes Procaine 2 – 5 minutes. Procaine 2 – 5 minutes. The lower the pK a the faster the onset. The lower the pK a the faster the onset.

13. Physiochemical properties: (cont.) Partition coefficient: Partition coefficient: This measures the relative solubility of an agent in fat and water. This measures the relative solubility of an agent in fat and water. High numerical value means: High numerical value means: High lipid-soluble High lipid-soluble less water-soluble. less water-soluble. More fat solubility, means rapid crossing of the lipid barrier of the nerve sheath. More fat solubility, means rapid crossing of the lipid barrier of the nerve sheath. The greater partition coefficient, The faster the onset The greater partition coefficient, The faster the onset

14. Physiochemical properties: (cont.) Protein binding: Protein binding: Local anaesthetic agents bind with: Local anaesthetic agents bind with: α 1 -acid glycoprotein, which possess high affinity but low capacity. α 1 -acid glycoprotein, which possess high affinity but low capacity. Albumin, with low affinity but high capacity Albumin, with low affinity but high capacity The binding is simple, reversible and tend to increase in proportion to the side chain. The binding is simple, reversible and tend to increase in proportion to the side chain. Lignocaine is 64% bound, Bupivacaine is 96% Lignocaine is 64% bound, Bupivacaine is 96% The duration of action is related to the degree of binding. The duration of action is related to the degree of binding. Lignocaine 15 – 45 minutes, Bupivacaine 6 hours Lignocaine 15 – 45 minutes, Bupivacaine 6 hours

15. Physiochemical properties: (cont.) Vasodilatory ability: Vasodilatory ability: Most Local anaesthetics possess a vasodilatory action on blood vessels except Cocaine. Most Local anaesthetics possess a vasodilatory action on blood vessels except Cocaine. It influence the duration of action of the agent. It influence the duration of action of the agent. Prilocaine is 50% bound to proteins but has a longer duration than Lignocaine (64%) since it possess no strong vasodilatory effect. Prilocaine is 50% bound to proteins but has a longer duration than Lignocaine (64%) since it possess no strong vasodilatory effect. Affect the duration of action of the agent Affect the duration of action of the agent

16. Physiochemical properties: (cont.) Summary Summary Rapid Onset: Rapid Onset: Low pK a value– more unionized – Amides Low pK a value– more unionized – Amides Higher Partition coefficient – more lipid soluble Higher Partition coefficient – more lipid soluble Long duration of action: Long duration of action: High protein binding. High protein binding. Low vasodilating property. Low vasodilating property.

17. Physiochemical properties: (cont.) Agent pK a %base pH 7.4 P-CP-B t 0.5 (m) Max dose mg/kg Lignocaine7.925364904.4 Prilocaine7.925150906.0 Mepivacaine7.6331771204.4 Bupivacaine8.11728961601.3 Etidocaine7.925141941608.0 Procaine9.020.6666.0

18. Pharmacodynamics: Pharmacological actions: Reversible block of conduction in nerve. Reversible block of conduction in nerve. Direct relaxation of smooth muscle & inhibition of neuro-muscular transmission in skeletal muscle producing vasodilatation. Direct relaxation of smooth muscle & inhibition of neuro-muscular transmission in skeletal muscle producing vasodilatation. Intra-arterial procaine reverse arteriospasm during I.V. Sedation Intra-arterial procaine reverse arteriospasm during I.V. Sedation Class I antidysrhythmic-like action on the heart. Class I antidysrhythmic-like action on the heart. Stimulation and/or depression of the CNS. Stimulation and/or depression of the CNS.

19. Pharmacodynamics: Mechanism of Action: (cont.) The site of action is the nerve cell membrane The site of action is the nerve cell membrane Theories: Theories: The membrane expansion theory. The membrane expansion theory. The specific binding theory. The specific binding theory.

20. Pharmacodynamics: Mechanism of Action: (cont.) Membrane expansion theory: Membrane expansion theory: A non-specific mechanism similar to the action of general anaesthetic agents. A non-specific mechanism similar to the action of general anaesthetic agents. Relies upon the lipophilic moiety of local anaesthetic agent. Relies upon the lipophilic moiety of local anaesthetic agent. The molecules of the agent are incorporated into the lipid cell membrane. The molecules of the agent are incorporated into the lipid cell membrane. The resultant swelling produces physical obstruction of the sodium channels, preventing nerve depolarization. The resultant swelling produces physical obstruction of the sodium channels, preventing nerve depolarization.

21. Pharmacodynamics: Mechanism of Action: (cont.) Specific receptor theory: Specific receptor theory: Local anaesthetic drug binds to specific receptor within the sodium channel producing physical obstruction to entry of sodium ions. Local anaesthetic drug binds to specific receptor within the sodium channel producing physical obstruction to entry of sodium ions. The act of binding produces a conformational changes within the channel. The act of binding produces a conformational changes within the channel. It bind to a closed gate and maintain it in the closed position. It bind to a closed gate and maintain it in the closed position. It is, then, essential that the nerve fires, and the gate assumes the closed position. (Use-dependant phenomenon It is, then, essential that the nerve fires, and the gate assumes the closed position. (Use-dependant phenomenon

22. Fate & Metabolism: Absorption: Absorption: Many factors influence entry of local anaesthetic into the circulation: Many factors influence entry of local anaesthetic into the circulation: Vasodilating ability of the drug. Vasodilating ability of the drug. Volume and concentration. Volume and concentration. Vascularity of the tissues. Vascularity of the tissues. The route of administration. The route of administration. The presence of vasoconstrictor. The presence of vasoconstrictor.

23. Ester-type drugs Cocaine : Cocaine : The first and most potent local anaesthetic agent, rarely used because of the problems of misuse. The first and most potent local anaesthetic agent, rarely used because of the problems of misuse. It is unique in it is ability to produce intense vasoconstriction. Half life 30 minutes. It is unique in it is ability to produce intense vasoconstriction. Half life 30 minutes. Dosage: Dosage: Used as topical 4 – 10% solution Used as topical 4 – 10% solution Maximum dose is 1.5 mg/kg – 100mg max. Maximum dose is 1.5 mg/kg – 100mg max. Used intranasally during apical surgery. Used intranasally during apical surgery.

24. Ester-type drugs Procaine: Procaine: The only indication for its use in dentistry is in patients with proven allergy to the amide group. The only indication for its use in dentistry is in patients with proven allergy to the amide group. Used intra-arterially, as part of the recognized regimen, to treat the arteriospasm which might occur during intravenous sedation. Used intra-arterially, as part of the recognized regimen, to treat the arteriospasm which might occur during intravenous sedation. It has an excellent vasodilatory properties. It has an excellent vasodilatory properties.

25. Ester-type drugs Procaine (cont) Onset & duration of Action: Onset & duration of Action: Has a very shot duration (5 minutes) and a long onset time of 10 minutes Has a very shot duration (5 minutes) and a long onset time of 10 minutes Dosages: Dosages: The maximum dose is 6 mg/kg, 400 mg max. The maximum dose is 6 mg/kg, 400 mg max. Used as 2% with 1:80 000 epinephrine to increase efficacy. Used as 2% with 1:80 000 epinephrine to increase efficacy. Metabolism: Metabolism: Rapidly by plasma esterase. Rapidly by plasma esterase.

26. Ester-type drugs Benzocaine: Benzocaine: Used mainly as topical, due to its poor water solubility, and because of its low toxicity, it is used in concentration up to 20%. Used mainly as topical, due to its poor water solubility, and because of its low toxicity, it is used in concentration up to 20%. Hydrolyzed rapidly by plasma esterase to p-aminobenzoic acid accounting for its low toxicity. Hydrolyzed rapidly by plasma esterase to p-aminobenzoic acid accounting for its low toxicity.

27. Fate & Metabolism: Metabolism of Ester drugs: Metabolism of Ester drugs: Metabolized in plasma by peudocholinesterase enzyme, and some in the liver. Metabolized in plasma by peudocholinesterase enzyme, and some in the liver. People, who lack the enzyme, are at risk of an overdose by the ester type local anaesthetic People, who lack the enzyme, are at risk of an overdose by the ester type local anaesthetic Para-aminobenzoic acid (PABA) is the major metabolite of ester with no anaesthetic effect. Para-aminobenzoic acid (PABA) is the major metabolite of ester with no anaesthetic effect. It is the agent responsible for ester allergies. It is the agent responsible for ester allergies. Rapid metabolism procaine half-life is 2 minutes Rapid metabolism procaine half-life is 2 minutes

28. Amide-type drugs: Lignocaine (Lidocaine): Lignocaine (Lidocaine): Synthesized in 1943 and used in dentistry since 1948 and is also known as Xylocaine Synthesized in 1943 and used in dentistry since 1948 and is also known as Xylocaine It highly lipophilic (partition coefficient 3), rapidly absorbed. It highly lipophilic (partition coefficient 3), rapidly absorbed. Metabolized only in the liver and its metabolites are less toxic with no action. Metabolized only in the liver and its metabolites are less toxic with no action. Has half-life ( t 0.5 ) of 90 minutes Has half-life ( t 0.5 ) of 90 minutes

29. Amide-type drugs Lignocaine (cont) Dosage: Dosage: 4.4 mg/kg – 300 mg max 4.4 mg/kg – 300 mg max Used as 2% plain or with 1:80 000 epinephrine Used as 2% plain or with 1:80 000 epinephrine 4 and 10% spray, 2% gel and 5% ointments. 4 and 10% spray, 2% gel and 5% ointments. Onset & duration of action: Onset & duration of action: Rapid onset 2 – 3 minutes Rapid onset 2 – 3 minutes Plain- short duration (10 minutes) Plain- short duration (10 minutes) With epinephrine- intermediate duration (45 – 60 minutes) With epinephrine- intermediate duration (45 – 60 minutes)

30. Amide-type drugs Prilocaine: Prilocaine: A very potent local anaesthetic and is less toxic than Lignocaine. A very potent local anaesthetic and is less toxic than Lignocaine. It produces less vasodilatation than lignocaine It produces less vasodilatation than lignocaine Rate of clearance is higher than other amide- types, suggesting extra-hepatic metabolism with relatively low blood concentration. Rate of clearance is higher than other amide- types, suggesting extra-hepatic metabolism with relatively low blood concentration. It’s metabolite o-toluidine lead to methaemo- globinaemia (more than 600 mg in adults) It’s metabolite o-toluidine lead to methaemo- globinaemia (more than 600 mg in adults)

31. Amide-type drugs Prilocaine: Used either plain 4% or 3% combined with 0.03IU/mL of Felypressin as vasoconstrictor. Used either plain 4% or 3% combined with 0.03IU/mL of Felypressin as vasoconstrictor. Onset & Duration: Onset & Duration: Slower onset – 4 minutes. Slower onset – 4 minutes. It’s duration of action is similar to Lignocaine. It’s duration of action is similar to Lignocaine. Dosage; Dosage; 6.0 mg/kg – max. 400 mg. 6.0 mg/kg – max. 400 mg. Combined with Lignocaine as a topical anaesthetic agent to be used prior to vene- section and during dental sedation in children. Combined with Lignocaine as a topical anaesthetic agent to be used prior to vene- section and during dental sedation in children.

32. Amide-type drugs Mepivacaine: Mepivacaine: Possess the least vasodilating effect. Possess the least vasodilating effect. Metabolized in the liver and has t 0.5 of 120 minutes. Metabolized in the liver and has t 0.5 of 120 minutes. It’s main indication is when local anaesthetic without vasoconstrictor is needed. 3% plain is more effective than lignocaine. It’s main indication is when local anaesthetic without vasoconstrictor is needed. 3% plain is more effective than lignocaine. Onset & duration: Onset & duration: Rapid onset but slightly shorter duration. Rapid onset but slightly shorter duration.

33. Amide-type drugs Bupivacaine: Bupivacaine: A long-acting local anaesthetic agent, with a t 0.5 of 160 minutes due grater binding capacity to plasma protein and tissue proteins A long-acting local anaesthetic agent, with a t 0.5 of 160 minutes due grater binding capacity to plasma protein and tissue proteins Metabolized in the liver. Metabolized in the liver. Used mainly in Oral surgical procedures for its long- lasting pain control. Used mainly in Oral surgical procedures for its long- lasting pain control. Longer onset and longer duration (Regional 6 – 8 hors) Longer onset and longer duration (Regional 6 – 8 hors) Dosage: Dosage: 1.3 mg/kg – Max 90 mg 1.3 mg/kg – Max 90 mg 0.25 – 0.75% with or without adrenaline 1:200 000 0.25 – 0.75% with or without adrenaline 1:200 000

34. Amide-type drugs Etidocaine: Etidocaine: A long-acting agent similar to Bupivacaine but with faster onset. A long-acting agent similar to Bupivacaine but with faster onset. Metabolized in the liver. Metabolized in the liver. Dosage: Dosage: 8 mg/kg – Max 400 mg 8 mg/kg – Max 400 mg 1.5% with 1:200 000 epinephrine. 1.5% with 1:200 000 epinephrine. Lignocaine is the most common used agent both topically and by injection as 2% with or without adrenaline, with a maximum dose of 4.4 mg/kg. Lignocaine is the most common used agent both topically and by injection as 2% with or without adrenaline, with a maximum dose of 4.4 mg/kg.

35. Fate & Metabolism: Amide Drugs: Amide Drugs: metabolized in the liver, except Prilocaine which undergo some biotransformation in the kidney and lungs. metabolized in the liver, except Prilocaine which undergo some biotransformation in the kidney and lungs. Some of the metabolites possess local anaesthetic and sedative properties. Some of the metabolites possess local anaesthetic and sedative properties. Normal local anaesthetic dose in patient with impaired liver function will result in relative overdosage. Normal local anaesthetic dose in patient with impaired liver function will result in relative overdosage. Old age patient shows reduction in liver function Old age patient shows reduction in liver function Reduce dose Reduce dose

36. Vasoconstrictors Originally added to reduce systemic uptake in an attempt to limit toxicity. Originally added to reduce systemic uptake in an attempt to limit toxicity. Prolong the duration Prolong the duration Produces profound anaesthesia. Produces profound anaesthesia. Reduce operative bleeding. Reduce operative bleeding. Two types: Two types: Sympathomimetic naturally occurring. Sympathomimetic naturally occurring. Synthetic polypeptides, Felypressin Synthetic polypeptides, Felypressin

37. Vasoconstrictors Epinephrine: (Adrenaline) Epinephrine: (Adrenaline) Uses in dentistry: Uses in dentistry: Local anaesthetic solution. Local anaesthetic solution. Gingival retraction cords. Gingival retraction cords. In the ER as life-saving drug in anaphylaxis. In the ER as life-saving drug in anaphylaxis. Mechanism of action: Mechanism of action: Interact with adrenergic receptors in the vessels Interact with adrenergic receptors in the vessels α 1 & α 2 producing vasoconstriction in skin & MM α 1 & α 2 producing vasoconstriction in skin & MM β 2 stimulation causing vasodilatation in skeletal muscles. β 2 stimulation causing vasodilatation in skeletal muscles.

38. Vasoconstrictors Epinephrine Metabolism: Metabolism: Appears very rapidly in the systemic circulation !!! Appears very rapidly in the systemic circulation !!! Exogenously administered epinephrine is metabolized extraneuronal and 1% is excreted in the urine unchanged. Exogenously administered epinephrine is metabolized extraneuronal and 1% is excreted in the urine unchanged. Dosage: Dosage: 1:80,000 is the commonest dose used, 12.5 µg/ml 1:80,000 is the commonest dose used, 12.5 µg/ml

39. Vasoconstrictors Epinephrine Systemic effect: Systemic effect: Being a naturally occurring hormone, it exert a number of physiological responses on the different systems. Being a naturally occurring hormone, it exert a number of physiological responses on the different systems. The heart: The heart: Has direct and indirect action. Has direct and indirect action. Direct action on β 1 receptors increases the rate and force of contraction raising cardiac output. Direct action on β 1 receptors increases the rate and force of contraction raising cardiac output. Indirect action, increase pulse and cardiac output, lead to rise in systolic blood pressure, (not with dental dose) Indirect action, increase pulse and cardiac output, lead to rise in systolic blood pressure, (not with dental dose)

40. Vasoconstrictors Epinephrine Blood vessels: Blood vessels: Contain α 1, α 2 and β 2 adrenoreceptors in the vessels of the skin, mucous membrane and skeletal muscles. Contain α 1, α 2 and β 2 adrenoreceptors in the vessels of the skin, mucous membrane and skeletal muscles. α 1 receptors causes vasoconstriction since they are susceptible to endogenous nor-epinephrine and exogenous epinephrine. Reduce operative bleeding α 1 receptors causes vasoconstriction since they are susceptible to endogenous nor-epinephrine and exogenous epinephrine. Reduce operative bleeding

41. Vasoconstrictors Epinephrine α 2 receptors are only susceptible to circulating epinephrine. α 2 receptors are only susceptible to circulating epinephrine. β 2 found in the skeletal muscles, and very uncommon in the skin and mucous membrane. β 2 stimulation result in vasodilatation, lowering peripheral resistance and a fall in the diastolic blood pressure. (with dental dose) β 2 found in the skeletal muscles, and very uncommon in the skin and mucous membrane. β 2 stimulation result in vasodilatation, lowering peripheral resistance and a fall in the diastolic blood pressure. (with dental dose)

42. Vasoconstrictors Epinephrine Haemostasis: Haemostasis: The vasoconstricting effect. The vasoconstricting effect. Adrenaline promote platelets aggregation in the early stages. Adrenaline promote platelets aggregation in the early stages. Fibrinolytic activity compromise clot stability. Fibrinolytic activity compromise clot stability. Lungs: Lungs: Stimulation of β 2 receptors in the lung lead to bronchial muscle relaxation, life-saving in bronchial (spasm) constriction during anaphylactic reaction. Stimulation of β 2 receptors in the lung lead to bronchial muscle relaxation, life-saving in bronchial (spasm) constriction during anaphylactic reaction. Wound healing: Wound healing: Reduced local tissue oxygen tension. Reduced local tissue oxygen tension. Epinephrine-induced fibrinolysis. Epinephrine-induced fibrinolysis.

43. Vasoconstrictors Felypressin: Felypressin: It is an analogue of the naturally occurring Vasopressin. It is an analogue of the naturally occurring Vasopressin. Bind to vasopressin V 1 receptor in the vascular smooth muscle producing vaso-constriction and reduce local blood flow. Bind to vasopressin V 1 receptor in the vascular smooth muscle producing vaso-constriction and reduce local blood flow. Less potent than the catecholamines &poorer control of bleeding during operative procedures. Less potent than the catecholamines &poorer control of bleeding during operative procedures. Acts on the venous side rather than the arterial side. Acts on the venous side rather than the arterial side. Dose: Dose: 0.03 IU/ml (0.54 µg/ml) 0.03 IU/ml (0.54 µg/ml)