Pharmacology of Local Anaesthesia Dr. S. Narayanan Division of Oral & Maxillofacial Surgery King Saud University

What is Anaesthesia? Anaesthesia is the loss of consciousness and all forms of sensation.

What is Local anaesthesia (L.A)? 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)

What are Local anaesthetic agents? They 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 all types of nerve fibres, sensory or motor.

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

L.A - Classification Classified according to their chemical structures and the determining factor is the intermediate chain, divided into two groups: Ester Amide They are different in two important aspects: Their ability to induce hypersensitivity reaction. Their pharmacokinetics - fate and metabolism.

L.A – Ester Group A few examples in this group are as follows: Cocaine Procaine Tetracaine Benzocaine Chloroprocaine

L.A – Amide Group A few examples in this group are as follows: Articaine Bupivacaine Lignocaine Etidocaine Mepivacaine Prilocaine

L.A - Mechanism of Action The site of action is the nerve cell membrane Theories The membrane expansion theory. The specific binding theory.

Pharmacology of L.A L.A is primarily given for blocking the conduction in nerve axons of the peripheral nervous system. Apart from the above local action or effect, the local anesthetic agent is also absorbed from the site of injection into the circulation and eventually into the C.V.S. This means that the local anesthetic agent will be carried to every cell in the body and has the potential to produce an alteration in the functioning of many of these cells.

L.A - Absorption Many factors influence entry of local anaesthetic into the circulation: Vasodilating ability of the drug. The route of administration. Volume and concentration. Vascularity of the tissues. The presence of vasoconstrictor.

L.A - Vasodilatory ability Most Local anesthetics possess a vasodilatory action on blood vessels except Cocaine. Cocaine is the only L.A that consistently produces vasoconstriction. Procaine is the most potent Vasodilating drug.

L.A - Vasodilatory ability The clinical effect of vaso-dilation is an increase in the rate of absorption of the L.A and therefore decrease in the duration of pain control, while increasing the anesthetic blood level and potential for overdose.

L.A - Routes of Administration. The rates at which L.A are absorbed into the blood stream and reach their peak blood level vary according to the route of administration of the L.A, (i.e) Oral Topical Intramuscular Subcutaneous

L.A - Route of Administration (Oral Route) With the exception of cocaine, the other L.A drugs are poorly absorbed from the G.I.T following oral administration.

L.A - Route of Administration – (Topical) L.A drugs are absorbed at differing rates after application to mucous membranes Tracheal mucosa – uptake is rapid Pharyngeal mucosa -- uptake is slower Esophageal / bladder mucosa – uptake is very slow Whenever there is no intact skin present, L.A drugs exert their action following topical application. For eg: Benzocaine,Lignocaie used for sunburns

L.A - Route of Administration – (Injection) The rate of uptake (absorption) of L.A after injection (subcutaneous, intramuscular or intravenous) is related to both the vascularity of the injection site and the vasoactivity of the drug. I.V administration of L.A provides the most rapid elevation of blood levels. Rapid I.V injection can on occasions produce serious toxic reactions.

L.A - Distribution In the circulation: Partially bound to plasma proteins (α 1 - glycoprotein and albumin) and red blood cells. The unbound is free to enter any organ and diffuse through the blood-brain barrier and the placenta. Highly perfused organs such as brain, liver, kidney, receive high level of local anaesthetic drug.

L.A – Metabolism (Biotransformation) There is a significant difference between the ester and Amide group of L.A in the way they undergo metabolic breakdown. Metabolism of L.A is important, because overall toxicity of the L.A depends on a balance between it’s rate of absorption into the bloodstream and it’s rate of removal from the blood through the process of tissue uptake and metabolism.

Ester L.A - Fate & Metabolism 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

Ester L.A - Fate & Metabolism Rapid metabolism (for procaine half- life is 2 minutes). Para-aminobenzoic acid (PABA) is the major metabolite of ester with no anaesthetic effect. It is the agent responsible for ester allergies.

Amide L.A - Fate & Metabolism 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.

Amide L.A - Fate & Metabolism Normal local anesthetic dose in patient with impaired liver function will result in relative over-dosage. Old age patient shows reduction in liver function (Reduce dose)

Ester-type drugs - Procaine The only indication for its use in dentistry is in patients with proven allergy to the amide group. It has an excellent vasodilatory properties.

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

Ester-type drugs - 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%. Hydrolyzed rapidly by plasma esterase to p- aminobenzoic acid accounting for its low toxicity.

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

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

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

Amide-type drugs - Lignocaine Amide-type drugs - Lignocaine 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.

Amide-type drugs - Prilocaine A very potent local anaesthetic and is less toxic than Lignocaine. It produces less vasodilatation than lignocaine Rate of clearance is higher than other amide-types. It’s metabolite o-toluidine lead to methaemo- globinaemia (more than 600 mg in adults)

Amide-type drugs- Prilocaine Used either plain 4% or 3% combined with 0.03IU/mL of Felypressin as vasoconstrictor. Dosage: 6.0 mg/kg – max. 400 mg. Onset & Duration: Slower onset – 4 minutes. It’s duration of action is similar to Lignocaine

Amide-type drugs - Mepivacaine Possess the least vasodilating effect. 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. Onset & duration: Rapid onset but slightly shorter duration.

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

Amide-type drugs - Etidocaine A long-acting agent similar to Bupivacaine but with faster onset. Metabolized in the liver. Dosage: 8 mg/kg – Max 400 mg 1.5% with 1: epinephrine.

L.A - Excretion The kidneys are the primary excretory organ for the L.A and it’s metabolites. Esters appear only in very small concentrations as the parent compound in urine, as they are hydrolyzed almost completely in the plasma. Amides are present in the urine as the parent compound in a greater percentage because of their more complex process of biotransformation.

L.A - Excretion Patients with significant renal impairment maybe unable to eliminate the parent L.A or it’s metabolites from the blood resulting in high blood levels of L.A and therefore causing toxicity. Patient’s with significant renal disease (ASA IV to VI) represent a contraindication to use of L.A. This includes patients undergoing renal dialysis and those with glomerulonephritis and/or pyelonephritis.

L.A - Systemic Effects on C.N.S Entry of local anesthetics into the brain causes depression of CNS pathways. At low levels in the brain no significant effect, however at higher levels can cause C.N.S toxicity CNS toxicity The clinical picture may include stimulation (e.g., excitement, disorientation, increased heart rate and respiration, tremors, and frank convulsions) if inhibitory neurons are affected initially.

L.A - Systemic Effects on C.N.S CNS depression may cause hypotension, respiratory depression, unconsciousness, and death. Treatment includes supportive measures. Excitement and convulsions may be controlled with 5 mg dosess of diazepam or 2 mg doses of midazolam. Respiratory depression requires oxygen and possibly rescue breathing.

L.A - Systemic Effects on C.N.S Anticonvulsant Properties: Some L.A drugs like, procaine, mepivacaine and lignocaine have been used to terminate or decrease the duration of both Grand mal and Petit mal seizures.

L.A - Systemic Effects on Respiratory system In non-overdose levels the L.A have a direct relaxant action on bronchial smooth muscle However overdose of L.A, can lead to CNS depression may cause hypotension, respiratory depression, unconsciousness, and death.

L.A - Systemic Effects on C.V.S CVS derangement—High plasma titers may depress the cardiovascular system directly. Blood pressure may fall because of arteriolar dilation, myocardial depression, and/or cardiac conduction disruption. Treatment includes patient positioning, I.V fluids, and vasopressors. Cardiac asystole will require CPR.

L.A - Prevention of systemic toxicity Limit the amount of drug employed. Use proper injection techniques.

L.A - Allergic Reactions Allergic reactions are rare, especially with amide local anesthetics. Urticarial rashes are most common, but more serious responses also occur. Mild skin reactions are treated with antihistamines; more serious sequellae require epinephrine

L.A - Syncopal Reactions The most common side effect of dental injections. Must be treated promptly since it may be dangerous in its own right and has to be differentiated from anaphylactic shock.

L.A - Local Toxic Reactions Selective destruction of skeletal muscle fibers. Epithelial damage from topical preparations. Local necrosis from vasoconstrictor actions.