LOCAL ANESTHETICS

Local anesthetics(LA) are drugs which have following features:

1. Used for topical application or local injection.

2. Cause reversible loss of sensory perception in a restricted area of the body.

3. Prevent generation and propagation of nerve action potential at all parts of the neuron where they come in contact, without causing any structural damage.

4. They interrupt sensory as well as motor impulses in a mixed nerve and can lead to muscular paralysis and loss of autonomic control as well.

5. Do not alter consciousness.

6. Can be used safely for poor health patient also.

7. Useful only for minor surgery.

Chemistry and Classification of Local anesthetics

The clinically useful local anesthetics are weak bases. They have amphiphilic property. They consist of a hydrophilic secondary or tertiary amine on one side and a lipophilic aromatic residue on the other side. Two are joined by an alkyl chain through an ester or amide linkage. So based on linkage they can be classified as:

I. Ester-linked Local anesthetics: Cocaine, procaine, chloroprocaine, tetracaine, cyclomethycaine, benzocaine, benoxinate.

II. Amide-linked Local anesthetics:

Lidocaine, mepivacaine, bupivocaine, dibucaine. They differ from the former group as under:

• They bind to alpha-i glycoprotein in plasma.
• Generally longer acting.
• Not hydrolyzed by plasma esterases.
• Hypersensitivity reactions are less frequent.
• No cross-sensitivity with ester-linked Local anesthetics.

Local anaesthetics can also be classified on the basis of type of local anaesthesia produced by them.

Mechanism of action: Local anesthetics block nerve conduction by reducing entry of Na4 through the voltage gated channels either by an effect on the membrane or by specifically plugging Na4 channels. Due to this, they block the initiation and propagation of nerve impulse. They block unreceptive and sympathetic transmission first and motor nerves are blocked last.

Pharmacokinetics: Surface Local anesthetics are rapidly absorbed from mucous membranes and abraded areas. However, procaine does not significantly penetrate mucous membranes. After oral administration, both procaine and lignocaine have high first pass metabolism in the live Most Local anesthetics are effective within 5 minutes. Their duration of action ranges between 1 and 1.5 hours. This cart be increased to 2—3 hours by the addition of a vasoconstrictor like adrenaline or noradrenaline or a synthetic vasopressin, felypressin.

Ester-linked Local anesthetics are rapidly hydrolyzed by plasma pseudocholinesterase and the remaining amount by esterases in liver. Amide-linked Local anesthetics are metabolized in the liver by microsomal enzymes (dealkylation and hydrolysis).

Pharmacological Actions of Local anesthetics

Local: Clinically used Local anesthetics have no/minimal local irritant action. They block sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic synapse and receptors (non-selectively). They also decrease release of acetylcholine from motor nerve endings. Local anesthetics block nerve conduction in the following order:

• Small myelinated axons (sensory, autonomic)

• Non-myelinated axons

• Large myelinated axons (motor)

So, unreceptive and sympathetic transmission is blocked first and motor nerves are blocked last.

Systemic: Any Local anesthetics applied locally or injected is ultimately absorbed. Depending on its concentration in the plasma and tissues, it can produce systemic effects.

Central nervous system: All Local anesthetics are capable of producing a sequence of stimulation followed by depression. The basic effect of these drugs is neuronal inhibition. Initial apparent stimulation is due to inhibition of inhibitory neurons.

Cocaine is a powerful CNS stimulant. At safe clinical doses, procaine and other. So for anti arrhythmic purpose, they are given parenterally.

synthetic Local anesthetics produce little apparent CNS stimulation. However, in higher doses, they produce CNS stimulation followed by depression. At clinical doses, lidocaine causes drowsiness and lethargy but higher doses produce excitation followed by depression.

Cardiovascular system: No significant effect is observed on heart in conventional doses of Local anesthetics. At high doses, they decrease excitability, conductivity and contractility. Lignocaine has antiarrhythmic activity.

Hypotension is due to direct vasodilatation, ganglionic blockade, and inhibition of sympathetic system.

Adverse reactions: Excessive systemic absorption can result in light headedness, dizziness, auditory and visual disturbances, mental confusion, disorientation, shivering, twitching, tremors and finally convulsions and respiratory arrest. These adverse reactions can be prevented or treated by diazepam. There also occurs bradycardia, hypotension, cardiac arrhythmias and vascular collapse. Hypersensitivity reactions (such as skin rashes, bronchial asthma, and anaphylactic shock) are rare. Lignocaine and prilocaine can induce methaemoglobinaemia due to an aniline metabolite.

Drug Interactions of Local anesthetics

• Antibacterial action of sulfonamides is interfered because procaine releases paraaminobenzoic acid (PABA) on hydrolysis.
• Cimetidine increases the plasma levels of llgnocaine and other amide type of Local anesthetics by inhibiting hepatic microsomal enzyme.
• Propranolol increases the plasma levels of amide type of Local anesthetics by decreasing hepatic blood flow.
• Phenobarbitone decreases plasma levels of amide Local anesthetics by hepatic enzyme induction.
• Lignocaine potentiates succinylcholine action.

Procaine

• As potent LA as lidocaine
• Duration of action short
• Not effective for surface anesthesia due to poor absorption from the mucous membranes
• Poor analgesic
• Readily hydrolyzed by plasma cholinesterase into para-amino benzoic acid

Uncharacteristic Features of Individual Local anesthetics

• Lidocaine (Lignocaine, Xylocaine)
• Most widely used Local anesthetics including dental practice
• Onset of action—quick
• Duration of action—long used with epinephrine)
• Metabolized in liver by oxidases
• Safely administered to patients who are sensitive to procaine
• Xyliclide is its active metabolite with Local anesthetics activity
• Also used i.v. to treat ventricular arrhythmias

Cocaine

• It is a drug of abuse
• Never injected due to central nervous system toxicity
• Causes cardiac depression in hypersensitive patients
• Onset of action—quick
• Duration of action—long
• Not used along with epinephrine as cocaine potentiates the action of epinephrine

Mepivacaine

• Chemically and pharmacologically related to lidocaine
• Not effective topically
• Used for infiltration, nerve block, and epidural anesthesia
• Generally used in dentistry

Bupivacaine

• Onset of action—slow
• Duration of action—long (8 hours)
• Mainly used in:

a. Spinal anesthesia

b. Lumbar blockade

c. During labour for analgesia

Prilocaine

• As effective as lidocaine
• Can cause methaemoglobinaemia
• Used for infiltration, nerve block and dental anesthesia

Amethocaine

• Used topically to venous puncture or venous cannulation.
• Should not be applied to inflamed, traumatized or highly vascular surfaces.

Benzocaine

• Useful in surface anesthesia
• Used in dusting powder
• Used in throat lozenges

Ropivacaine

• Used for surface anesthesia.

Spinal and Epidural Anesthesia

Spinal anesthesia is a safer alternative of general anesthesia in patients in whom general anesthetics are contraindicated. It is mainly used for surgical procedures carried out on lower abdomen, perineum and lower limbs. Its advantages on general anesthesia are:

• It is safe.
• Produces good analgesia and muscle relaxation without loss of consciousness.
• Cardiac, pulmonary, renal disease and diabetes pose fewer problems.

However, it can induce some complications, such as:

• Respiratory depression. It is rare. It occurs in lower level spinal anesthesia. It is mainly due to intercostal muscle paralysis. So breathing is maintained by diaphragm which is supplied by phrenic nerve.
• Hypotension may occur due to sympathetic blockage. It can be treated with vasopressor agents like mephentramine.
• Headache occurs due to leakage of cerebrospinal fluid. It can be corrected by the use of aspirin.
• Cauda equina syndrome may occur due to spinal cord injury.
• Septic meningitis may occur very rarely due to introduction of infection during lumbar puncture.
• Nausea and vomiting after abdominal operation.

Contraindications

• Uncooperative or mentally ill patient.
• Infants and children because control of level is difficult.
• Hypotension and hypovolemia.
• Vertebral abnormalities, e.g. kyphosis lordosis.
• Sepsis at injection site.

The clinical use of epidural anesthesia is similar to spinal anesthesia. It may be thoraxic, lumbar or caudal depending on the site of its administration. Technically, it is a more difficult procedure and large amount of anesthetic agent is required to be used which may induce systemic toxicity. However, the side effects of spinal anesthesia are rarely noted in this type of Local anesthetics or are less severe.

Biological Toxins with Local anesthetics like Actions

The following biological toxins cause blockade of Na conductance through the voltage-gated channels. So they inhibit action potential generation and propagation in all excitable tissues, including the heart, neuromuscular junction and nerves.

a. Tetrodotoxin (pufferfish)

b. Saxitoxin (marine shellfish)

c. Cignatoxin (marine fish)

The following biological toxins act by increasing Na conductance through the voltage-gated channels. So they cause persistent depolarization of excitable cells and lead to their inactivation.

a. Batrachotoxin (South American frog)

b. Scorpion venom

c. Sea anemone

Use of Vasoconstrictors along with Local anesthetics Agents

All clinically effective inject-able Local anesthetics possess some degree of vasodilating activity. The degree of vasodilatation varies. It is significant in case of procaine while minimal with prilocaine and mepivacaine. It also may vary with both injection site and individual patient response. The blood vessels are dilated after injection of Local anesthetics into tissues. This results in an increased perfusion at the site and leads to the following reactions:

• Rate of absorption of the Local anesthetics into the circulation is increased. So this removes it from the injection site (redistribution).
• Increased risk of toxicity due to higher plasma levels of the Local anesthetics.
• Decreased depth of anesthesia and a decreased duration of action due to rapid diffusion of Local anesthetics away from injection site.
• Increased bleeding at the site of treatment due to increased perfusion.

Vasoconstrictors are drugs that constrict blood vessels and thereby control tissue perfusion. They are added to Local anesthetics solutions to oppose their vasodilatory effects. The vasoconstrictors are, therefore, important additions to a Local anesthetics solution for the following reasons:

• Vasoconstrictors reduce blood flow (perfusion) to the site of administration by constricting blood vessels.

• Absorption of Local anesthetics into circulation is slowed and results in lower anesthetic plasma levels. Hence the risk of Local anesthetics toxicity is minimized.

• Increased amount of the Local anesthetics remains in and around the nerve for longer periods. Due to this, vasoconstrictor increases (in some cases significantly, in others minimally) the duration of action of most Local anesthetics.

• Vasoconstrictors decrease bleeding at the site of administration. They are, therefore, useful when increased bleeding is anticipated, e.g. during surgical procedures.

Commonly used vasoconstrictors in conjunction with Local anesthetics are following sympathomimetics:

• Epinephrine: It is most potent and widely used vasoconstrictor in dentistry. Least concentrated solution that produces effective pain control should be used. Lidocaine is available with two dilutions of epinephrine—1: 50,000 and 1: 100,000.

Epinepherine prevents or minimizes blood loss during surgical procedures effectively. However, it also produces a rebound vasodilatory effect as the tissue level of epinephrine declines. This leads tp possible bleeding post operatively, which potentially interferes with wound healing. Epinephrine possesses both a and 1 actions. It produces vasoconstriction through it’s a effects. Used in 1:50,000 concentration and even at 1:100,000 (but to a lesser extent), epinephrine induces a definite rebound n-effect once the a-induced vasoconstriction has ceased. This is responsible for increased postoperative blood loss, which if significant (usually in dentistry it is not), could compromise a patient’s cardiovascular status.

• Levonordefrin is used as a vasoconstrictor with mepivacaine in a 1:20,000 dilution. For all patients, the maximum dose should be 1 mg per appointment; 20 ml of a 1:20,000 dilution (11 cartridges).

• Felypressin (a synthetic vasopressin) is employed in a dilution of 0.03 rn/mi with 3% prilocaine. Felypressin containing solutions are not used when hemostasis is necessary. This is because of their predominant effect on the venous rather than the arterial circulation. The maximum recommended dose is 0.27 lU/mi; 9 ml of 0.03 IU/ml for patients with clinically significant cardiovascular impairment. It has the advantage that it does not affect the heart rate and blood pressure.

Points for Dental Students

1. Commonly used Local anesthetics in dentistry are xylocaine, mepivacaine, bupivacaine and priocaine. So thorough knowledge of Local anesthetics is required by dental students for their judicious and safe use. –

2. Nerve block anesthesia are to be avoided in a plastic anemia because of the risk of thrombocytopenia and the bleeding tendency. However, intraligamental anesthesia can be used safely in these cases.

3. For all patients and for some in particular, the benefits and risks of including vasopressor in Local anesthetics solution must be weighed against the benefits and risks of using a ‘plain’ anesthetic solution. In general these groups are:

• Patients with more significant cardiovascular diseases (ASA III and IV group)

• Patients with certain non-cardiovascular diseases, e.g. thyroid dysfunction, diabetes and sulfite sensitivity

• Patients receiving MACI, tricyclic anti- depressants and phenothiazines

However, it may be stated that Local anesthetics with vasoconstrictors are not absolutely contraindicated for patients whose medical condition has been diagnosed and is under control through medical or surgical means and if the vasoconstrictor is administered slowly in minimal doses, after regular routine aspiration has been ensured.

4. Local anesthetics should be carefully given in small children (up to 6 years) because maximum dose limits are quickly reached. Local anesthetics with opioid sedation may increase the risk of developing Local anesthetics overdose. So this should be particularly taken care of during pedodontic surgery in children to avoid fatalities.

Recently a useful non-invasive method has been developed to produce local anesthesia in pedodontic procedures by using EMLA (Eutectic mixture of Local anesthetics) cream consisting of 2.5% xylocaine ÷ 2.5% prilocaine.

5. Monitoring preoperative vital signs specially the blood pressure, heart rate and rhythm is strongly recommended for all patients but is especially in patients receiving J3-blockers. Re-recording of these vital signs at 5—10 minutes after the administration of a vasoconstrictor is strongly recommended.

6. Little higher dose of xylocaine + adrenaline combination is needed for proper Local anesthetics effect in patients with acute alcohol intoxication because much of the vasoconstrictor effects of adrenaline are rather neutralized by the cutaneous vasodilatory effects.

7. Take special care while injecting xylocaine + adrenaline to a patient of cardiac failure on digoxin to avoid developing cardiac arrhythmias which occur if vasoconstrictor enters intravascularly. Similarly in digitalized patients use haemostatic retraction cords impregnated with astringents in place of Local anesthetics + adrenaline.

8. Avoid use of Local anesthetics + adrenaline in Parkinson’s patients taking 1-dopa as cardiac arrhythmia may be precipitated due to stimulation of cardiac receptors by dopamine formed peripherally from 1- dopa.

9. Modest increase in plasma concentration of Local anesthetics by erythromycin due to hepatic enzyme inhibition.

10. Large doses of xylocaine are usually i.v. infused to treat ventricular arrhythmias in coronary care units. In such cases, coadministration of propranolol can lead to xylocaine toxicity due to:

• Inhibition of metabolic oxidation of xylocaine

• Decreased hepatic blood flow (responsible for diminished delivery of xylocaine in liver).

11. Local anesthetics + adrenaline can lead to serious rise in blood pressure and cardiac arrhythmia in hypertensive patients on prolonged use of guanethidine which induces super-sensitivity of adrenoceptor receptors to exogenously administered adrenaline.

TO REMEMBER

1.Local anesthetics : Used locally to abolish sensation in a limited region of the body. Generation and propagation of nerve impulse action potential are prevented by them.

2. Types of Local anesthetics: Surface, infiltration, nerve block, spinal and epidural.

3. Status of local anesthetics:

• Lidocaine: Most popular Local anesthetics. Used to induce all types of local anesthesia.

• Bupivacaine: Used as a surface anesthetic and occasionally for spinal anesthesia.

• Benzocaine and butylaminobenzoate:

Being not systemically absorbed they are used as lozenges/dusting powder /ointment and suppository for local applications.

• Oxethazine: Used in anesthetizing gastric mucosa being a very potent topical anesthetic and unique in ionizing to a very small extent even at low pH.

• Tetracaine: Use is restricted to topical application.

• Procaine: Rarely used after the introduction of lidocaine.

• Cocaine: Use not warranted because it is protoplasmic poison; produces psychological drug dependence and ocular toxicity.