Local Anesthetic and application in Anesthesia

Local anaesthetics

• Reversible loss of nerve impulse conduction
• Routes: Topical, subcutaneous, directly

Action potential

• Unidirectional
• All or none
• Saltatory conduction – jumps between nodes of ranvier

Local anaesthetic

• Blocks Na+ channel → Prevents entry of Na+
• No action potential is formed

• Ionic state changes occur after injection due to higher pH in tissues (7.4 instead of 6.0)
• Ionised form blocks the Na+ channels
• The greater the binding to the protein, the longer the duration of action

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Order of the block

• Small diameters nerves first before large ones
• Unmyelinated nerves first before myelinated
• Which senses: Autonomic (vasodilation), Temperature, Pain, Touch, Motor (paralysis)

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Clinical uses

• Local infiltration
• Topical anaes – eyes. urethra
• Peripheral nerve block
• Spinal – subarachnoid space
• Epidural - extradural space

Complications of central neural blockade

• Hypotension and bradycardia
• Nausea and vomiting
• Postdural puncture headache

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Local anaesthetic toxicity

• Rapid ansorption of a normally safe dose
• IV injection failure
• Administration of an overdose

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Effects on CNS and CVS

Types

Lignocaine

• Topically, nerve blocks, epidural and spinal anaesthesia
• Usually combined with adrenaline (vasoconstriction effect)
• Adrenaline→ reduce rate of absorption, reduce toxicity and extend duration of action. Careful with used around extremities can cause tissue necrosis
• Fast onset, medium duration of effect
• Metabolises in the liver
• Potential neurotoxicity (i.e. cauda equina syndrome) when lidocaine is administered for spinal anesthesia, especially when used with continuous spinal technique.

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Bupivacaine

• Slower onset greater duration than lignocaine
• Used as nerve blocks, epidural, spinal anaesthesia
• It’s cardiotoxic - When the blood concentrations is sufficiently ↑→ the local anesthetics can bind to sodium channels present on myocardial cells → ↓myocardial automaticity and ↓ the refractory period → Cardiac arrhythmias, depressed contractility & cardiac arrest
• Levobupivacaine (Chirocaine) → significant reduced cardiotoxicity

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Ropivacaine

• Local anaesthetic – amino amide group
• Ropivacaine hydrochloride = Naropin
• MOA: blocks the generation and conduction of nerve impulses by blocking Na channel (decrease chances of depolarisation)
• slowing propagation of nerve impulse
• Reducing the rate of rise of action potentials
• Metabolism: Hepatic
• Half-life: 4.2 hours
• Duration of action: 120-360 mins
• Indication: local anaesthesia in
• adults and children over 12 years old
• Nerve block, epidural, intrathecal anaesthesia
• Children 1-12 years old
• Peripheral nerve block and caudal epidural
• Pregnant women
• Epidural – co-administer with fentanyl (potent synthetic narcotic analgesia)

Ropivacaine

• Contraindications: IV regional anaesthesia
• Adverse Effects:
• Central nervous system (CNS) and cardiovascular effects
• CNS effects - blood plasma concentrations
• CNS excitation (nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures) followed by depression (drowsiness, loss of consciousness, respiratory depression and apnea).
• Cardiovascular effects - higher concentrations (cardiovascular collapse may also occur with low concentrations)
• hypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.
• Toxicity
• Toxic max dose without epinephrine: 2.5 mg/kg (max 300 mg)
• Toxic max adult dose with epi: 2.5 mg/kg
• Not to exceed 200mg for minor nerve block

Levobupivacaine

• Local anaesthetic – amino amide group
• Levobupivacaine hydrochloride = Chirocaine
• MOA: blocks the generation and conduction of nerve impulses by blocking Na channel (decrease chances of depolarisation)
• Metabolism: Hepatic
• Half-life: 3.3 hours
• Indication: local anaesthesia in
• adults
• Nerve block, epidural, intrathecal anaesthesia
• Children
• Infiltration analgesia, caudal anaesthesia

Levobupivacaine

• Contraindications: IV regional anaesthesia
• Adverse Effects:
• Same as ropivacaine
• Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations.
• Toxicity
• Toxic max dose without epinephrine: 2.5 - 3 mg/kg
• Toxic max adult dose with epi: 2.5 - 3 mg/kg

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Management of Acute Toxicity

• The airway is maintained and oxygen administered by facemask, using artificial ventilation if apnoea occurs.
• Convulsions should be treated with anticonvulsant drugs such as thiopentone (150-250mg I.V.) or diazepam (10-20 mg I.V.) repeated as necessary.
• Profound hypotension and brady -arrhythmias should be treated with intravenous atropine (0.5-1.5mg) and colloid or crystalloid infusions as plasma expanders may be necessary.
• Occasionally adrenaline may be required for severe hypotension or bradycardia.
• In patients with ventricular fibrillation due to bupivacaine toxicity, cardiopulmonary resuscitation should be continued for at least 60mins.
• Bretylium (aka bretylium tosylate) may facilitate cardioversion
• Lipid emulsion (intralipid)

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Procaine

• Procaine acts by stabilising the neuronal membrane thus preventing the generation and transmission of impulses along nerve fibers and at nerve endings. In general, loss of pain occurs before loss of sensory, autonomic and motor functions. A PABA ester, it does not penetrate intact mucous membranes well making it ineffective against surface application and admin is solely by injection.
• Absorption: Rapidly absorbed following parenteral admin.
• Distribution: About 6% bound to plasma proteins.
• Metabolism: Rapidly hydrolysed by plasma cholinesterases.
• Excretion: About 80% excreted unchanged or conjugated in urine.

Indications and Dosage

• Injection
• Percutaneous infiltration anaesthesia
• Adult: 350-600 mg using 0.25 or 0.5% solutions.
• Injection
• Peripheral nerve block
• Adult: 500 mg procaine HCl as a 0.5%, 1% or 2% solution. Up to 1 g may be used.

• Contraindications :-
• Hypersensitivity, complete heart block. Not to be applied to inflamed or traumatised surfaces, low plasma-cholinesterase conc, not to be instilled into the middle ear. Generalised septicaemia. Epidural or spinal block should not be used in patients with cerebrospinal diseases, cardiogenic/hypovolaemic shock or altered coagulation states.

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• Adverse Drug reactions :-
• CNS excitation; dizziness; tinnitus; blurred vision; nausea and vomiting; muscle twitching and tremors; convulsions. Numbness of tongue and perioral region. Bradycardia; arrhythmias. Hypersensitivity; methemoglobinemia; foetal intoxication; corneal damage.
• Potentially Fatal: Severe hypotension leading to cardiac arrest.

Special Precautions

• Epilepsy; impaired cardiac conduction or resp function; shock; hepatic impairment; myasthenia gravis.
• Those who received the anesthetic for procedures e.g. laryngoscopy or tracheoscopy should not eat or drink for 3-4 hr after anaesthetic.
• Patients should be warned not to rub or touch the eye while anesthesia persists and protect anesthetised eye from dust and bacterial contamination.
• Avoid application on to extensive areas for prolonged periods. Pregnancy. Elderly, debilitated and paediatrics.

Drug Interactions

• May antagonise the activity of aminosalicylic acid or sulfonamides. May enhance the neuromuscular blocking activity of suxamethonium and the amide local anaesthetics.

Prilocaine

Prilocaine is a local anaesthetic of the amide group. It has similar anesthetic potency to lignocaine but it has slower onset of action, less vasodilator activity and a slightly longer duration of action; it is also less toxic.

• Onset: Dental anaesthesia: 2 min. Inferior alveolar nerve block: 3 min.
• Duration: Dental anaesthesia: 10-15 min (pulp analgesia); 1-2 hr (soft tissue anaesthesia). Inferior alveolar nerve block: 2.5 hr (soft tissue anaesthesia).

Indication and Dosage

• Injection
• Dental infiltration and dental nerve block
• Adult: 40-80 mg (1-2 ml) as a 4% solution without felypressin or 30-150 mg (1-5 ml) as a 3% solution with felypressin 0.03 IU/ml. Max: 400 mg if used alone and 300 mg if used with felypressin.
• Child: <10 yr: 40 mg (1 ml) as a 4% soln without felypressin or 30-60 mg (1-2 ml) as a 3% soln with felypressin 0.03 units/ml.
• Topical/Cutaneous
• Local anaesthesia
• Adult: Eutectic mixture of prilocaine base 2.5% and lignocaine base 2.5% applied as a cream under occlusive dressing (except for removal of genital warts).

Contraindications :

• Hypersensitivity, hypovolaemia, complete heart block, congenital or idiopathic methemoglobinaemia, paracervical block in obstetrics, porphyria, pregnancy, anaemia and hypoxia.

AdverseDrug Reactions :-

• Methemoglobinaemia; cyanosis; restlessness; excitement; nervousness; paraesthesias; dizziness; tinnitus; blurred vision; nausea; vomiting; muscle twitching; tremors; convulsions; hypotension; bradycardia; arrhythmias; cardiac arrest.

Special Precautions

• Lactation. Rate of Inj shoud not be too rapid. Avoid inadvertent intravascular injection. Avoid prolonged use.
• Elderly; child; debilitated; epilepsy; impaired resp function or cardiac conduction; shock; hepatic impairment;
• Epidural or spinal block should not be employed to patients with cerebrospinal diseases; cardiogenic or hypovolemic shock; altered coagulation status, pyogenic infection of the skin at or near the Inj site. Do not inject into or apply to inflamed or infected tissues or damaged skin or mucosa. Do not instill into the middle ear.

Drug Interactions

• Sulfonamides, antimalarials, certain nitric compounds may potentiate methemoglobinemia. Additive toxic effects with agents structurally related to local anaesthetics. Increased risk of myocardial depression when used with antiarrhythmics.

EMLA

Eutectic Mixture of local anaesthetic

• lidocaine 25 milligram in 1 gram, prilocaine 25 milligram in 1 gram

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• Mechanism of action:Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action

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• Indications :

- normal intact skin for local analgesia.

- genital mucous membranes for superficial minor surgery and as pretreatment for infiltration anesthesia.

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Uses

•  For minor procedures such as IV cannulation and venipuncture,

apply 2.5 grams of EMLA Cream (1/2 the 5 g tube) over 20 to 25 cm² of skin surface for at least 1 hour.

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• Major Dermal Procedures:  such as split thickness skin graft harvesting, apply 2 grams per 10 cm² of skin and allow to remain in contact with the skin for at least 2 hours.

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• Adult Male Genital Skin: As an adjunct prior to local anesthetic infiltration, apply a thick layer of EMLA Cream (1 g/10 cm2) to the skin surface for 15 minutes. Local anesthetic infiltration should be performed immediately after removal of EMLA Cream.

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• Adult Female Patients − Genital Mucous Membranes

For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5-10 grams) of EMLA Cream for 5 to 10 minutes.

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• Pediatric Patients − Intact Skin

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Overdose

• Toxic levels of lidocaine (>5 µg/mL) and/or prilocaine (>6µg/mL) cause decreases in cardiac output, total peripheral resistance and mean arterial pressure. These changes may be attributable to direct depressant effects of these local anesthetic agents on the cardiovascular system.

• contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type or to any other component of the product

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• Methemoglobinemia: EMLA Cream should not be used in those rare patients with congenital or idiopathic methemoglobinemia and in infants under the age of twelve months who are receiving treatment with methemoglobin-inducing agents.

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• EMLA Cream should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

Adverse reactions

• Localized Reactions: During or immediately after treatment with EMLA Cream on intact skin, the skin at the site of treatment may develop erythema or edema or may be the locus of abnormal sensation. Rare cases of discrete purpuric or petechial reactions at the application site have been reported.

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•  Allergic Reactions: Allergic and anaphylactoid reactions associated with lidocaine or prilocaine can occur. They are characterized by urticaria, angioedema, bronchospasm, and shock.

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• Systemic (Dose Related) Reactions: CNS excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest).

Clinical

• Predisposing Factors
• �1. Patient Factors

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• Age—more common in old and young people

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• Weight—greater (lean) body weight can tolerate larger dose of drug before overdose

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• Other medications—if other drugs compete for protein binding sites, toxicity occurs at lower drug level (Meperidine, Phenytoin, Quinidine, Desipramine); competition for hepatic oxidative enzymes slow biotransformation of Lidocaine (Cimetidine)

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• Presence of disease—hepatic and renal dysfunction, congestive heart failure impair ability to transform drug to inactive produc

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• Genetics—alters response to drug (atypical pseudocholinesterase)

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• Mental attitude and environment—fear related to larger dose requirement and lower seizure threshold, increasing likelihood of overdose

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2. Drug Factors

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• A. Vasoactivity —vasodilation increases absorption into tissues and raises blood level

�B. Concentration—greater concentration increases circulating blood level

�C. Dose—larger dose increases circulating blood level

�D. Route of administration—inadvertent intravascular injection increases blood level of drug; rapid absorption of topical anesthetic can lead to overdose

�E. Rate of injection**(important)—rapid intravenous administration (<15 seconds) increases risk dramatically vs slow administration (>60 seconds)

�F. Vascularity of injection site—more risk of overdose in highly perfused areas

�G. Presence of vasoconstrictors—reduces clinical toxicity

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MINIMAL TO MODERATE OVERDOSE

• Signs
• Talkativeness�Apprehension�Excitability�Slurred speech�Generalized stutter, leading to muscular twitching and tremor in face and distal extremities�Euphoria�Dysarthria�Nystagmus�Sweating�Vomiting�Failure to follow commands or be reasoned with�Disorientation�Loss of response to painful stimuli�Elevated blood pressure�Elevated heart rate�Elevated respiratory rate

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SYMPTOMS

Light-headedness and dizziness�Restlessness�Nervousness�Numbness�Sensation of twitching before actual twitching�Metallic taste�Visual disturbances (inability to focus)�Auditory disturbances (tinnitus)�Drowsiness and disorientation�Loss of consciousness

MODERATE TO HIGH OVERDOSE LEVELS

• Tonic-clonic seizure activity followed by�Generalized CNS depression�Depressed blood pressure, heart rate, and respiratory rate

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• Pathophysiology

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• Local anesthetics exert DEPRESSANT effect

�Adverse reactions UNCOMMON at non-overdose levels of <5 micrograms/ml�(usual range of blood level is 0.5-2 micrograms/ml following administration of 40-160 mg of local anesthetic or 1-4 cartridges of Lidocaine, e.g.)

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• Signs of toxicity appear at cerebral blood level > 4.5 micrograms/ml—agitation, talkativeness, irritability�Tonic-clonic seizures occur at levels >7.5 micrograms/ml�Generalize CNS depression occurs at higher levels, resulting in respiratory depression and arrest

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• CVS develops later than CNS actions�Minor alterations in CVS occur at 5-10 micrograms/ml—myocardial depression, decreased cardiac output, peripheral vasodilation�At >10 micrograms/ml—massive peripheral vasodilation, marked reduction in myocardial contractility, severe bradycardia, possible cardiac arrest

Prevention of systemic local anesthetic toxicity

• Be vigilant. Monitoring electrocardiogram, blood pressure, and arterial oxygen saturation is recommended.

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• Communicate frequently with the patient to query for symptoms of toxicity.

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• Limit local anesthetic (LA) dose based on site of injection, hypercapnia, advanced age, poor cardiac function, ischemic heart disease, cardiac conduction abnormalities (see notes), metabolic (especially mitochondrial) disease, or abnormally low plasma protein concentration.

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• Aspirate syringe prior to each injection observing for blood or cerebrospinal fluid.

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• Inject small volumes (5 mL), incrementally (45–60 sec intervals) observing for signs and symptoms of toxicity between each injection

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