Local Anesthetics By Seba Hassan Attia Lecturer of Clinical Pharmacology Local Anesthetics ▪ Drugs that produce reversible inhibition of nerve function so abolish sensation in a limited area of the body without producing unconsciousness. ▪ Classification According to chemical structure ▪ Esters ▪ Amides According to duration of action: 1.Short-acting (20min) 2.Intermediate-acting (1-1.5 hrs): 3.Long acting (2-4 hrs) According to chemical structure: ▪ Esters of PABA: ▪ procaine, chloroprocaine, tetracaine, and the natural alkaloid (cocaine). ▪ Amides of PABA: lidocaine, prilocaine, mepivacaine, burupivacaine and ropivacine. According to duration of action: ➢ Short-acting (20 min): procaine, chloroprocaine. ➢ Intermediate-acting (1-1.5 hrs): lidocaine, mepivacaine and prilocaine. ➢ Long acting (2-4 hrs): tetracaine, bupivacaine, ropivacaine. Pharmacokinetics: ▪ Absorption: ▪ Systemic absorption from site of administration. ▪ The rate of systemic absorption concentration, total dosage. ▪ Dosage, site of injection, tissue-drug binding ▪ local blood flow, physicochemical properties of the drug ▪ use of local VC (e.g., epinephrine); that decrease systemic absorption and toxicity and increase local tissue concentration and effects. depends on: Pharmacokinetics: ▪ Metabolism: ▪ Esters ▪ Amides are metabolized primarily in the liver by hepatic microsomal enzymes. So, liver disease & HME inhibitors ↑toxicity of amide LA. are rapidly metabolized by plasma pseudocholinestrase to PABA. In deficiency of plasma cholinesterase as in advanced liver diseases and organophosphorus poisoning → stimulate action and systemic toxicity. ▪ Onset and duration of action: ▪ The most important factors affecting onset and duration are PH of the tissue and PKa of the drug; concentration and lipid solubility of the drug also play a role. ▪ LAs are weak bases made available clinically as salts. Physiological pH of the body fluids (slightly alkaline) favors the formation of free base (cationic form); the most active form at receptor site. ▪ Procaine Cl- + Na+ ▪ If injected into infected tissues small percentage of local anesthetic base less effective. NaCl + procaine. Mechanism of action: 1. LAs work by blocking voltage-dependent Na+ channels to prevent the transient increase in permeability of the nerve membrane to Na+ that is required for an action potential to occur blocks nerve conduction when applied locally around the nerve axons and other excitable membranes. Mechanism of action: ▪ The small nerve fibres that conduct impulses for pain, temperature, touch and autonomic activity are most sensitive to the action of LAs. Lastly, motor nerve (relax skeletal muscle). Recovery occurs in the reverse order. ▪ Their effects on cardiac cell membranes are of major clinical significance: ▪ Some local anesthetics are useful antiarrhythmic agents at concentrations lower than those required to produce nerve block. Others (e.g., bupivacaine, ropivacaine) may lethal arrhythmias in high concentrations. Methods of application of local anesthetics: ▪ Topical (surface): on nasal mucosa, skin (wound margins), cornea and mouth. ▪ Infiltration: S.C. injection as in dental operations. ▪ Nerve block: around nerve trunk (e.g., dental nerve), brachial plexus. ▪ Autonomic sympathetic: block sympathetic fibres (to evaluate the role of sympathetic tone in patients with vasospastic disorders). ▪ Paravertebral: around spinal root as they exit from paravertebral formina. ▪ Spinal: in the subarachnoid space between 3rd and 4th lumber vertebrae used in abdominal, pelvis and leg operations. ▪ Epidural: in epidural space - used in painless labor. Actions and toxicity Excess absorption may lead to: Central nervous system Cardiovascular system (CVS) Hematological effects Allergic reactions Local toxicity Central nervous system: ▪ Low concentrations: sleepiness, parathesia (face & tongue) light-headache, visual and auditory disturbances and restlessness. Also circumoral and tongue numbness and metallic taste. ▪ High concentrations: Nystagmus and muscle twitches. Lastly, → convulsions and death (from generalized CNS depression), cardiovascular collapse and respiratory failure. Cardiovascular system (CVS): ▪ CVS effects of local LAs results from direct depressant effects on the cardiac and smooth muscle membranes indirect effects on autonomic nervous system → cardiac depression and hypotension. ▪ Cocaine differs from other LAs in its CVS effects as it inhibits uptake of NE → hypertension, arrhysmias and myocardial failure in toxic doses. Hematological effects: 1. Large doses of methemoglobinemia. prilocaine 2. Treated with reducing agent (methyline blue or ascorbic acid). Allergic reactions: ▪ Esters are metabolized to PABA derivatives → allergic reactions (urticaria, edema and bronchospasm) in small percentage of patients. ▪ Amides are not metalolized to PABAs → allergy is extremely rare. Local toxicity 1. Pain and hematoma at site of injection 2. Nerve damage leads to prolonged sensory and motor loss 3. Tissue damage leads to necrosis, sloughing of tissue due to VC by adrenaline added to LA 4. Mucosal irritation Preanesthetic medication for LA: ▪A benzodiazepine as diazepam may be given before LA: 1. To counter act central stimulant action of LA & prevent convulsions. 2. To relieve anxiety of the patient. ▪ Common local anesthetic drugs ▪ A. Amides ▪ Lidocaine: The prototype amide; it has an intermediate duration of action. ▪ Generally preferred for infiltration blocks and for epidural anesthesia. ▪ Mepivacaine ▪ Has an intermediate duration of action that is longer than that of lidocaine. ▪ Has an action similar to lidocaine. Not used topically. ▪ ▪ Bupivacaine: Has a long duration of action. o Generally preferred for infiltration blocks and epidural anesthesia. o Has greater cardiotoxicity than other amide local anesthetics. ▪ B. Esters ▪ Procaine: Short-acting. Not effective topically. ▪ Cocaine: used only for the topical anesthesia of mucous membranes. ▪ Adverse effects of cocaine include euphoria, CNS stimulation, tachycardia, restlessness, tremors, convulsions, and arrhythmias. ▪ Cocaine should be used cautionsly with hypertension, cardiovascular disease, or thyrotoxicosis, and with other drugs that potentiate catecholamine activity. ▪ Tetracaine ▪ Long-acting but has a slow onset of action (>10 minutes). ▪ Often preferred for ophthalmological use. ▪ Not generally used for peripheral nerve block, infiltration anesthesia, or lumber epidural nerve block.
