Local anesthetics Assistant Professor Dr Hayder B Sahib

Local anesthetics Assistant Professor Dr. Hayder B Sahib Ph. D, MSc, DSc, BSc. Pharm

What are local anesthetics? • Local anesthetic: produce loss of sensation to pain in a specific area of the body without the loss of consciousness

Local Anesthetics - Classes Esters

Mechanism of action blockade of voltage-gated sodium channels reversible block of impulse conduction along nerve axons and other excitable membranes that utilize sodium channels as the primary means of action potential generation.

Mechanism of action • Local anesthetics bind to a receptor (R) within the channel near the intracellular end. • LA access it via the membrane or from the cytoplasm and block the channel in a timeand voltage-dependent fashion

Voltage- gated K channels also blocked by LA but the affinity of receptor is much less: Lidocaine is 4 -10 times less, Bupivacaine 10 -80 times less

Properties of Local Anesthetics 1 - Low systemic toxicity at an effective concentration. 2 - Onset of action should be quick, and duration of action should be sufficient to allow time for the surgical procedure. 3 - Should be soluble in water, stable in solution and should not deteriorate by the heat of sterilization. 4 - Should be effective both when injected into tissue and when applied topically to mucous membranes. 5 - Its effects should be completely reversible.

Local Anesthetics • Activity of local anesthetics is a function of their • 1 - Lipid solubility • 2 - Diffusibility • 3 - affinity for protein binding • 4 - percent ionization at physiologic p. H • 5 - blood flow

Pharmacokinetics Systemic absorption of injected local anesthetic from the site of administration is determined by: • dosage • site of injection • local blood flow, use of vasoconstrictors (e. g. , epinephrine) • drug-tissue binding • the physicochemical properties of the drug itself (lipid solubility).

Pharmacokinetics • Application of a local anesthetic to a highly vascular area such as the tracheal mucosa or the tissue surrounding intercostals nerves results in • more rapid absorption in comparison to anesthetic had been injected into a poorly perfuse tissue such as tendon, dermis, or subcutaneous fat.

Pharmacokinetics • Vasoconstrictor substances such as epinephrine reduce systemic absorption of local anesthetics from the injection site by decreasing blood flow in these areas. • This is important for drugs with intermediate or short durations of action such as procaine, lidocaine, and mepivacaine

Local Anesthetics • Potency is related to lipid solubility, because 90% of the nerve cell membrane is composed of lipid. This improve transit into the cell membrane. • the agent must retain sufficient water solubility to diffuse to the site of action on the neuronal membrane. • The smaller and more lipophilic the local anesthetic, the faster the rate of interaction with the sodium channel receptor.

Lidocaine, procaine, and mepivacaine are less • lipid-soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have • longer durations of local anesthetic action.

Local Anesthetics • Protein binding is related to the duration of action. The site of action (the Na channel) is primarily protein in a lipid environment. • Protein binding also plays a part in the availability of the drug as LA binds to lipoproteins in the blood stream. • LA may transfer to fetus

DISTRIBUTION • The amide local anesthetics are widely distributed after intravenous bolus administration. • After an initial rapid distribution phase (brain, liver, kidney, and heart) • slower distribution phase occurs with uptake into ( muscle and the gastrointestinal tract).

Elimination • -(amide type) The local anesthetics are converted in the liver • (ester type)in plasma by pseudo cholinesterase • to more water-soluble metabolites and then they are excreted in the urine.

• The rate of local anesthetic hydrolysis is important, since slow biotransformation may lead to drug accumulation and toxicity. • In patients with atypical plasma cholinesterase, the use of ester linked compounds, such as chloroprocaine, procaine and tetracaine, has an increased potential for toxicity.

• The hydrolysis of all ester-linked local anesthetics leads to the formation of paraaminobenzoic acid (PABA), which is known to be allergenic. • Therefore, some people have allergic reactions to the ester class of local anesthetics.

Local anesthetics - Duration • Determined by rate of elimination of agent from site injected • Factors include • • • 1 - protein binding 2 - lipid solubility 3 - dose given 4 - blood flow at site 5 - addition of vasoconstrictors (does not reliably prolong all agents)

This phenomenon is called differential blockade. • Differential blockade is the result of a number of factors, including 1 - the size of the nerve • 2 - the presence and amount of myelin • 3 - the location of particular fibers within a nerve bundle. • For conduction to be effectively blocked, the local anesthetic must exert its effects over the distance between several nodes of Ranvier. Since the smallest nerves (C fibers) have no myelin, they • can be most easily blocked; thus, sympathetic functions often are blocked soon after a local anesthetic is applied to a particular nerve bundle.

Clinical Uses 1 - Topical Anesthesia (Application to cornea, nasal or oral mucosa). 2 - Infiltration (i. e. , the injection of local anesthetics under the skin). 3 - Regional block, a form of anesthesia that include spinal and epidural anesthesia, involves injection near nerve or nerve plexus proximal to the surgical site. • It provides excellent anesthesia for a variety of procedures.

Clinical Uses 4 - Control of Cardiac Arrhythmias as lidocaine the primary drug for treating cardiac arrhythmias. 5 - Minor operation which need no loss of consciousness. 6 - In combination with general anesthesia in order to decrease the dose of general anesthetics. 7 - Relieve pain and itching.

Adverse Effects • high doses produce CNS stimulation characterized by restlessness, disorientation, tremors, and at times clonic convulsions. • Treatment by drugs to control the seizures. (The ultra –short-acting barbiturates and the benzodiazepine derivatives, such as diazepam) • Continued exposure to high concentrations results in general CNS depression; death occurs from respiratory failure secondary to medullary depression. • Treatment requires ventilatory assistance. • CNS manifestations generally occur before cardiopulmonary collapse.

Adverse Effects • Cardiac toxicity is generally the result of • 1 - drug- induced depression of cardiac conduction (e. g. , AV block, intraventricular conduction block) • and these effects may progress to severe hypotension and cardiac arrest. • 2 - Allergic reactions also may occur.

ESTERS Cocaine: useful in topical use because of the vasoconstriction. • Toxicity prohibits use for other than topical anesthesia. • Cocaine has a rapid onset of action (1 minute) and duration of up to 2 hours, depending on the dose. • The euphoria and cortical stimulation it produces is responsible for the drug’s abuse.

Procaine • It is not effective topically but is employed for infiltration, nerve block, and spinal anesthesia. • It has a relatively slow onset and short (1 hour) duration of action. • It can be combined with epinephrine. Other esters include Benzocaine , Tetracaine , Chloroprocaine.

AMIDES Lidocaine: (Xylocaine) is the most commonly used local anesthetic. • It is well tolerated, used in infiltration, regional nerve blocks, commonly used for spinal and topical anesthesia and as an antiarrhythmic agent. • Lidocaine has more rapid action, more intense and more prolonged duration of action than does procaine.

AMIDES • Bupivacaine: Its use for epidural anesthesia in obstetrics has attracted interest because: 1 - long action, and some nerve blocks last more than 24 hours; this is often an advantage for postoperative analgesia. 2 - it can relieve the pain of labor at concentrations as low as 0. 125% 3 - permitting some motor activity of abdominal muscles to aid in expelling the fetus. 4 - The lower concentration minimizes the possibility of cardiac toxicity. 5 - Fetal drug concentrations remain low, and drug-induced neurobehavioral changes are not observed in the newborn.

• Bupivacaine also is approved for spinal anesthesia • is approximately four times more potent and more toxic than mepivacaine and lidocaine. • It can be used with or without epinephrine. Ropivacaine: It is a recently developed long acting amide-linked local anesthetic. • Its duration of action is similar to that of bupivacaine, but it is slightly less potent. • Other amide include Levobupivacaine, Etidocaine, prilocaine, Mepivacaine,

Properties of Local Anesthetic PROPERTIES Agents ESTERS AMIDES rapid by plasma cholinesterase slow, hepatic Systemic toxicity less likely more likely Allergic reaction possible - PABA derivatives form very rare breaks down in ampules (heat, sun) very stable chemically slow as a general rule moderate to fast higher than PH = 7. 4 (8. 58. 9) close to PH = 7. 4 (7. 6 -8. 1) Metabolism Stability in solution Onset of action p. Ka's