Local anesthetics Assistant Professor Dr. Hayder B Sahib PhD, 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 conductionalong 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 cytoplasmand block the channel in a time- and 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 pH • 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 its 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 includeLevobupivacaine, Etidocaine, prilocaine, Mepivacaine,