Local anesthetics and additives
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Local anesthetics work by blocking sodium channels and inhibiting nerve impulse conduction. The document discusses the mechanism of action, classification of nerve fibers, pharmacokinetics, pharmacodynamics, effects on organ systems, clinical profiles of various local anesthetics, and additives that are commonly used. Toxicity can occur if maximum doses are exceeded, if there is inadvertent intravascular injection, or in susceptible patients.
Local anesthetics and additives
- 1. Resident: B.Ankhzaya (MNUMS) Local Anesthetics and Additives
- 2. 1. Mechanism of action of LA 2. Structure and Function 3. Pharmacokinetics of LA 4. Pharmacodynamics of LA 5. Effects of organ systems 6. Clinical profile of LA 7. Additives of LA 8. Toxicity of LA 9. Drugs Content
- 3. Local and regional anesthesia and analgesia techniques depend on a group of drugs—local anesthetics—that transiently inhibit sensory, motor, or autonomic nerve function, or a combination of these functions, when the drugs are injected or applied near neural tissue.
- 4. Mechanism of action of LA CLASSIFICATION OF NERVE FIBERS Classification Diameter(µ) Myelin Conduction(m/sec) Location Function A-α 6–22 + 30–120 Afferents/ efferents for muscles and joints Motor A- α 6–22 + 30–120 Proprioception A-β 5-12 + 30-70 Touch , pressure A-γ 3–6 + 15–35 Efferent to muscle spindle Muscle tone A-δ 1–4 + 5–25 Afferent sensory nerve Pain, touch, temperature B <3 +/- 3–15 Preganglionic sympathetic Autonomic function C /sympathetic/ 0.3–1.3 – 0.7–1.3 Postgang lionicsympathetic Afferent sensory nerve Autonomic function Pain, temperature C/dorsal root/ 0.4-1.2 - 0.5-2 Pain,temperature
- 6. • LAs disrupt conduction of impulses along nerve axons by inhibiting the action of sodium channels required for cellular depolarization. • In addition, LAs interact with other ionopores and G protein regulated channels suggesting a more complex mechanism of action 1. Sodium (Na+) enters cell via sodium channels. 2. Unionized local anaesthetic (LA) crosses lipid bilayer to enter the cell where it is promptly ionized. 3. Ionized LA blocks the sodium channel from the internal surface, preventing sodium entry and depolarization. LA also inhibits conduction by acting on potassium and calcium channels and G protein-mediated receptors.
- 7. Structure and Function • LAs have a common structure consisting of: • a lipophilic- aromatic ring • a hydrophilic-amine • a ‘link’ molecule which is either an ester or amide bond. • Most LAs are weak bases and are presented in an acidic solution (usually their hydrochloride salt) and the LA molecules are therefore ionized, water-soluble, and stable in solution.
- 8. • The minimum concentration of local anesthetic that will block nerve impulse conduction is affected by several factors, including fiber size, type, and myelination; pH (acidic pH antagonizes block); frequency of nerve stimulation; and electrolyte concentrations (hypokalemia and hypercalcemia antagonize blockade). Absorption: Factors that increase the uptake of LA into the plasma include: Patient factors: • cardiac output (determines perfusion of organs) • hepatic function (affects protein binding and metabolism). Drug properties: • low protein binding • vasodilatory effects: prilocaine > lidocaine > bupivacaine> ropivacaine > cocaine Site: • intercostal > epidural > plexus/nerve > subcutaneous. Pharmacokinetics of LA
- 9. Distribution: • Highly perfused organs (heart &brain) Metabolism & Excretion Esters- are metabolized in the body by plasma cholinesterase and other nonspecifc esterases, except cocaine which is metabolized in the liver by ester hydrolysis and demethylation. • Metabolites of ester LAs are excreted by the kidneys. • A breakdown product of ester LAs is para-amino benzoic acid (PABA), which is implicated in the high incidence of allergic reactions to these agents Amides- undergo phase I and II metabolism in the liver via the cytochrome p450 system. • Allergic responses are rarely associated with these agents. • Metabolism of amides is slower than esters, leading to a longer half-life and greater potential to accumulate if given as an infusion or repeated doses. • The amide bond is stronger than the ester, allowing amide LAs to be stored for longer and even withstand autoclaving. • Prilocaine (an amide) is further metabolized in the lungs to produce o-toluidine which in high doses can induce methaemoglobinaemia. Pharmacokinetics of LA
- 11. Onset of Action • The onset of action is dependent on the relative concentrations of unionized (lipophilic) and ionized (hydrophilic) LA molecules. Onset time is quicker in LAs where the proportion of unionized molecules is greater. (e.g For example, let us compare bupivacaine to lidocaine. Bupivacaine has a higher pKa than lidocaine; and is therefore a stronger base and more highly ionized at body pH. 85% of bupivacaine molecules are ionized at pH 7.4 compared to 72% of lidocaine, thus explaining the faster onset of action of lidocaine. Duration of Action • The duration of action of LAs is directly related to protein binding, agents which exhibit greater protein binding have a longer duration of action, e.g. bupivacaine. • Vascularity of the site of injection and the vasodilatory properties of the LA also influence duration of action. For example, lidocaine causes localized vasodilatation which leads to i uptake of the drug away from the site reducing the duration of action. Potency • The potency of LAs in vitro is determined by lipid solubility. Highly lipid-soluble LAs can enter the cell easily to act on sodium channels, and therefore a smaller quantity of drug is required. • However, other factors influence this relationship in vivo, e.g. vascularity of the area and the vasodilatory properties of the drug. Bupivacaine is more potent than lidocaine,because it is more lipophilic. Pharmacodynamics of LA
- 12. % Ionized (at Ph 7.4) 97 93 76 76 61 83 83
- 13. Effects of organ system(CNS) • Local anesthetics readily cross the blood–brain barrier, and generalized CNS toxicity may occur from systemic absorption or direct vascular injection. • Early symptoms include circumoral numbness, tongue paresthesia, dizziness, tinnitus, and blurred vision. • Excitatory signs include restlessness, agitation, nervousness, garrulousness, and a feeling of “impending doom.” • Central nervous system depression (eg, coma and respiratory arrest) • Tonic–clonic seizures • Potent, highly lipid-soluble local anesthetics produce seizures at lower blood concentrations than less potent agents. • local anesthetics such as lidocaine (1.5 mg/kg) can decrease cerebral blood flow and attenuate the rise in intracranial pressure • Cocaine- euphoria (overdose is heralded by restlessness, emesis, tremors, convulsions, arrhythmias, respiratory failure, and cardiac arrest ) • Transient neurological symptoms, which consist of dysesthesia, burning pain, and aching in the lower extremities and buttocks, have been reported following spinal anesthesia with a variety of local anesthetic agents, most commonly after use of lidocaine for outpatient spinal anesthesia in men undergoing surgery in the lithotomy position.
- 15. • Lidocaine-Infusions of lidocaine and procaine have been used to supplement general anesthetic techniques, as they are capable of reducing the MAC of volatile anestheticsby up to 40%. Infusions of lidocaine inhibit inflammation and reduce postoperative pain. Infused lidocaine reduces postoperative opioid requirements sufficiently to reduce length of stay after colorectal or open prostate surgery. • Bupivacain -one of the toxic effects on the heart of bupivacaine (in particular) is to inhibit the transportation of lipid substrates (for metabolism) into the cardiac myocytes. • Ropivacaine- Ropivacaine shares many physicochemical properties with bupivacaine. Onset time and duration of action are similar, but ropivacaine produces less motor block when injected at the same volume and concentration as bupivacaine (which may reflect an overall lower potency as compared with bupivacaine). • Levobupivacaine, the S(-) isomer of bupivacaine, which is no longer available in the United States, was reported to have fewer cardiovascular and cerebral side effects than the racemic mixture; studies suggest its cardiovascular effects may approximate those of ropivacaine. • Cocaine- Cocaine’s cardiovascular reactions are unlike those of any other local anesthetic. Adrenergic nerve terminals normally reabsorb norepinephrine afer its release. Cocaine inhibits this reuptake, thereby potentiating the effects of adrenergic stimulation. Cardiovascular responses to cocaine include hypertension and ventricular ectopy. Special of Drugs
- 16. • Apnea- can result from phrenic and intercostal nerve paralysis or depression of the medullary respiratory center (as may occur after retrobulbar blocks ) • Relax bronchial smooth muscle (Intravenous lidocaine (1.5 mg/kg) may be effective in blocking the reflex bronchoconstriction sometimes associated with intubation ) • Lidocaine (or any other inhaled agent) administered as an aerosol can lead to bronchospasm in some patients with reactive airway disease Effects of organ system (Respiratory) Effects of organ system (CVS) • All local anesthetics except cocaine produce smooth muscle relaxation at higher concentrations, which may cause some degree of arteriolar vasodilation. • Myocardial contractility and conduction velocity are also depressed at higher concentrations. • At increased blood concentrations the combination of arrhythmias, heart block, depression of ventricular contractility, and hypotension may culminate in cardiac arrest. • Myocardial contractility and arterial blood pressure are generally unaffected by the usual intravenous doses.
- 17. • Lidocaine mildly depresses normal blood coagulation (reduced thrombosis and decreased platelet aggregation). Effects of organ system (Hematological) Unintentional intravascular injection of bupivacaine during regional anesthesia may produce severe cardiovascular toxicity, including left ventricular depression, atrioventricular heart block, and life-threatening arrhythmias such as ventricular tachycardia and fibrillation. Pregnancy, hypoxemia, and respiratory acidosis are predisposing risk factors. Young children may also be at increased risk of toxicity.
- 18. • Esters appear more likely to induce a true allergic reaction (due to IgG or IgE antibodies) especially if they are derivatives (eg, procaine or benzocaine) of p-aminobenzoic acid, a known allergen. • Commercial multidose preparations of amides often contain methylparaben, which has a chemical structure vaguely similar to that of PABA. Effects of organ system (Immunological) Effects of organ system (Musculoskeletal) • When directly injected into skeletal muscle (eg, trigger-point injection treatment of myofascial pain), local anesthetics are mildly myotoxic. • Regeneration usually occurs 3–4 weeks after local anesthetic injection into muscle. Concomitant steroid or epinephrine injection worsens the myonecrosis.
- 19. Clinical profile of LA
- 20. Clinical profile of LA Maximum dose (mg/kg) 3 4.5 7(with epinephrine ) 4.5 7(with epinephrine ) 8 3 - NA 12 3 12 3
- 21. • Vasoconstrictors (Epinephrine)-Never add vasoconstrictors to LA when injecting near to an end artery, e.g. digits or penis, as this may cause irreversible, ischaemic damage. Many practitioners will also avoid vasoconstrictor containing LA solutions around the sciatic nerve due to a perceived poor blood supply. Typically, epinephrine is added in a concentration of 1:200,000 or 5 micrograms per mL, up to a maximum absolute dose of 200 micrograms (total of 40 mL 1:200,000 solution delivered). To prepare this concentration, use a 1mL syringe to draw up an ampoule of 1:1000 epinephrine (i.e. 1mg/mL epinephrine). Add 0.1 mL epinephrine to each 20mL LA. • Clonidine -Clonidine is primarily an α2-agonist; a dose of 1–2 micrograms/kg intensifies and prolongs sensory and motor blockade in both central and peripheral nerve blocks. Side effects include sedation and hypotension. • Glucose -Glucose (usually 80mg/mL) is added to LAs to produce a hyperbaric solution for spinal anaesthesia. Together with patient positioning, this provides more reliable spread of LA in the intrathecal space compared with isobaric solutions. Additives of LA
- 22. • Opioids (especially buprenorphine)-added to the local anesthetic solution placed into the epidural or subarachnoid space result in synergistic analgesia and anesthesia without increasing the risk of toxicity • Sodium bicarbonate Addition of sodium bicarbonate increases the pH of the solution thereby increasing the proportion of unionized LA molecules, which hastens the onset of action. Excessive bicarbonate can lead to precipitation of the unionized insoluble LA. • Steroids. Combined with intermediate- to long-acting local anesthetics, dexamethasone extends the duration of analgesia by approximately 50% after utilization of the supraclavicular or interscalene approach for brachial plexus block Additives of LA
- 23. Drugs /Esters / Chloroprocaine 1%,2%,3% Cocaine 4%, 10%
- 24. Procaine 1%, 2%, 10% Tetracaine (amethocaine) 0.2%, 0.3%, 0.5% ,1%,2% Drugs /Esters / Benzocaine 20%
- 25. Bupivacaine (Marcaine) 0.25%,0.5%,0.75% Levobupivacaine 0.25% 0.5% Drugs /Amides /
- 26. Mepivacaine 1% 1.5% 2% 3% Prilocaine 0.5%, 2% , 3%, 4% Drugs /Amides /
- 27. Ropivacaine 0.2% 0.5% 0.75% 1% Drugs /Amides / Lidocaine (lignocaine) 0.5% , 1%,1.5%, 2%, 4%, 5%
- 28. • Tonicaine -s a charged derivative of lidocaine and has shown a prolonged duration of action after subcutaneous infltration in animals • Sameridine-is a LA which is also an opioid receptors agonist and may provide additional postoperative analgesia. • Butyl amino-benzoate -was originally discovered in 1923, but a new formulation has produced a poorly soluble agent with a low pKa which appears selective for Aδ and C nerve fbres. Drugs
- 29. • Toxicity is estimated to occur 1 in 1000-10000 blocks. Causes: o Drug overdose (exceeding maximum doses). o Inadvertent intravascular injection: • needle tip in blood vessel • epidural vein cannulation • connection of LA infusions to IV cannula. o Rapid absorption of bolus dose. o Cumulative effect of infusions or repeated doses. o Susceptible patients (metabolic mitochondrial defects, pre-existing cardiac conduction blocks) may be at higher risk of toxicity. Toxicity of LA
- 30. • In fact, widely used LAs are all amphipathic (they have hydrophobic and hydrophilic moieties) so they are apt to bind both hydrophilic proteins (dissolved in cytosol) and hydrophobic proteins (dissolved in the lipid bilayer of the cell or organelle wall). • More specifcally, LAs have been shown to bind voltage-gated potassium and calcium channels as well as sodium channels and also inhibit intracellular signal transduction after G protein activation. Mechanism
- 31. • Inhibition of voltage-gated calcium channels slows cardiac automaticity (bradycardia) and conduction (conduction block). • Inhibition of voltage-gated sodium and potassium channels slows action potential propagation and repolarization, promoting re- entrant tachycardia before asystole supervenes. Mechanism
- 32. • local anaesthetic systemic toxicity (LAST) Clinical Presentation
- 35. Timing of lipid emulsion • Other clinicians have reported using lipid treatment successfully in cardiac collapse before frank cardiac arrest. • So the threshold for treatment with lipid is currently unclear, but it is sensible not to wait for full circulatory arrest to occur before giving lipid emulsion. Treatment • If, alternatively, the lipid has some metabolic effect, then adding an infusion would be rational. However, to date, patients that have received large doses of lipid emulsion have not reported any side effects
- 38. Mechanism of Lipid emulsion Lipid emulsion may act as a ‘lipid sink’, binding free LA molecules and thus reducing plasma concentration below toxic levels.
- 39. Lipid emulsion
- 40. • Epinephrine • Amiodarone • Muscle-relaxation Role of other drugs during resuscitation
- 41. Excessive doses Inadvertent intravascular injection • A small local anesthetic test dose 3ml • Frequetly aspiration • Slow injection or fractionation of the dose of LA Prevention
- 42. 1. file:///C:/Users/enkhbat/Documents/Resident%20Ankhzaya's%20files/Books%20of%20Anesthesiology/ Regional_Anaesthesia,_Stimulation,_and_Ultrasound_Techniques.pdf 2. file:///C:/Users/enkhbat/Documents/Resident%20Ankhzaya's%20files/Books%20of%20Anesthesiology/ Morgan%205th%20Edition.pdf 3. file:///C:/Users/enkhbat/Documents/Resident%20Ankhzaya's%20files/Books%20of%20Anesthesiology/ Barash's%20Handbook%20of%20Clinical%20Anesthesia%207th%20Edition.pdf 4. www.google.com References: