Pharmacology-1 PHL 211 2nd Term 2nd Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Local Anesthetics, Systemic Effects The unintentional intravascular injection of LA agents in dentistry can occur because of high vascularisation in this area Toxicity of LAs is mostly related to their inhibitory effects on excitable cells such as neurons, cardiac muscle, smooth muscle and skeletal muscle cells: CNS Following absorption, LAs cause stimulation of the CNS, producing restlessness and tremors that may progress to convulsion. Central stimulation is followed by depression; death usually is caused by respiratory failure Drowsiness is the most frequent complaint that results from the CNS actions of LAs Cocaine is addictive Both lidocaine and procaine may produce a loss of consciousness Peripheral nervous system LAs affect transmission at the neuromuscular junction and ganglionic synapse. These effects are due to block of the ion channel of the cholinergic receptor by high concentrations of the LAs Smooth muscles LAs depress contractions of intestine, vascular and bronchial smooth muscle

Local Anesthetics, Systemic Effects Cardiovascular system (CVS): Following systemic absorption, LAs act on the CVS: LAs block cardiac sodium channels and thus depress cardiac electrical excitability, conduction rate With the exception of cocaine, LAs depress the strength of cardiac contraction and cause arteriolar dilation, leading to systemic hypotension Cocaine differs from the other LAs: it blocks NE reuptake, resulting in vasoconstriction and hypertension, as well as cardiac arrhythmias Bupivacaine is more cardiotoxic than other LAs and may cause ventricular tachycardia and even cardiovascular collapse. The S-enantiomer (levobupivacaine) is equally efficacious and potent; however, it is less cardiotoxic. Ropivacaine is slightly less potent than bupivacaine in producing anesthesia, but it is less cardiotoxic than bupivacaine. Hypersensitivity to LAs Rare individuals are hypersensitive to LAs. The reaction may manifest itself as an allergic dermatitis or an asthmatic attack Hypersensitivity seems to occur more frequently with LAs of the ester type and frequently extends to chemically related compounds

Local Anesthetics, Individual Drugs, Ester Type Cocaine It is an ester-type LA that occurs in abundance in the leaves of the coca shrub. It is the first LA introduced into medical practice The clinically desired actions of cocaine are the blockade of nerve impulses (see MOA of LAs before), as a consequence of its LA properties, and local vasoconstriction, secondary to inhibition of local NE reuptake (other LAs do not) Toxicity and its potential for abuse have steadily decreased its clinical use Its high toxicity is due to reduced catecholamine uptake in both the CNS and PNS Procaine (Novocain) The first synthetic LA and the prototype of amino ester-type LAs It has been replaced by newer agents, and its use now is confined mainly to infiltration anesthesia. This is due to its low potency, slow onset, and short duration of action While its toxicity is fairly low, it is hydrolyzed in vivo to produce para-aminobenzoic acid, which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs It has a very high potential to cause allergic reactions Tetracaine (Pontocaine) It is a long-acting amino ester LA. It is more potent and has a longer duration of action than procaine. Tetracaine may exhibit increased systemic toxicity (CNS and cardiovascular) because it is more slowly metabolized than the other commonly used ester LAs. Currently, it is widely used in spinal anesthesia when a drug of long duration is needed and as LA to the eye. Tetracaine also is incorporated into several topical anesthetic preparations

Local Anesthetics, Individual Drugs, Amide Type Lidocaine (Xylocaine) Lidocaine is the prototypical amide LA. It is an intermediate-acting LA It produces faster, more intense, longer lasting, and more extensive anesthesia than does an equal concentration of procaine. Lidocaine is an alternative choice for individuals sensitive to ester-type Las. It is still the most widely used LA in America today Lidocaine is absorbed rapidly after parenteral administration. Although it is effective when used without any vasoconstrictor, epinephrine decreases the rate of absorption, such that the toxicity is decreased and the duration of action usually is prolonged The clearance of lidocaine is almost entirely due to liver metabolism The half-life may be prolonged two-fold or more in patients with liver dysfunction Toxicity. The side effects of lidocaine seen with increasing dose include drowsiness, tinnitus, dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest will occur. Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked CNS effects. However, Lidocaine is one of the least cardiotoxic of the currently used LAs Clinical Uses. Lidocaine has a wide range of clinical uses as a LA which include: Dental anesthetic Topical application to relieve itching, burning and pain from skin inflammations, It is used for infiltration anesthesia and for nerve block techniques including peripheral, sympathetic, epidural, and spinal block anesthesia. Lidocaine also is used as an anti-arrhythmic agent (only by the i.v. route; systemic effect)

Local Anesthetics, Individual Drugs, Amide Type, cont.d Bupivacaine (Marcaine) Bupivacaine is a widely used amide LA. It is a potent long-acting LA Its long duration of action plus its tendency to provide more sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period Toxicity. Bupivacaine is more cardiotoxic than equi-effective doses of lidocaine. Clinically, this is manifested by severe ventricular arrhythmias and myocardial depression after inadvertent intravascular administration of large doses of bupivacaine Although lidocaine and bupivacaine both rapidly block cardiac Na+ channels during systole, bupivacaine dissociates much more slowly than does lidocaine during diastole, so a significant fraction of Na+ channels at physiological heart rates remains blocked with bupivacaine at the end of diastole. Bupivacaine-induced cardiac toxicity can be very difficult to treat The S-enantiomer (levobupivacaine) is equally efficacious and potent, however it is less cardiotoxic Ropivacaine (Naropin) It is slightly less potent than bupivacaine in producing anesthesia. It is less cardiotoxic than equi-effective doses of bupivacaine. In clinical studies, ropivacaine appears to be suitable for both epidural and regional anesthesia, with a duration of action similar to that of bupivacaine. It seems to be even more motor-sparing than bupivacaine

Local Anesthetics, Individual Drugs, Amide Type, cont.d Mepivacaine (Carbocaine) Mepivacaine is an intermediate-acting amino amide LA Its pharmacological properties are similar to those of lidocaine. Mepivacaine, however, is more toxic to the neonate and thus is not used in obstetrical anesthesia It has a slightly higher therapeutic index in adults than does lidocaine Its onset of action is similar to that of lidocaine and its duration slightly longer (about 20%) than that of lidocaine in the absence of a co-administered vasoconstrictor Mepivacaine is not effective as a topical anesthetic Prilocaine (Citanest) Prilocaine is an intermediate-acting amino amide LA. It is used in dentistry for infiltration anesthesia and for nerve block anesthesia It has a pharmacological profile similar to that of lidocaine. The primary differences are that it causes little vasodilation and thus can be used without a vasoconstrictor if desired, and its increased volume of distribution reduces its CNS toxicity It is not used for obstetric analgesia because of risk of methaemoglobinaemia from its o-toluidine metabolite (usually appearing after a dose of 8 mg/kg) methaemoglobinaemia can be treated by the i.v. administration of methylene blue (1 to 2 mg/kg)