PHARMACOLOGICAL DESCRIPTION OF LOCAL ANAESTHETICS Local anaesthetics (an-non, aesthesis-sensitivity, pain) at the site of injection decrease reversibly the sensitivity of nerve endings and/or block nerve impulse formation and conduction through the nerve fibers. First of all LAs decrease pain sensation, then other types of sensation. As LAs mainly inhibit pain receptors and sensory nerve fibers, that`s why practically are used in the certain part of body to inhibit pain sensation. Action mechanism LAs in the sensory nerve fibers block potential–dependent Na channels. LAs consist of 3 parts – aromatic ring, hydrophyllic group and intermediate chain, which can be either etheric or amide. Aromatic ring determines drug lipophylicy (entrance through tissues), amine group – affinity toward receptors, intermediate etheric or amide chain - effect duration. For the optimal activity the ratio between lipophylic and hydrophyllic groups is necessary. LAs are weak basis. They are used as hydrochloride salts to increase their solubility and stability in the water. In tissues` weak basic environment (pH=7.4) they are hydrolyzed releasing free basis. The free basis are solved in lipid bilayers, have good penetration through nerve endings and nerve fibers, where are transformed into ionized-cationic form. LAs` cationic form interacts with receptors, which are located in the inner site of Na –channels and block channels. LAs block open Na channels increasing their inactivated state. 1 LAs don`t have action on the closed Na channels in the resting state. Selectivity of LAs LAs in the different dosages can block nerve impulse conduction through sensory, autonomic and motor fibers. The sensitivity of nerve fibers toward LAs depends on the nerve fiber myelinization level, frequency of impulse generation, diameter. The most sensitive are nonmyelinated C fibers and myelinated thin A delta fibers, which are generating high frequency and long-lasting action potentials. As a result first of all pain impulses are blocked. In somatic afferent nerves the blockage is going by the following sequence: pain sensation >heat sensation > tactile sensation > deep pressure sensation. 2 In myelinated fibers LAs block impulse conduction in Ranvye nodes, by the way in 3 Ranvye nodes blockade is necessary. The thicker is nerve fiber the more is distance between Ranvye nodes. That`s why tactile, deep pressure sensitivity conducting nerve fibers and motor nerve fibers are less sensitive toward LAs. Besides, motor nerve fibers are less sensitive toward LAs, because they are generating impulses with low frequency and short duration. In the inflammation site, because of acidosis, dissociation of LAs hydrochloride salts and formation of free basis is deteriorated, resulting in the weakening of the action of LAs. Classification of LAs by the chemical structure 1. Esthers Cocaine 3 Procaine (Novocaine) Tetracaine (Dicaine) Anaesthesine (Benzocaine) 2. Amides Lidocaine (Xilocaine) Trimecaine (Mesocaine) Bupivacaine (Marcaine) Articaine (Ultracaine) Pharmacokinetics Estheric LAs are hydrolyzed fastly in blood by pseudocholinesterase enzyme. Their duration of action is 1.5-1 hour. Amide LAs are metabolized in liver by microsomal enzymes. Their duration of action is 2-3 hours. Bupivacaine action duration is 6 hours, leading to long-lasting anaesthetic effect. Demands for LAs: high selectivity of the action, high efficacy for all types of local anaesthesia /universality/, additional vasoconstrictor action, short latent period of action, long duration of action, low toxicity. Types of local anesthesia and drugs Superficial (terminal anesthesia) Superficial anaesthesia is developed due to inhibition of sensory nerve endings (terminals). 4 For superficial anaesthesia are used drugs with high lipophylicy, which have good penetration through pain endings. Usage of LAs on the surface of tongue leads to loss of sensations by the following sequence bitter> sweet > sour > salt Only for the superficial anaesthesia drugs with high toxicity are used, which are not useful for other types of anaesthesia (Cocaine, Tetracaine), also drugs which have bad solubility in water (Anaesthesine). Anaesthesine as ointments and powders is used for the treatment of wounds, as tablets in a case of gastric diseases. Mepivacaine, Bupivacaine, Lidocaine, Trimecaine, Articaine are used also in superficial anaesthesia, because they have sufficient efficacy and low toxicity. By the anaesthetic activity and toxicity there is the following sequence of drugs. Tetracaine>Cocaine>Mepivacaine>Bupivacaine>Benzocaine=Lidocaine=Articaine>Trim ecaine. Superficial anaesthesia is used in opthalmology, for the treatment of burnings, in dentistry and LOR-practice. Conductive anesthesia LAs are injected in the tissues surrounding large nerve trunks. In the trunk`s sensory nerve fibers impulse conduction is blocked, leading to sensory loss (first of all pain sensation) of that part of body which is innervated by the following trunk. 5 In the mixed nerves impulse is inhibited firstly in sensory nerves than in motor nerves. The less is the distance of CNS to the injected site, the more is anesthesia surface. For the conductive anesthesia Bupivacaine, Lidocaine, Articaine, Trimecaine, Procaine is used. The spinal anesthesia is the example of conductive anesthesia. Solutions in small volume are injected in subarachnoid or epidural space. Impulse conduction is inhibited in spinal cord dorsal roots leading to regional anesthesia and myorelaxation. Infiltration anesthesia LAs are injected in the surgical surface layer by layer leading to blockade of sensory nerve endings and sensory nerves. Procaine, Trimecaine, Bupivacaine, Lidocaine, Articaine are used for infiltration anesthesia. 6 Drugs` diluted (0.25 % - 0.5%) solutions with large volume (till 800ml) are used for infiltration anesthesia. The large volume of diluted solution is expanded on the surface, but its` diffusion is insignificant, meanwhile concentrated solution in small volume isn`t expanded well, but has good diffusion. Less toxic drugs are used for infiltration and conductive anesthesia, because LAs can be absorbed having systemic toxic effect. Vasoconstrictors (adrenomimetics - adrenaline, noradrenaline, mesatone, xylometazoline, naphthyzine), vasopressine are used to decrease systemic toxic effect of LAs, to increase their duration of action and to decrease the possibility of bleeding. Overdosage of adrenomimetics increases the possibility of edema development at the site of injection, decreases wound healing, increases blood pressure, leads to arrhythmias development, makes injection more painful. Lidocaine and Articaine are used for all types of anesthesia. Interaction with other drugs Anticholinesterases increases the action of esthers. The product of hydrolysis of esthers – paraaminobenzoic acid decreases the bacteriostatic effect of sulfanylamides. 7 Side effects of LAs 1. Systemic effects All LAs from the site of injection can be absorbed leading to systemic effects. CNS: For the first period all LAs leading to CNS stimulation followed by inhibition. It is explained by the fact that LAs are inhibiting firstly CNS inhibitory neurons. In the higher doses LAs are inhibiting all neurons. At the middle therapeutic concentrations, all LAs have the ability to produce sleepiness, light-headedness, visual and auditory disturbances and restlessness. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and metallic taste. At higher concentrations nystagm and muscular twitching occur, followed by tonic- clonic convulsions. Cardiovascular system The cardiovascular effects of LAs result partly from direct effects on the cardiac and smooth muscle membranes and partly from indirect effects on the autonomic nervous system. LAs also depress the strength of cardiac contraction and cause arteriolar dilation, leading to systemic hypotension. Bupivacaine in high dosages leads to cardiotoxicity and development of collapse. Smooth muscles LAs dilate bronchi, uterus and decrease intestine peristalsis. Allergic reactions The ester-type LAs are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions such as rashes, angioedema, dermatitis, asthma and rarely anaphylaxis. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide LAs are extremely rare. Cocaine Cocaine, an ester of benzoic acid and methylecgonine, obtains from the leaves of the coca shrub. Besides inhibition of transmission through nerve fibers Cocaine has vasoconstrictor effect which is determined by inhibition of NA reuptake. 8 High toxicity is defined by inhibition of NA reuptake in central and peripheral nervous system. Development of Cocaine dependence is defined by DA accumulation in CNS. Cocaine leads to vasoconstriction, hypertension and different types of arrythmias. Vasoconstriction leads to ischemia development at the site of injection, in a case of chronic usage by nasal way it leads to necrosis of nasal mucous membrane, and even to septum perforation. The high toxicity of Cocaine and its` high ability to cause dependence are limiting its` usage. Adstringents These drugs protect nerve endings from the different impulses and substances. Adstringents bind to tissues` proteins leading to formation of colloid substances – albuminates (albuminum - protein). Application of these drugs on tissues leads to formation of strong, nonpermeable cover, which protects nerve endings from the external factors. 9 They have anti-inflammatory