XYLESTESIN-A

Uses

This is used for the production of local anesthesia for dental procedures by nerve block or infiltration techniques. Only accepted procedures for these techniques as described in standard textbooks are recommended.

XYLESTESIN-A is also used to associated treatment for these conditions: Anaphylaxis, Angioneurotic Edema, Bleeding, Bronchospasm, Complete Heart Block, Hypotension, Idiopathic Anaphylaxis, Laryngotracheobronchitis, Mild Intermittent Asthma, Nasal Congestion, Open Angle Glaucoma (OAG), Respiratory Distress, Severe Asthma, Syncope, Urticaria, Uterine Contractions, Ventricular Fibrillation, Resuscitation in cardiac arrest following anesthetic accidents, Serious allergic reactions, Severe hypersensitivity, Unresponsive Asystole, Unresponsive BradycardiaAcute Otitis Media, Anal Fissures, Anorectal discomfort, Arrhythmia, Back Pain Lower Back, Bacterial Vaginosis (BV), Burns, Cervical Syndrome, Earache, Hemorrhoids, Infection, Inflammatory Reaction caused by ear infection-not otherwise specified, Insect Bites, Joint Pain, Mixed Vaginal Infections, Multiple Myeloma (MM), Myringitis, Neuritis, Osteolysis caused by Bone Tumors, Osteoporosis, Otitis Externa, Pain caused by ear infection-not otherwise specified, Pain, Inflammatory, Post-Herpetic Neuralgia (PHN), Postherpetic Neuralgia, Primary Hyperparathyroidism, Rheumatic Diseases, Rheumatic Joint Disease, Sciatica, Skin Irritation, Soft Tissue Inflammation, Sore Throat, Sunburn, Susceptible infections, Trichomonas Vaginitis, Ulcers, Leg, Urethral Strictures, Vulvovaginal Candidiasis, Abrasions, Anal discomfort, Arrhythmia of ventricular origin, Cutaneous lesions, Gum pain, Minor burns, Superficial Wounds, Susceptible Bacterial Infections, Ulceration of the mouth, Viral infections of the external ear canal, Post Myocardial Infarction Treatment, Regional Anesthesia, Local anesthesia therapy

How XYLESTESIN-A works

Epinephrine acts on alpha and beta-adrenergic receptors. Epinephrine acts on alpha and beta receptors and is the strongest alpha receptor activator . Through its action on alpha-adrenergic receptors, epinephrine minimizes the vasodilation and increased the vascular permeability that occurs during anaphylaxis, which can cause the loss of intravascular fluid volume as well as hypotension. Epinephrine relaxes the smooth muscle of the bronchi and iris and is a histamine antagonist, rendering it useful in treating the manifestations of allergic reactions and associated conditions . This drug also produces an increase in blood sugar and increases glycogenolysis in the liver . Through its action on beta-adrenergic receptors, epinephrine leads to bronchial smooth muscle relaxation that helps to relieve bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis .

Lidocaine is a local anesthetic of the amide type . It is used to provide local anesthesia by nerve blockade at various sites in the body . It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action . In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes . At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions . The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization . As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential . This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place .

In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system . After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction .

Dosage

XYLESTESIN-A dosage

Adult: For normal healthy adults, the amount of lidocaine HCl administered should be kept below 500 mg, and in any case, should not exceed 7 mg/kg (3.2 mg/lb) of body weight.

Pediatric: Dosages in pediatric population should be reduced, commensurate with age, body weight and physical condition. It is difficult to recommend a maximum dose of any drug for pediatric patients since this varies as a function of age and weight. For pediatric patients of less than ten years who have a normallean body massand normal body development, the maximum dose may be determined by the application of one of the standard pediatric drug formulas (e.g., Clark's rule). For example, in pediatric patients of five years weighing 50 Ibs, the dose of lidocaine hydrochloride should not exceed 75-100mg when calculated according to Clark's rule. In any case, the maximum dose of lidocaine hydrochloride should not exceed 7 mg/kg (3.2 mg/lb) of body weight.

Side Effects

Anxiety, restlessness, dizziness, headache, palpitations, rapid pulse, tremors, weakness and coldness of the extremities may be reported even with small doses and especially when given in conjunction with local anaesthetics.

Arrhythmia, bradycardia, arterial spasms, CV collapse, oedema, flushing, hert block, hypotension, sinus node suppression, agitation, anxiety, coma, confusion, drowsiness, hallucinations, euphoria, headache, hyperaesthesia, hypoaesthesia, lightheadedness, lethargy, nervousness, psychosis, seizure, slurred speech, unconsciousness, somnolence, nausea, vomiting, metallic taste, tinnitus, disorientation, dizziness, paraesthesia, resp depression and convulsions. Patch: Bruising, depigmentation, petechiae, irritation. Ophth: Conjunctival hyperaemia, corneal epithelial changes, diplopia,visual changes.

Toxicity

Skin, LD₅₀ = 62 mg/kg (rat)

Pregnancy

Epinephrine is teratogenic in rats when given in doses about 25 times the human doses. It is unknown whether epinephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Epinephrine should be given to a pregnant woman only if clearly required in critical situations/emergencies .

Labor and Delivery Parenteral administration of epinephrine, if used as support for blood pressure during low or other spinal anesthesia for delivery, can lead to the acceleration of fetal heart rate and should not be used in obstetrics when maternal blood pressure is higher than 130/80. Epinephrine may delay the second stage of labour.

Common and generalized adverse effects: Transient and minor side effects of anxiety, headache, fear, and palpitations may occur with therapeutic doses of epinephrine, especially in hyperthyroid individuals. Repeated local injections may result in necrosis at sites of injection due to vascular constriction. Cerebral hemorrhage; hemiplegia; subarachnoid hemorrhage; anginal pain in patients with angina pectoris; anxiety; restlessness; throbbing headache; tremor; weakness; dizziness; pallor; respiratory difficulty; palpitation; apprehensiveness; sweating; nausea; vomiting .

Cardiovascular effects: Inadvertently induced high arterial blood pressure may result in angina pectoris (especially when coronary insufficiency is present), cardiac ischemia, or aortic rupture , . Epinephrine may cause serious cardiac arrhythmias in patients not suffering from heart disease and patients with organic heart disease receiving drugs that sensitize the cardiac muscle. With the injection of epinephrine 1:1,000, a paradoxical but transient lowering of blood pressure, bradycardia and apnea may occur immediately post-injection .

Cerebrovascular hemorrhage: Overdosage or accidental I.V. injection of epinephrine may lead to cerebrovascular hemorrhage resulting from the sharp rise in blood pressure .

Renal vasoconstriction: Parenterally administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation. High doses may cause complete renal shutdown .

Pulmonary edema: Fatality may also result from pulmonary edema due to the peripheral constriction and cardiac stimulation produced by epinephrine injection .

Digital vasoconstriction: Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may lead to the loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis .

Symptoms of overdose and/or acute systemic toxicity involves central nervous system toxicity that presents with symptoms of increasing severity . Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus . Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions . These signs must not be mistaken for neurotic behavior . Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes . Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway . In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics . Effects on the cardiovascular system may be seen in severe cases . Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome .

Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women . General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place . Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks . Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother . The ratio of umbilical to maternal venous concentration is 0.5 to 0.6 . The fetus appears to be capable of metabolizing lidocaine at term . The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult . Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery . Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia or respiratory depression may occur .

Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity . The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration . Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function .

Maternal hypotension has resulted from regional anesthesia . Local anesthetics produce vasodilation by blocking sympathetic nerves . Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure . The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable .

Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts . In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation . However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function . The use of obstetrical anesthesia may increase the need for forceps assistance .

The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life . The long-term significance of these observations is unknown . Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis . Fetal heart rate should always be monitored during paracervical anesthesia . The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress . Careful adherence to the recommended dosage is of the utmost importance in obstetrical paracervical block . Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection . Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours . Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication .

It is not known whether this drug is excreted in human milk . Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman .

Dosages in children should be reduced, commensurate with age, body weight and physical condition .

The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats .

Precaution

The solution should not be used if it is pinkish or darker than slightly yellow or if it contains a precipitate. Adrenaline is readily destroyed by alkalies and oxidizing agents. In the latter category are Oxygen, Chlorine, Iodine, Permanganates, Chromates, Nitrites and salts of easily reducible metals, especially Iron. Adrenaline should not be mixed with Sodium bicarbonate; the solution is oxidised to adrenochrome and then forms polymers.

Special warnings and precautions for use

Administer slowly with caution to elderly patients and to patients with ischemic heart disease, hypertension, diabetes mellitus, hyperthyroidism or psychoneurosis. Use with extreme caution in patients with long-standing bronchial asthma and emphysema who have developed degenerative heart disease. Anginal pain may be induced when coronary insufficiency is present.

Patient with pseudocholinesterase deficiency, resp depression. Hepatic and renal impairment. Elderly or debilitated patients. Pregnancy and lactation.

Interaction

Use of Adrenaline with excessive doses of digitalis, mercurial diuretics or other drugs that sensitize the heart to arrhythmias is not recommended. The adverse effects of Adrenaline may be potentiated by tricyclic antidepressants; certain antihistamines; e.g, Diphenhydramine, Tripelennamine, Chlorpheniramine and L-thyroxine Sodium.

May increase serum levels with cimetidine and propranolol. Increased risk of cardiac depression with β-blockers and other antiarrhythmics. Additive cardiac effects with IV phenytoin. Hypokalaemia caused by acetazolamide, loop diuretics and thiazides may antagonise effect of lidocaine. Dose requirements may be increased with long-term use of phenytoin and other enzyme-inducers.

Volume of Distribution

The volume of distribution determined for lidocaine is 0.7 to 1.5 L/kg .

In particular, lidocaine is distributed throughout the total body water . Its rate of disappearance from the blood can be described by a two or possibly even three-compartment model . There is a rapid disappearance (alpha phase) which is believed to be related to uptake by rapidly equilibrating tissues (tissues with high vascular perfusion, for example) . The slower phase is related to distribution to slowly equilibrating tissues (beta phase) and to its metabolism and excretion (gamma phase) .

Lidocaine's distribution is ultimately throughout all body tissues . In general, the more highly perfused organs will show higher concentrations of the agent . The highest percentage of this drug will be found in skeletal muscle, mainly due to the mass of muscle rather than an affinity .

Elimination Route

Following I.V. (intravenous) injection, epinephrine disappears rapidly from the blood stream. Subcutaneously or I.M. (intramuscular) administered epinephrine has a rapid onset and short duration of action. Subcutaneous (SC) administration during asthmatic attacks may produce bronchodilation within 5 to 10 minutes, and maximal effects may occur within 20 minutes. The drug becomes fixed in the tissues rapidly , .

In general, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin . The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream . And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism . After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues .

The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion . Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile . The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue . The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved . There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels .

Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent . Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration .

Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion .

Half Life

The plasma half-life is approximately 2-3 minutes. However, when administered by subcutaneous or intramuscular injection, local vasoconstriction may delay absorption so that epinephrine's effects may last longer than the half-life suggests .

The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2.0 hours . Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics . The half-life may be prolonged two-fold or more in patients with liver dysfunction .

Clearance

Intravenous injection produces an immediate and intensified response. Following intravenous injection, epinephrine disappears rapidly from the blood stream .

The mean systemic clearance observed for intravenously administered lidocaine in a study of 15 adults was approximately 0.64 +/- 0.18 L/min .

Elimination Route

The majority of the dose of epinephrine is seen excreted in the urine , . About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the rest as acetylated derivatives. These metabolites are excreted mainly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted completely unchanged .

The excretion of unchanged lidocaine and its metabolites occurs predominantly via the kidney with less than 5% in the unchanged form appearing in the urine . The renal clearance is inversely related to its protein binding affinity and the pH of the urine . This suggests by the latter that excretion of lidocaine occurs by non-ionic diffusion .

Pregnancy & Breastfeeding use

Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.

Nursing Mother: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman.

Contraindication

This contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any components of the injectable formulations.

Special Warning

Hepatic Impairment Parenteral: Dosage reduction may be needed.

Acute Overdose

Symptoms: Cardiac arrhythmia leading to ventricular fibrillation, severe hypertension leading to pulmonary edema and cerebral hemorrhage.

Treatment: Combined alpha and beta-adrenergic blocking agents such as Labetalol may counteract the effects of adrenaline, or a beta-blocking agent may be used to treat any supraventricular arrhythmias and Phentolamine to control the alpha-mediated effects on the peripheral circulation. Rapidly acting vasodilators such as nitrates and Sodium Nitroprusside may also be helpful. Immediate resuscitation support must be available.

Symptoms: Severe hypotension, asystole, bradycardia, apnoea, seizures, coma, cardiac arrest, resp arrest and death.

Management: Maintain oxygenation, stop convulsion and support the circulation.

Storage Condition

Store at controlled room temperature, below 25°C

Innovators Monograph

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