LIDOCEL INJECTION

Indications

• Ventricular arrhythmias, especially after myocardial infarction
• Local anesthesia for minor surgical procedures
• Pain relief in conditions such as oral ulceration and inflammation

Dosage

Children: Refer to the BNF for Children

Adults: For ventricular arrhythmias, an initial intravenous bolus of 100 mg is given over a few minutes, followed by a continuous infusion of 4 mg/minute for 30 minutes, then reduced to 2 mg/minute for 2 hours, and finally to 1 mg/minute. The total dose should not exceed 3 mg/kg.

Mechanism of action

Lidocaine hydrochloride exerts its effects by blocking voltage-gated sodium channels in neurons, which inhibits the influx of sodium ions during depolarization. This action prevents the generation and conduction of nerve impulses, resulting in local anesthesia. The drug also stabilizes neuronal membranes and decreases the excitability of both peripheral and central nerves.

Pharmacodynamics

The onset of action for lidocaine is rapid, typically occurring within minutes of administration, with a duration of action that can vary based on the route of administration and the presence of additives such as epinephrine. Lidocaine can be used to manage ventricular arrhythmias by decreasing myocardial excitability and conduction velocity, thus stabilizing the cardiac rhythm.

Pharmacokinetics

Lidocaine is well-absorbed when administered intravenously, with peak plasma concentrations occurring shortly after infusion. It is extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP1A2 and CYP3A4, producing active metabolites. The elimination half-life of lidocaine ranges from 1.5 to 2 hours, and it is excreted mainly in urine. Caution is advised in cases of hepatic impairment, as the metabolism of lidocaine may be significantly reduced, leading to increased plasma levels.

Contra-indications

• All grades of atrioventricular block
• Severe myocardial depression
• Sino-atrial disorders

Adverse effects

• Anxiety
• Arrhythmias
• Cardiac arrest
• Circulatory collapse
• Confusion
• Dizziness
• Drowsiness
• Euphoric mood
• Headache
• Hypotension (may lead to cardiac arrest)
• Loss of consciousness
• Methaemoglobinaemia
• Muscle twitching
• Nausea
• Neurological disorders
• Tinnitus
• Tremor
• Blurred vision
• Vomiting

Interactions

• Antiarrhythmics

Precautions

• Acute porphyrias (consider infusion of glucose for its anti-porphyrinogenic effects)
• Congestive cardiac failure (consider lower dose)
• Post cardiac surgery (consider lower dose)
• Monitor serum potassium
• Caution in hepatic impairment (risk of increased exposure)
• Caution in renal impairment (possible accumulation of lidocaine and active metabolites)

Pregnancy

Crosses the placenta but not known to be harmful in animal studies-use if benefit outweighs risk.

Breast-feeding

Present in milk but amount too small to be harmful.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Lidocaine hydrochloride 5 mg per 1 ml solution for injection
• Lidocaine hydrochloride 10 mg per 1 ml solution for injection
• Lidocaine hydrochloride 10% solution for oral use

Indications

• Anaphylaxis
• Cardiac arrest
• Severe asthma exacerbations
• Croup
• Vasodilatory shock

Dosage

Adults: For anaphylaxis, 0.5 mg (0.5 mL of 1:1000 solution) intramuscularly may be administered. In cardiac arrest, 1

Mechanism of action

Epinephrine acts on alpha and beta-adrenergic receptors. It minimizes vasodilation and increases vascular permeability during anaphylaxis, counteracting hypotension. Additionally, it relaxes bronchial smooth muscle, alleviating bronchospasm and wheezing. Its positive inotropic and chronotropic effects increase myocardial contractility and heart rate, respectively. The drug also raises blood sugar levels through glycogenolysis in the liver and acts as a histamine antagonist, beneficial in allergic reactions.

Pharmacodynamics

Epinephrine mimics sympathetic nervous system actions, increasing heart rate, myocardial contractility, and renin release via beta-1 receptors. Its beta-2 effects produce bronchodilation, aiding in asthma treatment. In croup, nebulized epinephrine results in significant symptom reduction. It also alleviates pruritus, urticaria, and angioedema, and relaxes smooth muscle in the gastrointestinal and genitourinary tracts, enhancing its efficacy in anaphylaxis.

Pharmacokinetics

Epinephrine is rapidly absorbed and has a short duration of action. It is metabolized mainly by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in the liver and other tissues. The onset of action occurs within minutes when administered parenterally, while the effects may last for several minutes, depending on the route of administration. The drug is excreted mainly in the urine as metabolites.

Contra-indications

• Hypersensitivity to adrenaline or any of its components
• In patients with narrow-angle glaucoma
• During general anaesthesia with halogenated hydrocarbons
• In cases of cardiomyopathy or ventricular tachyarrhythmias

Adverse effects

• Tachycardia
• Hypertension
• Anxiety
• Tremors
• Headache
• Nausea
• Vomiting
• Palpitations

Interactions

• Betablockers, selective: Increases risk of hypertension and bradycardia
• Entacapone: Increases risk of cardiovascular adverse effects
• Opicapone: Increases risk of cardiovascular adverse effects
• Tolcapone: Increases effects

Precautions

• Caution in patients with cardiovascular disease
• Caution in patients with hyperthyroidism
• Caution in patients with diabetes mellitus due to glycemic effects
• Monitor patients for potential adverse cardiovascular effects

Pregnancy

Epinephrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It crosses the placenta.

Breast-feeding

Epinephrine is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, protected from light. Do not freeze.

Formulations

• Injection solution (1:1000, 1:10,000)
• Inhalation solution
• Auto-injector device

Indications

• Local anesthesia for surgical and diagnostic procedures
• Management of certain types of arrhythmias
• Topical anesthesia for mucosal surfaces

Dosage

Children: Refer to the BNF for Children for specific pediatric dosing information.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Lidocaine acts by diffusing through neural sheaths into the axoplasm, where it is ionized and binds reversibly to sodium ion channels on nerve cell membranes. This binding keeps the channels in an open state, preventing nerve depolarization and thus blocking action potential transmission. This mechanism facilitates its anesthetic effects by aborting pain signal generation and preventing their transmission to the brain.

Pharmacodynamics

Excessive blood levels of lidocaine may lead to changes in cardiac output, total peripheral resistance, and mean arterial pressure. The block of autonomic fibers and the direct depressant effect on the cardiovascular system can cause hypotension when recommended dosages are exceeded. Lidocaine's action on sodium channels affects cardiac myocytes, potentially leading to hypotension, bradycardia, myocardial depression, arrhythmias, or even cardiac arrest.

Pharmacokinetics

Lidocaine is absorbed rapidly and widely distributed throughout the body. It undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, leading to various metabolites. Its elimination half-life is approximately 1.5 to 2 hours, but this can vary based on factors such as hepatic blood flow and enzyme activity.

Contra-indications

• Hypersensitivity to lidocaine or any amide local anesthetics
• Severe degree of heart block
• A history of malignant hyperthermia

Adverse effects

• Hypotension
• Bradycardia
• Myocardial depression
• Cardiac arrhythmias
• CNS stimulation followed by depression
• Dizziness
• Nausea
• Vomiting
• Tinnitus

Interactions

• cimetidine+lidocaine: Moderate (increases exposure)
• cobicistat+lidocaine: Unknown (increases concentration)
• lidocaine+suxamethonium: Unknown (increases effects)
• ciprofloxacin+lidocaine: Unknown (increases exposure)

Precautions

• Use with caution in patients with hepatic impairment
• Use with caution in patients with cardiac conditions
• Monitor for signs of systemic toxicity, especially after high doses or rapid administration

Pregnancy

Lidocaine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is categorized as FDA pregnancy category B.

Breast-feeding

Lidocaine is excreted in breast milk, but at therapeutic doses, it is not expected to cause adverse effects in nursing infants. Monitor infants for any signs of sedation.

Storage

Store at room temperature, away from moisture and heat. Protect from light. Do not freeze.

Formulations

• Lidocaine injection solution
• Lidocaine cream
• Lidocaine gel
• Lidocaine patch

Mechanism of action

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. The mechanism of rise in blood pressure ... is threefold: a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic action), vasoconstriction in many vascular beds, especially in precapillary resistance vessels of skin, mucosa, and kidney, along with marked constriction of veins. ... Epinephrine affects respiration primarily by relaxing bronchial muscle. It has a powerful bronchodilator action, most evident when bronchial muscle is contracted because of disease, as in bronchial asthma, or in response to drugs or various autacoids. In such situations, epinephrine has a striking therapeutic effect as a physiological antagonist to substances that cause bronchoconstriction. The beneficial effects of epinephrine in asthma also may arise from inhibition of antigen-induced release of inflammatory mediators from mast cells, and to a lesser extent from diminution of bronchial secretions and congestion within the mucosa. Inhibition of mast cell secretion is mediated by beta2 receptors, while the effects on the mucosa are mediated by alpha receptors The electrophysiologic effects of circulating epinephrine in humans were examined in four study groups of 10 subjects each. In 10 subjects without structural heart disease (Group 1) and in 10 patients with coronary disease or dilated cardiomyopathy (Group 2) epinephrine infusion at 25 and 50 ng/kg body weight per min for 14 min resulted in an elevation of the plasma epinephrine concentration in the physiologic range. In both groups it produced a dose-dependent decrease in the effective refractory period of the atrium, atrioventricular node and ventricle and improvement in atrioventricular node conduction. Epinephrine facilitated the induction of sustained ventricular tachycardia in 3 of the 20 subjects. In Group 3, a beta-adrenergic blocking dose of propranolol was added to the infusion of 50 ng/kg per min of epinephrine. Propranolol not only reversed the effects of epinephrine, but also lengthened these variables compared with baseline values. In group 4, propranolol was administered first, followed by 50 ng/kg per min of epinephrine. Propranolol alone slowed atrioventricular node conduction and mildly prolonged the refractory periods. In the presence of beta-blockade, epinephrine had no effect on atrioventricular node properties but resulted in a lengthening of the atrial and ventricular effective refractory periods. In conclusion, epinephrine in physioloic doses shortens the effective refractory period of the atrium, atrioventricular node and ventricle, improves atrioventricular node conduction and may facilitate the induction of sustained ventricular tachycardia. The overall electrophysiologic effects of epinephrine result from stimulation of beta-receptors. Stimulation of alpha-receptors by epinephrine has no effect on the atrioventricular node but prolongs the effective refractory period of the atrium and ventricle, partially offsetting the shortening of refractory periods mediated by beta-receptor stimulation. Epinephrine

Pharmacodynamics

Epinephrine is a sympathomimetic drug. It causes an adrenergic receptive mechanism on effector cells and mimics all actions of the sympathetic nervous system except those on the facial arteries and sweat glands. Important effects of epinephrine include increased heart rate, myocardial contractility, and renin release via beta-1 receptors. Beta-2 effects produce bronchodilation which may be useful as an adjunct treatment of asthma exacerbations as well as vasodilation, tocolysis, and increased aqueous humor production. In croup, nebulized epinephrine is associated with both clinically and statistically significant transient reduction of croup symptoms 30 minutes post-treatment. Epinephrine also alleviates pruritus, urticaria, and angioedema and may be helpful in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxing effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

Mechanism of action

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. Abnormal, repetitive impulse firing arising from incomplete inactivation of Na+ channels may be involved in several diseases of muscle and nerve, including familial myotonias and neuropathic pain syndromes. Systemic local anesthetics have been shown to have clinical efficacy against myotonias and some forms of neuropathic pain, so we sought to develop an in vitro model to examine the cellular basis for these drugs' effects. In frog sciatic nerves, studied in vitro by the sucrose-gap method, peptide alpha-toxins from sea anemone (ATXII) or scorpion (LQIIa) venom, which inhibit Na+ channel inactivation, induced repetitively firing compound action potentials (CAPs) superimposed on a plateau depolarization lasting several seconds. The initial spike of the CAP was unaffected, but the plateau and repetitive firing were strongly suppressed by 5-30 uM lidocaine. Lidocaine caused a rapid, concentration-dependent decay of the plateau, quantitatively consistent with blockade of open Na(+) channels. Early and late repetitive firing were equally suppressed by lidocaine with IC50 = 10 uM. After washout of lidocaine and LQIIa, the plateau and repetitive firing remained for > 1 hr, showing that lidocaine had not caused dissociation of channel-bound alpha-toxin. These findings indicate that therapeutic concentrations of lidocaine can reverse the "abnormal" features of action potentials caused by non-inactivating Na+ channels without affecting the normal spike component. Lidocaine controls ventricular arrhythmias by suppressing automaticity in the His-Purkinje system and by suppressing spontaneous depolarization of the ventricles during diastole. These effects occur at lidocaine concentrations that do not suppress automaticity of the sinoatrial (SA) node. At therapeutic plasma concentrations, lidocaine has little effect on atrioventricular (AV) node conduction and His-Purkinje conduction in the normal heart. Specialized conducting tissues of the atria are less sensitive to the effects of lidocaine than are those of ventricular tissues. Lidocaine has a variable effect on the effective refractory period (ERP) of the AV node; the drug shortens the ERP and the action potential duration of the His-Purkinje system. Lidocaine does not appear to affect excitability of normal cardiac tissue. Prilocaine and lidocaine are classified as amide-type local anesthetics for which serious adverse effects include methemoglobinemia. Although the hydroly

Pharmacodynamics

Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels.