ANGINOVAG

Indications

• Adrenocortical insufficiency
• Inflammatory bowel disease
• Severe acute asthma
• Acute hypersensitivity reactions
• Congenital adrenal hyperplasia
• Replacement therapy in adrenal insufficiency

Dosage

Children: For children aged 1-5 months: Initially 25 mg 3 times a day, adjusted according to response. For children aged 6 months-5 years: Initially 50 mg 3 times a day, adjusted according to response. For children aged 6-11 years: Initially 100 mg 3 times a day, adjusted

Adults: 100-500 mg 3-4 times a day or when required. For replacement in adrenocortical insufficiency, 20-30 mg once daily, adjusted according to response.

Mechanism of action

Hydrocortisone binds to the glucocorticoid receptor, leading to decreased vasodilation and permeability of capillaries, inhibition of leukocyte migration to inflammation sites, and changes in gene expression that promote anti-inflammatory pathways. It inhibits phospholipase A2, NF-kappa B, and other inflammatory transcription factors, stabilizing leukocyte lysosomal membranes and reducing the release of destructive enzymes. High doses can raise sodium levels and decrease potassium levels through mineralocorticoid receptor activity.

Pharmacodynamics

Hydrocortisone's pharmacodynamic profile includes the inhibition of various inflammatory mediators and the promotion of anti-inflammatory cytokines. Its effects are dose-dependent, with lower doses providing anti-inflammatory benefits, while higher doses exhibit immunosuppressive effects. It has a wide therapeutic index and moderate duration of action.

Pharmacokinetics

Hydrocortisone is metabolized primarily in the liver, with its effects lasting for several hours to days. The onset of action varies with the route of administration, being more rapid when given intravenously. Its half-life is influenced by factors such as dose and administration route, and it is excreted through urine as metabolites.

Contra-indications

• Systemic fungal infections
• Hypersensitivity to hydrocortisone or any excipients

Adverse effects

• Increased risk of infections
• Hyperglycemia
• Hypertension
• Fluid retention and edema
• Gastrointestinal disturbances
• Mood changes
• Osteoporosis
• Peptic ulcer disease
• Cushing's syndrome with long-term use

Interactions

• Mitotane: Moderate decrease in hydrocortisone exposure
• Rifampicin: Moderate decrease in hydrocortisone exposure
• Cobicistat: Unknown effect, potential increase in hydrocortisone exposure
• Idelalisib: Unknown effect, potential increase in hydrocortisone exposure
• Clarithromycin: Unknown effect, potential increase in hydrocortisone exposure

Precautions

• Use with caution in patients with diabetes
• Monitor for signs of infection during therapy
• Consider dose adjustment in patients with hepatic impairment
• Gradual withdrawal is recommended to avoid adrenal insufficiency after prolonged therapy

Pregnancy

Hydrocortisone is categorized as category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Hydrocortisone is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• Injectable form (sodium succinate)
• Modified-release tablets
• Immediate-release tablets

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

• Bacterial vaginosis
• Trichomonal infections
• Other vaginal and vulval infections

Dosage

Adults: For adults aged 18 to 55 years, 10 mg once daily for 6 days, inserted intravaginally.

Mechanism of action

Dequalinium chloride disrupts bacterial cell membranes by diffusing through the cell wall, leading to increased cell permeability. It denatures proteins involved in bacterial metabolism and inhibits mitochondrial ATP synthesis by targeting F1-ATPase, thereby depleting bacterial energy sources. Additionally, it can intercalate into DNA, which may lead to cell lysis. These actions result in rapid bactericidal effects against various pathogens.

Pharmacodynamics

In vitro studies demonstrate that dequalinium is effective against both gram-positive and gram-negative bacteria, as well as fungi and protozoa. It exhibits rapid bactericidal and fungicidal activity, with effects observable within 30 to 60 minutes. Dequalinium's minimal inhibitory concentration (MIC) against relevant vaginal pathogens varies significantly, underscoring its potent antimicrobial properties. Moreover, it has shown potential anticancer effects in human leukemia cells through modulation of signaling pathways.

Pharmacokinetics

Dequalinium is administered intravaginally, where it acts locally with minimal systemic absorption. The pharmacokinetic profile in terms of absorption, distribution, metabolism, and excretion has not been extensively characterized, but its local action limits systemic exposure and potential side effects.

Contra-indications

• Vaginal ulceration
• Increased risk of infection

Adverse effects

• Skin reactions
• Constipation
• Diarrhoea
• Dizziness
• Gastrointestinal discomfort
• Headache
• Increased risk of infection
• Nausea
• Vertigo
• Vomiting
• Vulvovaginal irritation

Interactions

• Damages latex condoms and diaphragms
• Avoid use of non-latex condoms and intravaginal devices

Precautions

• Use during pregnancy only if essential due to limited information available

Pregnancy

Manufacturer advises to avoid unless essential; limited information available.

Storage

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

Formulations

• Dequalinium chloride 10 mg vaginal tablets
• Fluomizin 10 mg vaginal tablets

Indications

• Bacterial infections
• Fungal infections
• Protozoal infections
• Local antiseptic applications
• HIV-1 infection
• Leukemia treatment

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines.

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Dequalinium acts by disrupting bacterial cell permeability upon absorption into the bacterial cell surface. It denatures proteins involved in the respiratory chain and glycolysis, thus impairing bacterial metabolism. The drug inhibits mitochondrial ATP synthesis by blocking bacterial F1-ATPase, leading to energy depletion. Additionally, it intercalates with nucleic acids, potentially causing cell lysis through osmotic imbalance.

Pharmacodynamics

In vitro studies show that dequalinium exhibits rapid bactericidal and fungicidal activity against both gram-positive and gram-negative organisms, with sensitivity varying between species. Its minimal inhibitory concentration (MIC) against vaginal pathogens can range from 0.2 to ≥ 1024 µg/mL. Dequalinium also demonstrates anticancer effects by inducing apoptosis in leukemia cells through modulation of redox balance and downregulation of specific signaling pathways. Furthermore, it has noted antiviral properties, particularly against HIV-1.

Pharmacokinetics

The pharmacokinetics of dequalinium are characterized by rapid uptake by bacteria, leading to effective concentrations at the site of action. Its accumulation in mitochondria contributes to its mechanism as a mitochondrial poison. Specific absorption, distribution, metabolism, and excretion profiles in humans are not well-documented, necessitating cautious use in clinical settings.

Adverse effects

• Local irritation
• Allergic reactions
• Nausea
• Vomiting

Precautions

• Use with caution in patients with known hypersensitivity to dequalinium or quaternary ammonium compounds.
• Monitor for signs of local irritation or allergic reaction.

Pregnancy

There is limited data on the use of dequalinium in pregnancy. Use only if clearly needed and if the benefits outweigh the risks.

Breast-feeding

It is not known whether dequalinium is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Topical solution
• Vaginal tablets

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

Indications

• Superficial skin infections
• Minor cuts
• Skin abrasions
• Infections of the oral cavity

Dosage

Children: For paediatric dosing, refer to the BNF for Children for specific recommendations based on age

Adults: For topical use only. Apply to the affected area 2 to 3 times daily.

Mechanism of action

Tyrocidines have a β-sheet structure that allows them to form dimers, which orient themselves at the membrane-water interface of bacterial cells. The hydrophobic side chains of the dimer interact with the lipid bilayer, disrupting the cell membrane and causing leakage of cellular contents. Tyrocidines also act as reversible non-competitive inhibitors of acetylcholinesterase and β-galactosidase, although the relevance of this to their antibacterial action is not fully understood. Gramcidins, on the other hand, can form β-helices and are capable of transporting monovalent cations through the membrane, further contributing to their bactericidal properties.

Pharmacodynamics

Tyrothricin exerts a bacteriocidal effect due to its ability to disrupt the integrity of bacterial cell membranes. This action clears the area of pathogenic bacteria, facilitating the healing process of wounds and skin damage. The presence of both tyrocidines and gramcidins in tyrothricin enhances its antibacterial efficacy, especially against Gram-positive organisms.

Pharmacokinetics

Tyrothricin is administered topically, and its systemic absorption is minimal, making it effective for localized treatment of infections. Due to its localized action, pharmacokinetic data regarding distribution, metabolism, and excretion are not extensively documented, as the drug primarily acts at the site of application without significant systemic exposure.

Pregnancy

There is limited data available on the use of tyrothricin during pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Tyrothricin may be excreted in breast milk. Caution is advised if the drug is administered to a nursing mother.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Topical ointment
• Topical powder

Mechanism of action

Dequalinium has multiple modes of action. Dequalinium absorbs into the bacterial cell surface and diffuses through the cell wall, disrupting bacterial cell permeability. It is taken up by the bacteria rapidly. Once in the bacteria, dequalinium denatures proteins involved in the respiratory chain and glycolysis of bacteria, interfering with bacterial cell metabolism and ribosomal protein synthesis. By inhibiting bacterial F1-ATPase, dequalinium inhibits mitochondrial ATP synthesis and blocks glucose metabolism. These molecular actions ultimately deplete bacterial energy sources. As dequalinium accumulates in the mitochondria, it is considered a mitochondrial poison. Dequalinium can also precipitate nucleic acids, as it can intercalate one of its quinoline chromophores between DNA base pairs. Depending on the drug concentration, dequalinium can lyse the bacterial cell by promoting osmotic imbalance.

Pharmacodynamics

_In vitro_, dequalinium possesses antimicrobial activity against gram-positive and gram-negative bacteria, yeasts, and protozoa. Dequalinium has a rapid bactericidal and fungicidal action. The antiparasitic and antiviral properties of dequalinium have also been noted. For example, dequalinium can bind to the membrane-proximal external region (MPER) of the spike envelope of the human immunodeficiency virus HIV-1. As with other quaternary ammonium compounds similar to dequalinium, gram-positive bacteria are more sensitive to dequalinium than gram-negative bacteria. The bactericidal and fungicidal effects of dequalinium can occur within 30 to 60 minutes. According to _in vitro_ studies, the minimal inhibitory concentration (MIC) for dequalinium against relevant vaginal pathogens ranges from 0.2 to ≥ 1024 µg/mL. There is evidence that dequalinium exhibits anticancer activity in human leukemia cells: dequalinium induces a cytotoxic effect by altering redox balance, downregulating Raf/MEK/ERK1/2 and PI3K/Akt signalling pathways, and promoting apoptosis of leukemic cells. Dequalinium was also shown to block small conductance Ca²⁺-activated K⁺ channels, called SK channels, which are often expressed in some cancer cells to play a role in cell proliferation and migration. One study showed that dequalinium reduced macrophage motility in mice, inhibiting macrophage infiltration of irradiated tumours and attenuating local metastasis. Interestingly, dequalinium was shown to modulate and induce self-oligomerization of alpha-synuclein, a synaptic protein known to cause aggregates in several neurodegenerative disorders. This finding highlights the neuroprotective actions of dequalinium; however, further investigations are warranted as dequalinium is a neurotoxic agent.

Mechanism of action

The short-term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. Following topical application, corticosteroids produce anti-inflammatory, antipruritic, and vasoconstrictor actions. The activity of the drugs is thought to result at least in part from binding with a steroid receptor. Corticosteroids decrease inflammation by stabilizing leukocyte lysosomal membranes, preventing release of destructive acid hydrolases from leukocytes; inhibiting macrophage accumulation in inflamed areas; reducing leukocyte adhesion to capillary endothelium; reducing capillary wall permeability and edema formation; decreasing complement components; antagonizing histamine activity and release of kinin from substrates; reducing fibroblast proliferation, collagen deposition, and subsequent scar tissue formation; and possibly by other mechanisms as yet unknown. Corticosteroids, especially the fluorinated corticosteroids, have antimitotic activity on cutaneous fibroblasts and the epidermis. /Corticosteroids/ Reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNL) and mononuclear cells (MNC) is inhibited following the intravenous administration of hydrocortisone. This is associated with a parallel decrease in intranuclear NFkappaB, known to modulate inflammatory responses including ROS generation. Plasma levels of interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine produced by TH2 cells, are also increased after hydrocortisone administration. In this study, we have investigated the effect of hydrocortisone on p47(phox) subunit, a key component of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, in MNC and the pharmacodynamics of this effect with ROS generation and plasma IL-10 levels /were investigated/. p47(phox) subunit protein levels in MNC showed a progressive decrease after hydrocortisone administration. It reached a nadir at 4 hours and increased thereafter to a baseline level at 24 hours. ROS generation also decreased, reached a nadir between 2 and 4 hours, and returned to a baseline level at 24 hours. IL-10 concentrations increased, peaked at 4 hours, and reverted to the baseline levels at 24 hours. In conclusion, p47(phox) subunit suppression may contribute to the inhibition of ROS generation in MNC after hydrocortisone administration. This suppression occurs in parallel with the suppression of NFkappaB and an increase in IL-10 plasma levels. Therefore, it would appear that the decrease in intranuclear NFkappaB and an increase in IL-10 may cause the inhibitory modulation on p47(phox) subunit and ROS generation by MNC following hydrocortisone and other glucocorticoids.

Pharmacodynamics

Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such as inhibition of phospholipase A2, NF-kappa B, other inflammatory transcription factors, and the promotion of anti-inflammatory genes. Hydrocortisone has a wide therapeutic index and a moderate duration of action. Patients should stop taking the medication if irritation or sensitization occurs.

Mechanism of action

Dequalinium has multiple modes of action. Dequalinium absorbs into the bacterial cell surface and diffuses through the cell wall, disrupting bacterial cell permeability. It is taken up by the bacteria rapidly. Once in the bacteria, dequalinium denatures proteins involved in the respiratory chain and glycolysis of bacteria, interfering with bacterial cell metabolism and ribosomal protein synthesis. By inhibiting bacterial F1-ATPase, dequalinium inhibits mitochondrial ATP synthesis and blocks glucose metabolism. These molecular actions ultimately deplete bacterial energy sources. As dequalinium accumulates in the mitochondria, it is considered a mitochondrial poison. Dequalinium can also precipitate nucleic acids, as it can intercalate one of its quinoline chromophores between DNA base pairs. Depending on the drug concentration, dequalinium can lyse the bacterial cell by promoting osmotic imbalance.

Pharmacodynamics

_In vitro_, dequalinium possesses antimicrobial activity against gram-positive and gram-negative bacteria, yeasts, and protozoa. Dequalinium has a rapid bactericidal and fungicidal action. The antiparasitic and antiviral properties of dequalinium have also been noted. For example, dequalinium can bind to the membrane-proximal external region (MPER) of the spike envelope of the human immunodeficiency virus HIV-1. As with other quaternary ammonium compounds similar to dequalinium, gram-positive bacteria are more sensitive to dequalinium than gram-negative bacteria. The bactericidal and fungicidal effects of dequalinium can occur within 30 to 60 minutes. According to _in vitro_ studies, the minimal inhibitory concentration (MIC) for dequalinium against relevant vaginal pathogens ranges from 0.2 to ≥ 1024 µg/mL. There is evidence that dequalinium exhibits anticancer activity in human leukemia cells: dequalinium induces a cytotoxic effect by altering redox balance, downregulating Raf/MEK/ERK1/2 and PI3K/Akt signalling pathways, and promoting apoptosis of leukemic cells. Dequalinium was also shown to block small conductance Ca²⁺-activated K⁺ channels, called SK channels, which are often expressed in some cancer cells to play a role in cell proliferation and migration. One study showed that dequalinium reduced macrophage motility in mice, inhibiting macrophage infiltration of irradiated tumours and attenuating local metastasis. Interestingly, dequalinium was shown to modulate and induce self-oligomerization of alpha-synuclein, a synaptic protein known to cause aggregates in several neurodegenerative disorders. This finding highlights the neuroprotective actions of dequalinium; however, further investigations are warranted as dequalinium is a neurotoxic agent.

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.

Mechanism of action

Tyrocidines have a β-sheet structure containing both L and D amino acids. These structural features contribute to the formation of a curved dimer in which most amino acid side chains are located on the convex surface. The dimer orients itself at the membrane-water interface on bacterial cells with the relatively hydrophilic back-bone on the concave side facing the external environment and the many hydrophobic side chains on the convex side facing into the cell's lipid bilayer. The tyrocidine dimer is able to disrupt the cell membrane producing leakage of cell contents but the exact mechanism of this permeabilization is unclear. Tyrocidines appear to act as reversible non-competitive inhibitors of acetylcholinesterase and β-galactosidase. The relation of this to their antibacterial action is unknown. Gramcidins adopt similar β-sheet structures but are capable of forming β-helices. They can either form a double helix, running either parallel or anti-parallel, or a helical dimer wherein the N-termini of each polypeptide meets in the middle of the lipid bilayer. The alternating L and D amino acid structure allows the hydrophobic side chains to point outwards into the lipid bilayer, leaving the more hydrophilic backbone to form the lumen of the pore. The carbonyl oxygen atoms aid in the transport of cations through the pore. In both double helix and helical dimer conformations, gramcidins are capable of transporting monovalent cations through the membrane. Divalent cations result in blockage of the pore or channel when bound. Loss of potassium ions through membrane permeabilization seems to inhibit bacterial growth. Gramcidin also appears to be able to insert into the mitochondial membrane and conduct hydrogen ions. This results in an uncoupling of oxidative phosphorylation from ATP generation due to the loss of the hydrogen ion gradient necessary for H+ATPase function.

Pharmacodynamics

Tyrothricin consists of a mix of tyrocidines and gramcidins which exert a bacteriocidal effect. This clears the area of pathogenic bacteria to allow the body to heal wounds or other damage to the skin.