INVEL FORTE L

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

• Amebiasis
• Trichomoniasis
• Giardiasis
• Anaerobic bacterial infections
• Bacterial vaginosis
• Clostridium difficile infection

Dosage

Children: For children aged 1 month to 11 years, 7.5 mg/kg every 8 hours for 7 days (maximum dose 400 mg). For children aged 12-17 years, 400 mg every 8 hours for 7 days.

Adults: 1 g three times a day for 3 days, then 1 g twice daily for a total treatment duration of 7 days. In cases of Clostridium difficile infection, treatment may extend to 10 days.

Mechanism of action

The exact mechanism of action of metronidazole is not fully established. However, it is believed that anaerobic bacteria and protozoa reduce metronidazole to reactive intermediates that bind to DNA and inhibit nucleic acid synthesis, leading to cell death. Metronidazole is selectively activated in anaerobic conditions, making it effective against obligate anaerobes.

Pharmacodynamics

Metronidazole exhibits both antibacterial and antiprotozoal activities, effectively treating infections caused by anaerobic bacteria. It demonstrates significant antibacterial activity against most obligate anaerobes but is less effective against facultative anaerobes and obligate aerobes. The drug's cytotoxic effects result from DNA strand damage in susceptible microorganisms, which can lead to cell death. Caution is advised due to the potential for peripheral neuropathy and convulsions, especially at higher doses.

Pharmacokinetics

Metronidazole is well absorbed following oral administration and is distributed widely throughout the body, including the central nervous system. It undergoes hepatic metabolism, primarily through oxidation and conjugation, and is excreted mainly in urine. The pharmacokinetic profile may vary in patients with hepatic impairment, and dosage adjustments may be necessary.

Adverse effects

• Peripheral neuropathy
• Convulsions
• Nausea
• Vomiting
• Diarrhea
• Headache
• Dizziness
• Abdominal cramps
• Metallic taste
• Skin rash

Interactions

• Metronidazole + Coumarins: Increases anticoagulant effect
• Metronidazole + Lithium: Increases concentration
• Metronidazole + Busulfan: Increases risk of toxicity (unknown)
• Metronidazole + Capecitabine: Increases risk of capecitabine toxicity (unknown)
• Metronidazole + Fluorouracil: Increases risk of toxicity (unknown)
• Metronidazole + Alkylating agents: Increases risk of toxicity (unknown)

Precautions

• Caution in patients with history of neurological disorders
• Monitor for signs of peripheral neuropathy
• Use with caution in patients with hepatic impairment
• Avoid excessive alcohol consumption during treatment

Pregnancy

No information available; manufacturer advises avoidance unless essential.

Breast-feeding

Amount in milk probably too small to be harmful.

Storage

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

Formulations

• Metronidazole 0.75% gel
• Metronidazole 0.75% cream
• Metronidazole powder and solvent for nebuliser solution
• Metronidazole injection
• Metronidazole oral tablets (various strengths)

Indications

• Vaginal candidiasis
• Oropharyngeal candidiasis
• Vulvovaginal infections
• Superficial fungal infections

Dosage

Adults: For vaginal candidiasis, miconazole cream is typically applied twice daily, using 5 g inserted into the vagina for 7 days. For oropharyngeal candidiasis, the oral gel is usually administered as 2.5 mL four times a day.

Mechanism of action

Miconazole primarily acts through the inhibition of the CYP450 14α-lanosterol demethylase enzyme, leading to disrupted ergosterol production in fungal cell membranes. This disruption results in increased cell membrane permeability and leakage of essential cellular constituents. Additionally, miconazole inhibits fungal peroxidase and catalase, increasing the production of reactive oxygen species (ROS) which contribute to fungal cell death. Miconazole also elevates intracellular levels of farnesol, which disrupts quorum sensing in Candida, preventing the transition to more virulent forms.

Pharmacodynamics

Miconazole is predominantly applied topically, leading to minimal systemic absorption. Its primary adverse reactions are usually localized to hypersensitivity reactions, with the potential for anaphylaxis in rare cases. Patients using intravaginal miconazole are advised to avoid reliance on other contraceptive methods and not to use tampons simultaneously due to the risk of altered vaginal flora.

Pharmacokinetics

Miconazole is poorly absorbed when applied topically or intravaginally, resulting in low systemic exposure. The pharmacokinetics of miconazole can vary based on the route of administration, but systemic absorption is generally low, thus limiting systemic side effects and interactions. Miconazole is extensively metabolized in the liver, and its metabolites are excreted primarily through the urine.

Contra-indications

• Hypersensitivity to miconazole or any of its excipients
• Recent arterial thromboembolic disease (e.g. angina, myocardial infarction)
• Undiagnosed vaginal bleeding
• Oestrogen-dependent tumors (e.g. breast cancer in first-degree relatives)
• Acute porphyrias
• Severe diabetes (increased risk of heart disease)

Adverse effects

• Dysmenorrhoea
• Skin reactions
• Increased risk of gallbladder disease
• Migraine or migraine-like headaches
• Abdominal pain
• Dysuria
• Nausea
• Pelvic cramps
• Vaginal hemorrhage
• Angioedema

Interactions

• Miconazole + antihistamines (non-sedating): Severe (increases exposure)
• Miconazole + mizolastine: Severe (increases exposure)
• Miconazole + oral benzodiazepines: Severe (increases exposure)
• Miconazole + ergometrine: Severe (increases exposure)
• Miconazole + ergotamine: Severe (increases exposure)
• Miconazole + alkylating agents: Moderate (increases concentration)
• Miconazole + busulfan: Moderate (increases concentration)
• Miconazole + antiarrhythmics: Moderate (increases exposure)
• Miconazole + disopyramide: Moderate (increases exposure)
• Miconazole + benzodiazepines: Moderate (increases exposure)

Precautions

• Caution in patients with history of breast cancer
• Monitor breast status regularly in women on oestrogen therapy
• Risk of endometrial cancer with prolonged use of oestrogens
• Risk of ovarian cancer with long-term use of combined HRT
• Increased risk of venous thromboembolism in women using combined or oestrogen-only HRT

Pregnancy

Pregnant women may require a longer duration of treatment, usually about 7 days, to clear the infection. Caution is advised.

Breast-feeding

Manufacturer advises caution; no specific information available.

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

The exact mechanism of action of metronidazole has not been fully established, however, it is possible that an intermediate in the reduction of metronidazole which is only made by anaerobic bacteria and protozoa, binds deoxyribonucleic acid and electron-transport proteins of organisms, blocking nucleic acid synthesis. After administration, metronidazole enters cells by passive diffusion. Following this, ferredoxin or flavodoxin reduce its nitro group to nitro radicals. The redox potential of the electron transport portions of anaerobic or microaerophilic microorganisms renders metronidazole selective to these organisms, which cause nitro group reduction, leading to the production of toxic metabolites. These include N-(2-hydroxyethyl) oxamic acid and acetamide, which may damage DNA of replicating organisms. Microbicidal; active against most obligate anaerobic bacteria and protozoa by undergoing intracellular chemical reduction via mechanisms unique to anaerobic metabolism. Reduced metronidazole, which is cytotoxic but short-lived, interacts with DNA to cause loss of helical structure, strand breakage, and resultant inhibition of nucleic acid synthesis and cell death. Metronidazole is bactericidal, amebicidal, and trichomonacidal in action. The exact mechanism of action of the drug has not been fully elucidated. Metronidazole is un-ionized at physiologic pH and is readily taken up by anaerobic organisms or cells. In susceptible organisms or cells, metronidazole is reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin) to unidentified polar product(s) which lack the nitro group. The reduction product(s) appears to be responsible for the cytotoxic and antimicrobial effects of the drug which include disruption of DNA and inhibition of nucleic acid synthesis. Metronidazole is equally effective against dividing and nondividing cells. In in vivo studies in rats given metronidazole in dosages of 2-4 mg/100 g of body weight, the drug reportedly inhibited the development of formalin-induced edema in the rat paw. In vitro in neutrophils, metronidazole has a dose-dependent inhibitory effect on generation of hydrogen peroxide and hydroxyl radicals, oxidants that may cause tissue injury at the site of inflammation. This antioxidant effect appears to be caused by a direct effect on neutrophil function and may contribute to the drug's anti-inflammatory effect in vivo. Results of in vitro studies using leukocytes obtained from patients with Crohn's disease indicate that exposing the cells to metronidazole concentrations of 10 or 50 mcg/mL improved both spontaneous and induced leukocyte migration in cells that previously exhibited reduced migration; the drug had no effect on leukocytes obtained from healthy adults or patients with Crohn's disease when the cells exhibited normal migration prior to exposure to the drug. This effect on leukocyte migration also was observed in vivo in adults with Crohn's disease who received a single 400-mg dose of metronidazole. It has been suggested that metronidazole may increase leukocyte migration by a direct effect on the leukocytes, possibly by causing the release of surface-bound immune complexes from the cell surface.

Pharmacodynamics

Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities. Metronidazole is an effective treatment for some anaerobic bacterial infections. Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes. The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses. If convulsions or numbness of an extremity occur, discontinue the drug immediately. Metronidazole has been found to be carcinogenic in mice and rats. The relevance to this effect in humans is unknown. It is advisable to only administer metronidazole when clinically necessary and only for its approved indications.

Mechanism of action

Miconazole is an azole antifungal used to treat a variety of conditions, including those caused by _Candida_ overgrowth. Unique among the azoles, miconazole is thought to act through three main mechanisms. The primary mechanism of action is through inhibition of the CYP450 14α-lanosterol demethylase enzyme, which results in altered ergosterol production and impaired cell membrane composition and permeability, which in turn leads to cation, phosphate, and low molecular weight protein leakage. In addition, miconazole inhibits fungal peroxidase and catalase while not affecting NADH oxidase activity, leading to increased production of reactive oxygen species (ROS). Increased intracellular ROS leads to downstream pleiotropic effects and eventual apoptosis. Lastly, likely as a result of lanosterol demethylation inhibition, miconazole causes a rise in intracellular levels of farnesol. This molecule participates in quorum sensing in _Candida_, preventing the transition from yeast to mycelial forms and thereby the formation of biofilms, which are more resistant to antibiotics. In addition, farnesol is an inhibitor of drug efflux ABC transporters, namely _Candida_ CaCdr1p and CaCdr2p, which may additionally contribute to increased effectiveness of azole drugs.

Pharmacodynamics

Miconazole is an azole antifungal that functions primarily through inhibition of a specific demethylase within the CYP450 complex. As miconazole is typically applied topically and is minimally absorbed into the systemic circulation following application, the majority of patient reactions are limited to hypersensitivity and cases of anaphylaxis. Patients using intravaginal miconazole products are advised not to rely on contraceptives to prevent pregnancy and sexually transmitted infections, as well as not to use tampons concurrently.

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.