Ketineal

Indications

• Endogenous Cushing's syndrome
• Cushing's disease
• Topical treatment of fungal infections (limited to specific formulations)

Dosage

Children: For paediatric dosing, refer to the BNF for Children

Adults: For Cushing's syndrome, the maximum dose is 200 mg daily with concurrent use of cobicistat-boosted regimens. The dosing should be adjusted based on patient response and liver enzyme levels.

Mechanism of action

Ketoconazole interacts with 14-alpha-sterol demethylase, a cytochrome P-450 enzyme essential for converting lanosterol to ergosterol. This inhibition results in reduced ergosterol levels in the fungal cell membrane, compromising its integrity and function. The metabolic blockage also leads to the accumulation of toxic sterol precursors, which further disrupt cellular processes. Ketoconazole's fungistatic properties prevent the growth and spread of fungal cells by altering cellular membranes and increasing membrane permeability.

Pharmacodynamics

As a fungistatic agent, ketoconazole halts growth in fungal cells, preventing their proliferation. It primarily targets the ergosterol biosynthesis pathway, which is crucial for maintaining fungal cell membrane integrity. This mechanism leads to increased membrane fluidity, impairing membrane-bound enzyme systems and resulting in growth inhibition of fungal pathogens.

Pharmacokinetics

Ketoconazole is well absorbed when taken orally, but its absorption can be affected by gastric pH. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, leading to various metabolites. The drug has a half-life of approximately 2-8 hours, but this can vary based on dose and individual metabolism. Ketoconazole is excreted mainly through the feces, with some renal excretion of unchanged drug.

Contra-indications

• Acquired QTc prolongation
• Acute porphyrias
• Congenital QTc prolongation
• Cushing's syndrome

Adverse effects

• Dizziness
• Flushing
• Hyperglycaemia
• Diarrhoea
• Gastrointestinal discomfort
• Nausea
• Vomiting
• Skin reactions
• Allergic conditions
• Alopecia
• Angioedema
• Asthenia
• Drowsiness
• Headache
• Thrombocytopenia
• Fever
• Hepatic disorders
• Taste alteration
• Appetite abnormality
• Arthralgia
• Dry mouth
• Epistaxis
• Flatulence
• Fontanelle bulging
• Gynaecomastia
• Hot flush
• Insomnia
• Increased intracranial pressure
• Malaise
• Myalgia
• Nervousness
• Papilloedema
• Paraesthesia
• Peripheral oedema
• Photophobia
• Photosensitivity reaction
• Tongue discolouration

Interactions

• Severe: phenobarbital decreases ketoconazole concentration
• Severe: primidone decreases ketoconazole concentration
• Severe: rifamycins increase ketoconazole concentration
• Severe: rifabutin increases ketoconazole concentration
• Severe: nevirapine decreases ketoconazole exposure
• Severe: rifampicin decreases ketoconazole exposure
• Moderate: anti-androgens increase ketoconazole exposure
• Moderate: darolutamide increases ketoconazole exposure
• Moderate: coumarins increase anticoagulant effect
• Moderate: warfarin increases anticoagulant effect

Precautions

• High dosage may cause proximal myopathy
• Avoid in chronic therapy
• Pre-treatment liver enzymes should not exceed 2 times the normal upper limit
• Risk of adrenal insufficiency

Pregnancy

Manufacturer advises avoid-teratogenic in animal

Indications

• Bowel sterilization before surgery
• Hepatic coma
• Topical infections caused by susceptible organisms

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: By mouth: 1 g every 1 hour for 4 hours, then 1 g every 4 hours for 2–3 days. For hepatic coma: Up to 4 g daily in divided doses usually for 5–7 days.

Mechanism of action

Neomycin sulfate binds to the 30S ribosomal subunit of bacteria, leading to the misreading of mRNA and the inhibition of protein synthesis. This disrupts the production of essential proteins needed for bacterial growth and function, ultimately resulting in cell death.

Pharmacodynamics

Neomycin demonstrates bactericidal activity against susceptible bacteria. Its efficacy is enhanced in alkaline environments, which is why it is often used in combination with other agents for surgical prophylaxis. The drug is primarily effective against a range of gram-negative organisms, including Escherichia coli and Klebsiella species, but also has some activity against gram-positive organisms.

Pharmacokinetics

Neomycin is poorly absorbed from the gastrointestinal tract, and its systemic absorption is minimal when administered orally. In cases of systemic use, such as intramuscular or intravenous administration, neomycin is distributed widely in the body but is primarily excreted unchanged in the urine. The elimination half-life varies but is generally around 2 to 3 hours in individuals with normal renal function. Monitoring of serum concentrations is essential to prevent toxicity, especially in patients with renal impairment.

Adverse effects

• neurotoxicity
• ototoxicity
• nephrotoxicity
• allergic reactions
• skin rashes
• hearing loss

Interactions

• other nephrotoxic drugs
• loop diuretics
• neuromuscular blocking agents

Precautions

• monitor renal function
• use cautiously in patients with hearing impairment
• avoid concurrent use with other ototoxic medications
• ensure adequate hydration

Pregnancy

Safety in pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Use caution; neomycin can be absorbed systemically and may affect the nursing infant.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• oral tablets
• topical ointments
• injectable solutions

Indications

• Psoriasis
• Eczema
• Dermatitis
• Lichen planus
• Seborrheic dermatitis

Dosage

Adults: Apply a thin film to the affected area twice daily, ensuring not to exceed the recommended duration of treatment as indicated in the B

Mechanism of action

The short-term effects of corticosteroids like clobetasol include decreased vasodilation and permeability of capillaries, as well as reduced leukocyte migration to sites of inflammation. Clobetasol binds to the glucocorticoid receptor, which mediates changes in gene expression leading to multiple downstream effects over hours to days. It inhibits neutrophil apoptosis and demargination, reduces phospholipase A2 activity (decreasing the formation of arachidonic acid derivatives), and inhibits inflammatory transcription factors such as NF-Kappa B. This promotes anti-inflammatory genes like interleukin-10, resulting in a potent anti-inflammatory effect at lower doses and immunosuppressive effects at higher doses.

Pharmacodynamics

Clobetasol propionate binds to the glucocorticoid receptor to inhibit pro-inflammatory signals while promoting anti-inflammatory signals. It is generally applied twice daily, providing a long duration of action. Corticosteroids like clobetasol have a wide therapeutic window, allowing for doses that can be significantly higher than the body's natural production. Patients should be informed of the risks of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections when using corticosteroids.

Pharmacokinetics

Clobetasol propionate is well-absorbed through the skin, with its absorption depending on the vehicle used and the condition of the skin. It is metabolized primarily in the liver, and its elimination half-life allows for sustained effects when applied topically. Due to its potency, careful consideration must be given to the duration of treatment and the area of application to minimize systemic absorption and potential side effects.

Adverse effects

• Skin atrophy
• Striae
• Telangiectasia
• Acne
• Burning sensation
• Pruritus
• Allergic contact dermatitis

Precautions

• Use with caution in patients with a history of skin infections
• Avoid prolonged use to minimize the risk of systemic absorption and adrenal suppression
• Monitor for signs of local or systemic infections

Pregnancy

Clobetasol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Long-term use should be avoided.

Breast-feeding

Clobetasol may be excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store below 25 degrees Celsius. Protect from light and keep out of reach of children.

Formulations

• Topical cream
• Topical ointment
• Topical solution

Indications

• Bacterial infections caused by aerobic organisms
• Topical treatment of skin infections

Mechanism of action

Neomycin binds to specific proteins and 16S rRNA within the 30S ribosomal subunit of susceptible bacteria. This binding interferes with the decoding site, causing misreading of mRNA and leading to the incorporation of incorrect amino acids into polypeptides. As a result, nonfunctional or toxic peptides are produced, and polysomes are disrupted into nonfunctional monosomes. Neomycin's bactericidal action is characterized by its ability to irreversibly bind to the 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

Pharmacodynamics

Neomycin is primarily active against aerobic bacteria and is not effective against fungi, viruses, or most anaerobic bacteria. It mediates its bactericidal effects by inhibiting protein synthesis, which suppresses bacterial growth and survival. Following oral administration, neomycin exhibits a duration of bactericidal activity lasting between 48 to 72 hours. It is particularly useful in treating infections caused by strains of E. coli and Klebsiella, and it also acts to reduce colonic bacterial populations in patients with hepatic coma.

Pharmacokinetics

Neomycin is poorly absorbed from the gastrointestinal tract when taken orally, which limits its systemic availability and enhances its utility in targeting colonic bacteria. It is generally not used parenterally due to its potential for nephrotoxicity and ototoxicity. The duration of action following oral administration can last from 48 to 72 hours, and it is primarily excreted unchanged in the urine. Caution should be exercised when using neomycin in patients with renal impairment, as the risk of toxicity increases.

Adverse effects

• Nephrotoxicity
• Ototoxicity
• Allergic reactions
• Diarrhea
• Nausea
• Vomiting

Interactions

• neomycin+digoxin: Unknown (decreases absorption)
• neomycin+sorafenib: Unknown (decreases exposure)

Precautions

• Use with caution in patients with renal impairment
• Monitor renal function during therapy
• Evaluate hearing function in long-term use

Pregnancy

Neomycin is classified as category D; it should be used only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Neomycin is excreted in breast milk; caution should be exercised when administered to nursing mothers.

Storage

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

Formulations

• Topical ointment
• Cream
• Eye drops
• Oral tablets

Mechanism of action

Ketoconazole interacts with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability due to reduced amounts of ergosterol present in the fungal cell membrane. This metabolic inhibition also results in accumulation of 14α-methyl-3,6-diol, a toxic metabolite. The increase in membrane fluidity is also thought to produce impairment of membrane-bound enzyme systems as components become less closely packed. Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14alpha-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. Like other azole antifungal agents, ketoconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition. Although the exact mechanism of action of ketoconazole has not been fully determined, it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis, probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol). The fungicidal activity of ketoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell membrane.

Pharmacodynamics

Ketoconazole, similarly to other azole antifungals, is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body.

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.

Pharmacodynamics

Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. Clobetasol propionate is generally applied twice daily so the duration of action is long. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.

Mechanism of action

Framycetin binds to specific 30S-subunit proteins and 16S rRNA, four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes. Like other aminoglycoside antibiotic drugs, neomycin inhibits bacterial ribosomes by binding to the 30S ribosomal subunit of susceptible bacteria and disrupting the translational machinery of bacterial protein synthesis. Bacterial translation is normally initiated by the mRNA binding to the 30S ribosomal subunit and subsequent binding with 50S subunit for elongation. Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/ A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy. ... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

Pharmacodynamics

Framycetin is used for the treatment of bacterial eye infections such as conjunctivitis. Framycetin is an antibiotic. It is not active against fungi, viruses and most kinds of anaerobic bacteria. Framycetin works by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA, leaving the bacterium unable to synthesize proteins vital to its growth. Framycetin is useful primarily in infections involving aerobic bacteria bacteria. Neomycin mediates its bactericidal action by inhibiting bacterial protein synthesis, thereby suppressing the growth and survival of susceptible bacteria. Following oral administration, the duration of bactericidal activity of neomycin ranged from 48 to 72 hours. By decreasing colonic bacteria that produce ammonia, neomycin was shown to be effective as an adjunctive therapy in hepatic coma to improve neurologic symptoms. Neomycin is active against both gram positive and gram negative organisms, including the major _E. coli_ species resident in the colon as well as the enteropathogenic forms of _E. coli_. It is also active against _Klebsiella_-_Enterobacter_ group. Resistant strains of _E. coli_, _Klebsiella_ and _Proteus spp_. may emerge from neomycin therapy. Neomycin has no antifungal activity and has some activity against some protozoa.