GEMCIDERM CREAM COMBINATION PRODUCT CREAM

Indications

• Vaginal candidiasis
• Vulval candidiasis
• Superficial fungal infections
• Otitis externa (as part of combination therapy)

Dosage

Adults: For vaginal candidiasis, 1 pessary of 500 mg can be inserted at night. Alternatively, for treatment with 1% cream, apply 2–3 times a day to the affected area for at least 14 days. For recurrent vulvovaginal candidiasis

Mechanism of action

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. It inhibits ergosterol biosynthesis, which is essential for maintaining the integrity of fungal cell membranes. The inhibition of lanosterol 14-demethylase (CYP51) is a key mechanism behind its antifungal properties, leading to decreased ergosterol synthesis and resulting in cell membrane dysfunction. Clotrimazole also affects calcium homeostasis by inhibiting sarcoplasmic reticulum Ca2+-ATPase and blocking calcium-dependent potassium channels, contributing to its overall pharmacological effects.

Pharmacodynamics

Clotrimazole is considered a broad-spectrum antifungal that alters the permeability of fungal cell membranes, leading to inhibition of growth in pathogenic yeasts. At lower concentrations, it exhibits fungistatic properties, while at higher concentrations, it may be fungicidal against certain strains like Candida albicans. However, resistance to clotrimazole has become more common in recent years, limiting its efficacy in some populations.

Pharmacokinetics

Clotrimazole is primarily applied topically, and its absorption varies depending on the formulation and site of application. Following topical administration, systemic absorption is minimal, thereby reducing the risk of systemic side effects. The drug is metabolized in the liver and excreted via urine and feces. The pharmacokinetics may differ based on the dosing regimen and specific formulation used.

Contra-indications

• Hypersensitivity to clotrimazole or any excipients in the formulation
• Not recommended if trying to conceive due to potential damage to latex condoms and diaphragms

Adverse effects

• Skin reactions
• Vaginal burning
• Angioedema

Interactions

• Clotrimazole may increase the exposure of lomitapide, though the specific nature of this interaction is unknown

Precautions

• Avoid use in pregnancy without medical advice
• Use caution in patients with a history of hypersensitivity reactions

Pregnancy

Clotrimazole should be used during pregnancy only if clearly needed. Oral antifungal treatments should be avoided.

Breast-feeding

Clotrimazole is excreted in breast milk; caution is advised when used in breastfeeding mothers.

Storage

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

Formulations

• Clotrimazole 1% cream
• Clotrimazole 2% cream
• Clotrimazole 500 mg vaginal pessaries
• Clotrimazole 10% vaginal cream
• Clotrimazole 1% solution (ear drops)

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Allergic rhinitis
• Nasal polyps

Dosage

Children: For children aged 5 to 12 years with asthma, the usual inhaled dose is 50 to 200 micrograms twice daily. For allergic rhinitis, refer to the BNF for Children

Adults: For asthma, the usual dose of inhaled beclomethasone is 100 to 400 micrograms twice daily, adjusted based on clinical response. For allergic rhinitis, 200 to 400 micrograms as a nasal spray may be administered once daily.

Mechanism of action

Beclomethasone acts by binding to glucocorticoid receptors in the cytoplasm of target cells. This complex translocates to the nucleus, where it influences gene transcription, leading to the downregulation of pro-inflammatory cytokines and the upregulation of anti-inflammatory proteins. This mechanism results in decreased inflammation, mucus production, and airway hyper-responsiveness.

Pharmacodynamics

The anti-inflammatory effects of beclomethasone are attributed to its ability to inhibit the release of inflammatory mediators, including leukotrienes and prostaglandins. It also reduces the recruitment of inflammatory cells to the site of inflammation. The onset of action for inhaled beclomethasone may take several hours to days, with maximum benefits typically observed after continuous use.

Pharmacokinetics

Beclomethasone is well-absorbed following inhalation, with a significant portion undergoing first-pass metabolism in the liver, thereby reducing systemic exposure. Its half-life is approximately 2.5 hours, but the duration of action may extend due to the drug's accumulation in lung tissue. The elimination of beclomethasone is primarily hepatic, with metabolites excreted in urine and feces.

Contra-indications

• Hypersensitivity to beclomethasone or any of its components
• Untreated systemic fungal infections

Adverse effects

• Cushing's syndrome
• Adrenal suppression
• Osteoporosis
• Growth retardation in children
• Skin thinning
• Increased risk of infections
• Oral candidiasis

Interactions

• CYP3A4 inhibitors may increase systemic exposure to beclomethasone
• Vaccines (live) may have reduced efficacy

Precautions

• Use with caution in patients with active or quiescent tuberculosis
• Monitor for signs of adrenal insufficiency
• Consider risks in patients with diabetes mellitus
• Use with caution in patients with hypertension

Pregnancy

Beclomethasone is classified as category C. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Beclomethasone is excreted in breast milk, caution should be exercised when administering to nursing women.

Storage

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

Formulations

• Inhalation aerosol
• Nasal spray
• Topical cream
• Topical lotion

Indications

• Severe infections caused by Gram-negative bacteria
• Urinary tract infections
• Bacteremia
• Sepsis
• Pneumonia
• Intra-abdominal infections
• Skin and soft tissue infections

Dosage

Adults: The usual dosage for adults is 3 to 5 mg/kg/day divided into 3 doses, given intravenously or intramuscularly. Adjustments should be made based on renal function and severity of infection.

Mechanism of action

Gentamicin acts by binding to the bacterial 30S ribosomal subunit, leading to misreading of mRNA and subsequent production of nonfunctional or toxic peptides. This disrupts protein synthesis and leads to bacterial cell death. The drug enters bacterial cells in a three-phase process: first, ionic binding occurs with the cell membrane, increasing permeability. Second, energy-dependent transport allows the drug to access its intracellular target. Third, concentration-dependent killing is observed as gentamicin accumulates within the cell, amplifying its effects on protein synthesis and membrane integrity.

Pharmacodynamics

Gentamicin exhibits concentration-dependent bactericidal activity, meaning that its efficacy increases with higher concentrations. The pharmacodynamic properties highlight the rapid and delayed bactericidal effects, with membrane disruption occurring immediately followed by impaired protein synthesis. The drug's action is particularly effective against aerobic Gram-negative bacteria, while its effectiveness is significantly reduced in anaerobic conditions.

Pharmacokinetics

Gentamicin is poorly absorbed from the gastrointestinal tract; thus, it is typically administered intravenously or intramuscularly. It has a volume of distribution that reflects extensive tissue penetration, particularly in renal and gastrointestinal tissues. The elimination half-life ranges from 2 to 3 hours in healthy individuals, but it can be prolonged in patients with renal impairment. The drug is primarily eliminated by renal excretion, with dosage adjustments required in cases of renal dysfunction.

Contra-indications

• Hypersensitivity to gentamicin or other aminoglycosides
• Severe renal impairment
• Myasthenia gravis

Adverse effects

• Nephrotoxicity
• Ototoxicity (hearing loss, balance disorders)
• Neuromuscular blockade
• Allergic reactions (rash, pruritus)
• Peripheral neuropathy

Interactions

• Increased risk of nephrotoxicity with other nephrotoxic agents (e.g., cisplatin, vancomycin)
• Increased risk of ototoxicity with loop diuretics (e.g., furosemide)
• Synergistic effects with beta-lactam antibiotics

Precautions

• Monitor renal function during treatment
• Use caution in patients with pre-existing hearing loss
• Adjust dosage in patients with renal impairment
• Consider potential drug interactions

Pregnancy

Gentamicin should be used during pregnancy only if clearly needed, due to potential risk of fetal harm.

Breast-feeding

Gentamicin is excreted in breast milk, but is generally considered safe. Monitor for possible effects on the infant.

Storage

Store in a cool, dry place, away from light. Do not refrigerate or freeze.

Formulations

• Injection (solution for injection)
• Topical ointment
• Eye drops

Mechanism of action

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. Clotrimazole causes inhibition of ergosterol biosynthesis, an essential constituent of fungal cell membranes. If ergosterol synthesis is either completely or partially inhibited, the cell is no longer able to construct an intact and functional cell membrane,. Because ergosterol directly promotes the growth of fungal cells in a hormone‐like fashion, rapid onset of the above events leads to dose-dependent inhibition of fungal growth. Though decreased ergosterol, due to the inhibition of lanosterol 14-demethylase (also known as _CYP51_) is accepted to be primarily responsible for the antimycotic properties of clotrimazole, this drug also shows other pharmacological effects. These include the inhibition of sarcoplasmic reticulum Ca2+‐ATPase, depletion of intracellular calcium, and blocking of calcium‐dependent potassium channels and voltage‐dependent calcium channels. The action of clotrimazole on these targets accounts for other effects of this drug that are separate from its antimycotic activities. Clotrimazole exerts its antifungal activity by altering cell membrane permeability, apparently by binding with phospholipids in the fungal cell membrane. In contrast to polyene antibiotics (eg, amphotericin B), the action of clotrimazole is less dependent on the sterol content of the cell membrane. As a result of alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost.

Pharmacodynamics

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by changing the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal _in vitro_ against Candida albicans and other species of the genus Candida at higher concentrations. Unfortunately, resistance to clotrimazole, which was rare in the past, is now common in various patient populations. Clotrimazole is generally considered to be a fungistatic, and not a fungicidal drug, although this contrast is not absolute, as clotrimazole shows fungicidal properties at higher concentrations.

Mechanism of action

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry. The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane. Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified. The necessity of oxygen-dependent active transport explains why aminoglycosides are ineffective against anaerobic bacteria. Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model. Inhibition of protein synthesis is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, elongation, and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation. Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. 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/ ... 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/