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Antifungaldrugs
- 1. R.GAYATHRI DEVI PHARM D Antifungal Drugs
- 8. What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.
- 20. Azole Structures Fluconazole Ketoconazole
- 32. Ketoconazole Fluconazole Itraconazole 1 Broad spectrum Still wider range Fungi static 2 Dermatophyte & deep mycosis Cryptococcal & coccidial meningitis immunocompromised patients 3 Absorbed at low pH Good oral absorption Varies with food & pH 4 Highly bound to PP Not much Highly bound 5 More S/E, headache, androgen inhibition Less S/E, headache & rash Hypokalemia, pruritis & dizziness 6 Causes hepatic impairment Mild Not hepatotoxic 7 Inhibit cytochrome P450 Inhibit only fungal P450 No effect 8 Used for Monilial vaginitis. Cushing’s syn Candidiasis, Keratitis, Cryptococcal meningitis Mycosis, meningitis Chromo & paracocci
- 42. Thank you
Notas do Editor
- There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.
- Around 100 polyene antibiotics have been described, but few have been developed for clinical use. Amphotericin B was first isolated by Gold et al from Streptococcus nodosus in 1955. It is an amphoteric compound composed of a hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other. Amphotericin B is poorly soluble in water. It binds to sterols of susceptible fungal cells. Amphotericin B has a selective action, binding avidly to membranes of fungi and less avidly to mammalian cells. The relative specificity for fungi may be due to the drug’s greater avidity for ergosterol than for cholesterol. On binding to the fungal cell membranes, Amphotericin B interferes with permeability and transport functions. The drug is thought to form a pore in the membrane, the hydrophilic core of the molecule creating a transmembrane ion channel. One of the repercussions of this is a loss of intracellular potassium, magnesium, sugars and metabolites and then cellular death. Until the introduction of voriconazole, amphotericin B was the most broad spectrum intravenous antifungal available, although not always very potent.
- Above are antifungals which target the cell membrane. First of all we will look at the azole family. These drugs are far less toxic than amphotericin B.
- The azoles inhibit the fungal P450 enzymes responsible for the synthesis of ergosterol, the main sterol in the fungal cell membrane. The azoles act through an unhindered nitrogen, which binds to the iron atom of the heme, preventing the activation of oxygen which is necessary for the demethylation of lanosterol. In addition to the unhindered nitrogen, a second nitrogen in the azoles is thought to interact directly with the apoprotein of lanosterol demethylase. It is thought that the position of this second nitrogen in relation to the apoprotein may determine the specificity of different azole drugs for the enzyme. The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of membrane-associated enzymes. The overall effect is an inhibition of replication (ie. the azoles are fungistatic drugs). A further repercussion is the inhibition of transformation of candidal yeast cells into hyphae-the invasive and pathogenic form of the parasite. Since no drug acts with complete specificity, it is not surprising that the azoles also have some effect on the closely related mammalian p450 enzymes. These are a large family of haem proteins. Hepatic p450 enzymes are involved in the detoxification of drugs whereas extrahepatic enzymes play an important part in several synthetic pathways including steroid biosynthesis in the adrenal gland.
- The time taken for peak serum concentrations to be reached is 2-4 hrs. This is determined by several factors including: disintegration/dissolution rate (favoured by acidic pH?) Gastric emptying rate Intestinal transit time Intestinal metabolism (CYP 3A4 in intestinal wall) Rate of absorption from the intestine First Pass effect (metabolism in liver) Clearance rate. Food delays absorption, but does not decrease peak serum concentrations significantly.
- Molecular mechanisms of azole resistance. In a susceptible cell, azole drugs enter the cell through an unknown mechanism, perhaps by passive diffusion. The azoles then inhibit lanosterol 14- demethylase ( ERG11 ) (pink circle), blocking the formation of ergosterol. Two types of efflux pumps are expressed at low levels. The CDR proteins are ABC transporters (ABCT) with both a membrane pore (green tubes) and two ABC domains (green circles). The MDR protein is an Major Facilitator transport protein (MF) with a membrane pore (red tubes). ABC transporters use ATP as their energy source, whereas MF transporters use the proton motive force. In a “model” resistant cell, the azoles also enter the cell through an unknown mechanism. In a resistant cell, the azoles are blocked from interacting normally with the target enzyme because the enzyme can be modified. Lanosterol 14- demethylase is encoded by the gene ERG11. Several genetic alterations have been identified that are associated with the ERG11 gene of C. albicans , including point mutations in the coding region, overexpression of the gene, gene amplification (which leads to overexpression) and gene conversion or mitotic recombination. Several different specific point mutations (dark slices in pink circles) have been identified by comparing azole-resistant clinical isolate with a sensitive isolate from a single strain of C. albicans. The first point mutation to be identified within ERG11 of a clinical isolate of C. albicans which altered the fluconazole sensitivity of the enzyme was discovered in 1997 by White et al. This mutation results in the replacement of arginine with lysine at amino acid 467 of the ERG11 gene (abbreviated R467K). Overexpression of ERG11 has been described in several different clinical isolates. In each case, the level of overexpression is not substantial (less than a factor of 5). It is difficult to assess the contribution of ERG11 overexpression to a resistant phenotype, since these limited cases of overexpression have always accompanied other alterations associated with resistance, including the R467K mutation, and overexpression of genes regulating efflux pumps. In addition to alterations in the lanosterol demethylase, a common mechanism of resistance is an alteration in other enzymes in the same biosynthetic pathway (dark slices in blue spheres). The sterol components of the plasma membrane are modified (darker orange of membrane). Finally, the azoles are removed from the cell by overexpression of the CDR genes (ABCT) and MDR (MF). The CDR pumps are effective against many azole drugs, while MDR appears to be specific for fluconazole. Overexpression of the transporters may be a result of gene amplification or increased gene transcription. The more efficient removal of the azoles means that the drugs never reach their therapeutic concentrations within the cell. For more detail read: White T.C., Marr K.A., Bowden R.A. Clinical Microbiology Reviews 1998 11 ; 382-402. Available on internet at aac.asm.org/.
- Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage.
- In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium ; yeasts are unicellular fungi that do not grow as hyphae.