2Antifungal agents:These drugs are used for superficial or deep systemic fungal infection .Fungal infection termed as mycoses.
3FUNGI AND FUNGAL INFECTION: Fungi are Eukaryotic cells. They possess mitochondria, nuclei & cell membranes.They have rigid cell walls containing chitin as well as polysaccharides, and a cell membrane composed of ergosterol.While bacterial cells are prokaryotic. So, antibacterial agents can exhibit Selective toxicity.In contrast, similarity between fungal & mammalian cells makes Antifungal drugs non-selective.Thus, Antifungal drugs are in general more toxic than antibacterial agents.
4Exampels of Fungi:YeastsMoldsMushroomsPuffballsShelf fungiAnimal pathogenPlant pathogen
5Clinically important fungi may be classified into four main types: 1.yeasts(cryptococcus neoformans)2.yeast like fungi that produce a structure resembling a mycelium(candida albicans)3.filamentous fungi with true mycelium(Aspergillus fumigatus)4.Dimorphic fungi that,depending on nutritional consraints,may grow as either yeasts or filamentous fungi(histoplasma capsulatum)
6Superficial fungal infections can be classified into 1.dermatomycoses:Infection of hair,skin,nailsMost commonly caused by Trichophyton,Microsporum or Epidermophyton,giving rise to various types of ‘ring worm’ or tine.
72.candidiasis:Yeast like organisam may infect the mucous membranes of the mouth or vagina(thrush) or the skin.2) Systemic fungal infection:Blastomycosis,histoplasmosis,coccidiomycosis and paracoccidomycosis;thses are the primary infections.Involve the internal organs
12Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membrane’s integrity. Allylamines inhibit ergosterol synthesis.flucytosine inhibit DNA/RNA synthesis.griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function.
131.Antibiotics: Polyenes: Amphotericin B(AMB): It is the drug of choice used in the treatment of the systemic mycoses although it is toxic.It is sometimes used in combination with flucytosine to decrease the toxicity of amphotericin B.
14M/A: It binds with ergosterol(component of fungal cell membrane) AMB-ergosterol complex alter the membrane permeabilitycreates pore in the membranepores allows the leakage of inracellular ions,amino acid & micromoleculescell death
15Pharmacokinetics: i.v.(t½ - 24 hours) mostly metabolized some is excreted by kidneydoes not readily pass the blood brain barrierextensively bound to plasma proteins, and is distributed throughout the body. However, amphotericin B does cross the placenta; some is also eliminated via the bile. Liposomal preparations of amphotericin B are available and have shown therapeutic efficacy.
16Clinical use:topically applied for ,oral,vaginal, cutaneous candidasisotomycosisleishmaniasis:it is a reserve drug for resistant cases of kala azar and mucocutaneous leishmaniasis.
17Adverse effects:Infusion related: fever,chills,aches ,nausea,vomiting and dyspnoea and can be alleviated partly by pretreatment with NSAIDs,antihistamines,meperidine and adrenal steroids.Dose dependent:Nephrotoxicity includes reduce g.f.r,acidosis, hypokalemia and inability to concentrate urine.anemia:it is due to bone marrow depression(decrease erythropoietin)CNS toxicity:occurs only on intrthecal injection – headache,vomiting,nerve palsies.
19LIPID amphotericin B formulations in use Amphotericin B Lipid Complex: (ABLC; Abelcet®)Amphotericin B Colloidal Dispersion: (ABCD; Amphocil® or Amphotec®)Liposomal Amphotericin B:(L-AMB; Ambisome®)
202.Nystatin(fungicidin): It is similar in structure to amphotericin and same mechanism action.No absorption from the mucous membranes of the body or from skinuse:Use limited to candida infection of skin,git,mucous membraneunwanted effects:nausea,vomiting,diarrhoea.
21Hetrocyclic benzofuran: Griseofulvin: It is isolated from Penicillium griseofulvum and cure infections due todermatophytes(ringworm) when administered orally.It is ineffective against candida albicans.M/A:It interacts with microtubules of miotic spindle and with cytoplasmicmicrotubulesdisorientation of miotic microtubules and interfere in the mitosisinhibit the growth of fungal hyphae.
22It is very low water soluble drug,low absorption,absorption improved by taking with fatty meals and microfine the drug particles.Adverse effects:Headache,GIT disturbances,peripheral neuritis,rashes,leukopenia.Interaction:It induces warfarin metabolism and reduces efficacy of oral contaceptives.
232.Antimetabolite: Flucytosine(5-fc): It is pyrimidine analogue related to the chemotherapeutic agent 5-FU(5 Fluorouracil).M/A:This permeates the fungal cell wall and converts into 5-FUphosphorylation of 5-FU and formation of UDP and UTPwhich inhibits to thymidylate synthesisinhibitn the DNA and RNA synthesisinghibit fungal cell grpwth
24Adverse effects:Bone marrow depressionLeucopeniaRashDiarrhoeaHepatitisUse:In cyptococcosis its synergistic action with AMB is utillized to reduce the total dose of the more toxic latter dose.
253.Azoles : M/A: Inhibit the fungal cytochrome P450 enzyme lanosterol 14-methylase impair ergosterol synthesis membrane abnormalities in fungus.
26Ketoconazol:Orally used for mucocutaneous candidiasis or dermatophytoses.PharmacokineticsVariable oral absorption, dependent on pH (often given with cola or fruit juice)T1/2 = 7-10 hoursProtein binding > 99%Hepatic, bile and kidney elimination
27A/E:Decrease androgen production and displace testoterone from protein binding sites gynaecomastia,loss of libido and oligospermia.Menstrual irregularities in female.Dose-related inhibition of CYP P450 .
28Interaction:Potent inhibitor of cytochrome P450 3A4Rifampin and phenytoin decrease ketoconazole levelsKetoconazole increases cyclosporin, warfarin and terfenadine levels.Drugs that increase gastric pH will decrease blood levels of ketoconazoleAntacids, omeprazole, H2 blockers
29Fluconazole:Fluconazole is clinically important because of its lack of the endocrine side effects of ketoconazole, and its excellent penetrability into the CSF & ocular fluids.Water soluble having wider range of activity than KetoconazolDrug of choice in fungal meningitisNon-albicans Candida species more likely to exhibit primary resistanceItraconazoleL:Uses:HistoplasmosisSporotrichosis (This fungal disease usually affects the skin, although other rare forms can affect the lungs, joints, bones, and even the brain).AspergillosisBlastomycosis
30Posaconazole & Ravuconazole: Voriconazole:Given iv and orallySimilar to itraconazole in spectrumLittle interaction at CYP450Posaconazole & Ravuconazole:For Invasive candidiasis, and aspergillosis infectionsOnly orally availableInhibits CYP3A4Adverse effects include: GI effects, dizziness, cardiac arrhythmias, abnormal liver function
31local azolesVery popular local azoles are – Clotrimazole, Econazole and Miconazole(For Tinea, Ring worm, Athlete’s foot, otomycosis, oral, cutaneous & vaginal candidiasis)Mechanism of action is same as that of Ketoconazole i.e. ergosterol inhibition by inhibiting CYP450Clotrimazole is favoured in vaginitis because of long lasting residual effect and once daily dosingMiconazole causes frequently vaginal irritation & pelvic cramp.Available as lotion, cream, powder, vaginal tablet etc.
324.Allylamine:Terbinafine:M/A:inhibit the enzyme squalene epoxidaseinhibit synhesis of ergosterol.Possible superior to greiseofluvin in onchomycoses.A/E:GI distress,rash,headache,possible hepatotoxicity.
335. β-glucan synthase inhibitors: CaspofunginMetabolized by hydrolysis and N-acetylationNot inhibitor/inducer/substrate of CYPEnzymes induced by carbamazepine, cyclosporine, dexamethasone, efavirenz, nelfinavir, nevirapine, phenytoin, rifampinMicafungin:Substrate 3A4 minor; weak inhibitor of 3A4Increased levels of nifedipineIncreased monitoring for toxicity and dosage adjustment needed.Anidulafungin:Degrades at normal pH and condition to an open-ringed peptide
346.Other topical agents:All these drugs are used in dermatophytosis.Tolnaftate:Effective drug fof tinea cruris and tinea corporis.It causes little irritation and is better than other topical agents.Ciclopirox olamine:It used in tinea infections,pityriasis versicolor , dermal candidiasisand vaginal candidiasis.Undecylenic acid:It used for tinea pedis,nappy rash and tinea cruris.Used in combination with its zinc salt.
35Benzoic acid:Antifungal+AntibacterialUsed in combination with salicyclic acid,its kerolytic action helps to remove the infected tissue and promotes the penetration of benzoic acidinto the lesion.Quiniodochlor:Weak antifungal+antibacterialUsed in dermatophytosis,mycosis barbae,seborrhoeic dermatitis,infected eczematricomonas vaginitis.Sodium thiosulphate:It is effective in pityriasis versicolor.
36Future Targets Moving into the cell: Aspartate pathway: Fungi must synthesize Met, Ile, Thr.Siderophore biosynthesis:Iron importation mechanismFungi must scavenge for iron inside hostSiderophores bind soluble iron with high affinityActively transported through cell wall
37Summary of Treatments Pathogen Primary Secondary Cryptococcus neoformansAmphotericin B + Flucytosine followed by FluconazoleItraconazole or Amphotericin BHistoplasma capsulatumFluconazoleMucomycosisAmphotericin BPosaconazoleSporothrix schenckiiAmphotericin B ItraconazoleSaturate solution of potassium iodide
38References:1)Tripathi KD.Essentials of medical pharmacology,Jaypee brothermedical publisher,5th edition(2005),p.p:2)Rang H.P.,Dale M.M,Ritter J.M.,Flower R.J.,Churchill livingstoneElsevier,6th edition(2007),p.p:3) Goodman and Gilman, The pharmacological basis of therapeutics, 11th Edition,2008,p.p: