QUESTION1—; Discuss with named examplesthe clinical pharmacology of Azole antifungi agent and potential threat to itsusage ?Answer —- ; Azoles are a class of membered heterocyclic compounds containing a nitrogenatom and at least one other non carbon atom as part of the ring. Azole antifungi agent prevent the synthesisof ergosterol, a major component of fungal plasma membranes , by inhibiting thecytochrome P-450 dependent enzyme lanosterol demethylase also referred to as 14alpha-sterol demethylase. This enzyme also plays an important role incholesterol synthesis in mammals when azoles are present in therapeuticconcentrations , their antifungal efficacy is attributed to their greateraffinity for fungal P450dm than for the mammalian enzyme.
Exposure of fungi toan azole causes depletion of ergosterol and accumulation of 14alpha -methylatedsterol. This interferes with the bulkfunction of ergosterol in fungal membranes and distrupts both the structure ofthe membrane and several of its functionsuch as nutrient, transport and chitin synthesis. Clinicalimportance of Azole Antifungal agents. The azole antifungal agents in clinical usecontain either two or three nitrogens in the azole ring and are there byclassified as imidazoles and triazoles.
Imidazoles are ;(1) Ketoconazole(2) Miconazole(3) ClotrimazoleTriazoles are ;ItraconazoleFluconazoleWith the expection of ketoconazole , the useof the imidazole is limited to the treatment of superficial mycoses , whereas,the triazoles have a broad range of appilications in the treatment of both superficial andsystemic fungal infections. Another advantage of the triazole is their greateraffinity for fungal rather than mammalian cytochrome P-450 enzyme , which contributesto an improved safety profel.QUES (2) Mention 3 categories of antineoplasm agentwith named examples , discuss briefly the mechanism of action of one examplesin each categoryAnswer—- Catogory 1—-; Alkylatingagents which are cell cycle non specific (CCNS)Nitrogen mustard ; Melphalan ,cyclophosphamide , ifosfamideNitrosoureasAlkysulfunatesEthyleneiminesTriazenesMethylhydrazinesMechanism of action ofcyclophosphamide–;Is an inactive drug, with the help of cytochrome P-450oxidase system in the liver , theinactive drug is converted into phosphoramide mustard and aerolein which arevery active compounds. Phosphoramide mustard has an ability to introduces alkylradicals into DNA strands with interferes DNA replication by forming DNA crosslinkage. Cross linked cancer cell DNA is unable to complete normal celldivision . Thus , it stops cancer cells from growing , causing them to die.Cyclophosphamide also produces immunosuppresive effects possible through acytotoxic effect on lymphocytes.
Category 2 ——Antimetabolities which arecell cycle specific (CCS)Folate antagonism ; methotrexatePurine antagonistPyrimidine antagonist ; 5 -fluorouracil ,cytarabibeMechanism of action of 5-fluorouracil —;It is an antimetabolite fluoropyrimidine analog of the nucleoside pyramidinewith antineoplastic activity. Fluorouracil and its metabolites possess a number of different mechanism of action .In vivo , fluorouracil is converted to the active matabolites 5-fluoroxyuridine monophosphate (F-UMP) ;replacing uracil, F-UMP incorporates into RNA processing , thereby inhibitingcell growth.
Another active metabolite ,5-5-fluoro-2′-deoxyuridine-5′-O-monophosphate(F-dUMP) , inhibits thymidylate synthase, resulting in the depletion ofthymidine triophosphates used in the in vivo synthesis of DNA. Otherfluorouracil metabolites incorporate both RNA and DNA ; incorporation into RNA results in major effects on RNAprocessing and functions.Category 3—–; Natural ptoducts are divided into two parts which are (1) plant and(2) micro organism products.(1) Plantproducts are ; Vinca Alkaloids ;- Vincristine ,Vinblastine .Epipodophyllotoxins , Etoposide.
Camptothecins : Irinotecan(2) Micro organism Products ;Antibiotics such as Doxorubicin , BleomycinEnzymes ; L-Asparaginase.Mechanism of action of Vinblastine (plantproduct)It binds to tubulin , leading to disruptionof mitotic spindle apparatus and arrest of cell cycle.Mechanism of action of Doxorubicin (Microorganism product)It intercalates and binds to DNA disrupting helical structure and DNA template : inhibits RNA and DNA polymerases ; causesDNA topoisomerase -ll-mediated chain scission ; generates free radicals thatcause DNA scission and cell membrane damage. Ques 3—–; Which of the classes of antifungi agent will you considered to be ideal and whileAnswer–; ECHINOCANDINS ——; is a new class of antifungi drugs andit is cyclic lipo peptide antibiotics that interfere with fungal cell wallsynthesis by inhibition of B(1,3) D-glucan synthase. E.g Capso fungin ,micafungi , anidulafungin. Advantagesof Echinocandins over other anti fungi agentsBroad range (especially against all candida), thus can be given – emperically in febrile neutropenia and stem celltransplant.It can be used in case of azole-resistantcandida or use as a second -line agent for refractory aspergillosis.
Long half-life (polyphasic elimation :alpha phase 1-2 hours + beta phase 9-11 hours + gamma phase 40-50 hours) lowtoxicity : only histamine release (3%) ,fever (2.9%) ,nausea and vomiting (2.9%)and phlebitis at the site of injection (2.9%) , veryrarely allergy andanaphylaxis. Not an inhibitor, inducer or substrate of the cytochrome P450 system , orP-glycoprotein , thus minimal drug interactions.
Lack of interference from renal failure andhaemodialysis. No dose adjustment is necessary based onage , gender and race.Better (or no less effective) than AmphotericinB and fluconazole against yeast infections. Ques 4—-; list the principle ofchemotherapeutic resistance. Write short note on the one you considered mostimportant?Answer —–; (a) Pharmacokinectic or Pharmacodynamicfactors.MutationsGene regulationsGeneration or use of alternativebiochemical pathways.Drug misuse.(b) MUTATIONS A drug must interact with its target(s) toachieve the therapeutic effects.
Mutation in drug target is a criticalmachanism that results in drug resistance. There are several scenarios underwhich a mutation could lead to drug resistance , it could reduce the bindingaffinity of a drug to its target or render the target constitutively active .Worse yet , mutations could turn a drug from antagonist to agonist. Forexample, current therapeutic strategy for advanced prostrate cancer is toinhibit the androgen receptor (AR) signaling. However, the W741C mutation inthe AR was found to convert bicalutamide from an antagonist of the wild type ARinto an agonist of the W741C AR mutant, which actually promotes tumor growth.
Mutation could cause disruption or aberrantinteraction of a specific protein-protein interaction, resulting in drugresistance.In general , resistant mutations in drugtargets are derived from tissue specimen of the patients that are resistant to the drug. Next , mutation relatedresistance is demonstrated in a series of in vitro and in vivo models.