370Adverse effects include haemolysiswhich is most common and dose related.Patients with G-6-PD deficiency are moresusceptible. Nausea, vomiting, anorexia,headache, methaemoglobinaemia, drugfever, allergic skin reactions, insomnia andparesthesia. Rarely hepatitis andagranulocytosis.It is also used with pyrimethamine inchloroquine resistant malaria.PHENAZINE DERIVATIVESCLOFAZIMINEClofazimine is phenazine dye and usedas alternative to dapsone in dapsoneintolerant/resistant cases and incombination with dapsone and rifampicinin the multidrug treatment of leprosy. It’sprobable mechanism of action is itsinvolvement in DNA binding, it mayinterfere with template function of DNA.After oral administration, it is slowlyabsorbed, stored widely in reticuloendot-helial system and fatty tissues. It has longelimination half life.Adverse effects include discolourationof skin (red brown to black) and skin lesionpersists for month after discontinuation oftherapy. Other side effects include dry skin,itching, phototoxicity, nausea, abdominalpain, anorexia and diarrhoea.ANTITUBERCULAR DRUGSRIFAMPICINIt is bactericidal and highly effective inleprosy. A single monthly dose of 600 mgmay be used in combination with otherantileprosy drugs to avoid any probablerisk of rifampicin resistant M. leprae.The detailed pharmacology is discussedin chapter ‘Chemotherapy of Tuberculosis’.ETHIONAMIDEIt is antitubercular drug used as analternative to clofazimine in the treatmentof leprosy. But due to its hepatotoxicity, itsuse in leprosy is very limited.OTHER ANTIMICROBIAL AGENTSAmong fluoroquinolones, ofloxacin,pefloxacin and sparfloxacin can be used inalternative regimen, when drugs likerifampicin can not be used. Detailedpharmacology of quinolones is discussed inchapter ‘Sulfonamides, nitrofurans andquinolones’.Among macrolide antibiotics,clarithromycin is effective against M. lepraeas an alternative multidrug therapy (MDT)regimen (detailed pharmacology isdiscussed in ‘Macrolide antibiotics’).MINOCYCLINEIt is a tetracycline which is activeagainst M. leprae and its bactericidalactivity is higher than that ofclarithromycin. Used in alternativemultidrug treatment regimen (MDT).CLARITHROMYCINOnly macrolide antibiotic useful inleprosy. It is used in alternative MDT regimen.Recently, thalidomide (50-100 mgcapsule form, approved by FDA), animmunomodulatory agent is used inerythema nodosum leprosum (ENL) whichis a complication of leprosy occurring inapproximately one half of borderlinelepromatous and lepromatous leprosypatients.
(Mode of Action of Drugs)PharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsChapterChapter9.13Chemotherapy ofMalignancyCancer is a disease of cells characterizedby a shift in the control mechanism whichgovern cell proliferation and differentiationand the anticancer agents either kill cancercells or modify their growth. The variousanticancer agents are classified accordingto their mode of action as in table 9.13.1.Chemotherapy ofMalignancyTable 9.13.1: Classification of anticancer agents.I. Alkylating agentsCyclophosphamide (CYCLOXAN) 2-3 mg/kg/day oral; 10-15 mg/kg IV every 7-10 daysMesna (UROMITEXAN) 20% of a dose of anticancer agent IVChlorambucil (LEUKERAN) 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg dailyfor maintenanceBusulfan (MYLERAN) 4-8 mg/day, 1-3 mg/day for maintenanceLomustine (LUSTIN) 120-130 mg/m2 BSA single dose orally every 6weeksThio-TEPA (THIOTEPA) 0.3-0.4 mg/kg IV every 1-4 week intervalII. AntimetabolitesMethotrexate (ONCOTRAX) 15-30 daily for 5 days orally repeat after one weekor 20-40 mg/m2 BSA IM/IV twice weekly.6-Mercaptopurine (ZYPURIN) 2.5 mg/kg daily5-Fluorouracil (FLURACIL) 12 mg/kg OD for 4 successive days IV, 10-15 mg/kg/week maintenanceCytarabine (Cytosine arabinoside; CYTABIN) 1.5-3.0 mg/kg IV BD for 5-10 daysIII. Cytotoxic antibioticsDactinomycin (Actinomycin-D) (COSMEGEN) 15 µg/kg IV daily for 5 daysDoxorubicin (ONCODRIA) 60-75 mg/m2 BSA every 3 wks slow IVBleomycin (ONCOBLEO) 30 mg twice weekly IV/IMMitomycin-C (MITODUS) 2-10 mg/m2 BSA IV twice weeklyContd.…
372ALKYLATING AGENTSThe alkylating agents can transfer an alkylradical to a suitable receptor site. Alkylationof DNA within the nucleus represent themajor interactions which will lead to celldeath. These agents react chemically withsulfhydryl, carboxyl, amino and phosphategroups of other cellular nucleophiles in thecells which make them unavailable for thenormal metabolic reactions. Alkylatingagents react with nucleic acid and inhibitDNA synthesis and also interfere with cellreplication. Alkylating agents has got cytotoxicaction and damage the nuclei of growing andmultiplying cells. They have gotimmunosuppressant action also and suppressantibody production. They also haveradiomimetic (like ionizing radiation) actions.CYCLOPHOSPHAMIDEIt is an alkylating agent given orally orby intravenous route. It exerts its actionby alkylation of DNA.…Contd.IV. Vinca alkaloidsVincristine (Oncovin; BIOCRISTINE) 1.5 mg/m2 BSA IV weeklyVinblastine (CYTOBLASTIN) 0.1-0.15 mg/kg IV weekly (total 3 doses)Vinorelbine (VINELBINE) 30 mg/m2 BSA IV weeklyV. TaxanesPaclitaxel (MITOTAX) 175 mg/m2 BSA IV infusion repeated every 3 weeksDocetaxel (DOXOTEL)VI. Topoisomerase-I inhibitorsIrinotecan (IRINOTECAN) 125 mg/m2 BSA weekly IVTopotecan (TOPOTEL) 1.5 mg/m2 BSA IV infusion for five consecutive daysVII. Hormone & hormone antagonistsFosfestrol (Stilboestrol) 40-80 mg IM every 2-4 weeksEthinyl estradiol (LYNORAL) 1-3 mg dailyTamoxifen (ONCOTAM) 10-20 mg BDVIII. Radioactive isotopesRadioactive iodine (131I) 3-6 mci oral/IVRadioactive phosphorus (32P) 2.5-5.0 mci IVRadioactive gold (198AU) 35-150 mci IPIX. Miscellaneous agentsHydroxyurea (CYTODROX) 20-30 mg/kg daily or 80 mg/kg every 3rd dayProcarbazine 100-300 mg/dayL-Asparaginase (LEUNASE) 50-200 KU/kg daily IV infusion for 2-4 weeksCisplatin 50-100 mg/m2 BSA single IV dose every 3-4 wksInterferon alfa (ALFERON) 3-36 million IU daily SC/IM (depending upon theX.Immunosuppressantstype of cancer)AzathioprineCyclosporine* BSA = Body surface area
Chemotherapy of Malignancy373After oral administration it is wellabsorbed. It is a prodrug and converted inthe blood and liver to its active form(metabolites) namely hydroxyphosphamideand aldophosphamide. It is excreted in urine.Adverse effects include nausea,vomiting, visual blurring, facial burningwith IV administration, teratogenic effect,haemorrhagic cystitis, bone marrowdepression, hyponatremia, sterility,inappropriate secretion of ADH, alopeciaand increased skin pigmentation.It is indicated in leukaemias,lymphogranulomatosis, lymphosarcoma,reticulum cell sarcoma, Hodgkin’s disease,multiple myeloma, retinoblastoma,carcinoma of the breast, adenocarcinomaof the ovary, inoperable solid malignancies.It is used in combination with surgery,radiation and other therapeutic measures.MESNACyclophosphamide and ifosfamidecause urothelial toxicity (haemorrhagiccystitis) which is caused by metabolite ‘ac-rolein’. Mesna reacts with this metabo-lites in the urinary tract to prevent toxic-ity and is used in prevention of toxicityto the urinary passage caused byoxazaphosphorins e.g. ifosfamide andcyclophosphamide.CHLORAMBUCILIt is a slow acting alkylating agent.After oral administration, it showsadequate and reliable absorption andalmost completely metabolised.It is indicated in chronic lymphocyticleukaemia (drug of choice), primary(Waldenstrom’s) macroglobulinaemia,advanced ovarian adenocarcinoma, breastcancer, certain forms of nonHodgkin’slymphoma and Hodgkin’s disease.Adverse effects include nausea,vomiting, pulmonary fibrosis, dermatitis,hepatotoxicity, seizures, amenorrhoea,azoospermia, peripheral neuropathy andbone marrow depression.BUSULFANAfter oral administration, it is wellabsorbed and excreted in urine asmethanesulfonic acid. It is mainly used inchronic myeloid leukaemia, polycythemiavera, essential thrombocythemia andmyelofibrosis.Adverse effects include, thrombocy-topenia, amenorrhoea, azoospermia, skinpigmentation, nausea, vomiting, cataract,gynaecomastia, pulmonary fibrosis andhyperuricaemia.LOMUSTINEIt is rapidly absorbed from GIT afteroral administration and is completely andrapidly metabolised. It is indicated inHodgkin’s disease, brain tumour, lungcarcinoma, solid tumours and malignantmelanoma.Adverse effects include nausea, vom-iting, delayed bone marrow depression(four to six weeks), leucopenia, thrombocy-topenia and pulmonary fibrosis.THIO-TEPAChemically it is ethylenimine andbecause of high toxicity, it is rarely used.
374ANTIMETABOLITESAntimetabolites are analogues of normalDNA components or of coenzymesinvolved in nucleic acid synthesis. They getincorporated or competitively inhibitutilization of normal substrate to formdysfunctional nucleic acid molecules.METHOTREXATEIt is a broad spectrum antineoplasticdrug which act as an antimetabolite of folicacid.It acts by inhibiting dihydrofolatereductase. It inhibits conversion ofdihydrofolic acid to tetrahydrofolic whichis essential for purine synthesis and aminoacid interconversions. It primarily affectsDNA synthesis but also RNA and proteinsynthesis. It has cell cycle specific action andkills cells in S phase. It is readily absorbedfrom gastrointestinal tract but larger dosesare absorbed incompletely, little drug ismetabolised and it is excreted largelyunchanged in urine.Adverse effects include nausea,vomiting, diarrhoea, anaphylaxis, hepaticnecrosis, fever, bone marrow depression,osteoporosis, menstrual dysfunction,cirrhosis, pulmonary infiltrates and fibrosis,renal toxicity and depigmentation.It is indicated in lymphoblastic leukemiaand choriocarcinoma, psoriasis, adjuvanttherapy of non-metastatic osteosarcoma andto reduce corticosteroid requirement inpatients with severe steroid dependent asthma.It is also used as ‘disease modifyingdrug’ in rheumatoid arthritis as it reduceslymphocyte proliferation, rheumatoidfactor production and interferes with therelease of inflammatory cytokines.6-MERCAPTOPURINEIt is an antimetabolite antineoplastic,which being an analogue of hypoxanthineand adenine inhibits purine metabolism.After oral administration absorption isincomplete and drug is metabolised in liver.The active metabolites have longer half lifethan parent drug.Adverse effects include nausea,vomiting, diarrhoea, cholestasis, bonemarrow depression, pancreatitis, oral andintestinal ulcers. Rarely hepatic necrosis.It is used in acute leukaemia,choriocarcinoma and chronic granulocyticleukaemia.FLUOROURACILIt is fluorinated analogue of pyrimidine,act by binding the enzyme thymidylatesynthetase and preventing the productionof basic component of DNA-thymine. Itis converted into 5-fluorouridinetriphosphate and is incorporated into RNAwhere it interferes with RNA processingand function.It is used in the treatment of carcinomaof breast, colon, urinary bladder, stomachliver, rectum and ovaries.The major toxicity includes myelosup-pression and mucositis.CYTARABINECytarabine or cytosine arabinosidecompetitively inhibits DNA polymerase
Chemotherapy of Malignancy375and blocks generation of cytidylic acidand is a drug of choice for acute myeloidleukaemia.It is indicated in acute myelocyticleukaemia, acute lymphocytic leukaemia,chronic myeloid leukaemia (blast phase),non-Hodgkin’s lymphoma in children,treatment and maintenance of meningealneoplasms, erythroleukaemia.Adverse effects include depression ofbone marrow which gives rise to leukopenia,thrombocytopenia, reticulocytopenia. GIdisturbances, oral and anal ulceration,hepatic and renal dysfunction andperipheral neurotoxicity with high doses.CYTOTOXIC ANTIBIOTICSThese drugs are obtained from variousmicroorganisms and have antitumor activity.They act by binding to double stranded DNAand interfere with its functions.DACTINOMYCIN (ACTINOMYCIN D)It is a potent antitumor antibioticisolated from Streptomyces organism. Itbinds tightly to double stranded DNAthrough intercalation between adjacentguanine cytosine base pair and inhibit allforms of DNA dependent RNA synthesis.It is used in choriocarcinoma,Hodgkin’s disease and Wilm’s tumour incombination with irradiation.Adverse effects include damage ofskin, alopecia, bone marrow depression,vomiting and diarrhoea.DOXORUBICINIt is a cytotoxic anthracycline antibioticisolated from Streptomyces pneuceticus. It isDNA intercalator and it generates freeradicals.It is usually administered byintravenous route. It does not cross bloodbrain barrier.Adverse effects include nausea, vom-iting, diarrhoea, fever, red urine (harmless),ventricular arrhythmia, severe local tissuedamage on extravasation, cardiotoxicity,bone marrow depression, anorexia, stoma-titis, alopecia, conjunctivitis.It is indicated in GI tract carcinoma,acute myeloblastic leukaemia, bronchogenic,breast and ovarian carcinoma, soft tissueand bone sarcomas, malignant lymphoma;primary management of nonmetastaticbladder carcinoma (intravesical administra-tion), Wilm’s tumor and neuroblastoma.Epirubicin (FARMORUBICIN) isstructurally similar to doxorubicin and issimilarly effective in the treatment of breastcancer, lung cancer and lymphoma.BLEOMYCINIt is a mixture of cytotoxic glycopeptideantibiotic isolated from a strain ofStreptomyces verticillus.It exerts its cytotoxic action by causingfragmentation of DNA and it generatesfree radicals.It is usually administered by parenteralroute. It does not cross blood brain barrier.Adverse effects include nausea, vom-iting, allergic reactions, fever, anaphylaxis,skin rash, Raynaud’s phenomenon, stoma-titis, pulmonary fibrosis, hyperpigmenta-tion, renal and hepatic toxicity.Bleomycin is used as palliative and ad-juvant to surgery and radiation therapy in
376testicular tumour, squamous cell carcinomaof skin, neck and head, genitourinary tractand oesophagus neoplasm, malignancy ofcervix, Hodgkin’s and non Hodgkin’s lym-phoma, choriocarcinoma and embryonalcell carcinoma of testis, brain tumour andglioma.MITOMYCIN-CIt is a highly toxic antibiotic withantitumour activity isolated fromStreptomyces caespitosus.It inhibits DNA synthesis and crosslinks DNA.After oral administration it exhibitsinconsistent absorption. Hence it isadministered by IV route and is metabolisedin liver.It is used in the treatment of adenocar-cinoma, lymphosarcoma and seminoma. Itis also used in squamous cell carcinoma ofcervix.Adverse effects include nausea,vomiting, alopecia, pulmonary fibrosis,bone marrow depression, sterility,amenorrhoea and renal toxicity.VINCA ALKALOIDSThe vinca alkaloids are isolated from plantVinca rosea. They are cell cycle specific andmitotic inhibitors.VINCRISTINEIt blocks mitosis and producesmetaphase arrest by binding to microtu-bular protein ‘tubulin’, preventing itspolymerization.After oral administration the absorp-tion is unpredictable. It is metabolised inliver.Adverse effects include local reactionif extravasation occurs, constipation, para-lytic ileus, jaw pain, alopecia, bone mar-row depression, peripheral neuropathy,inappropriate ADH secretion, shortness ofbreath and bronchospasm.It is indicated in acute leukaemias, lym-phomas, Ewing’s sarcoma, neuroblastoma,Wilm’s tumour and idiopathic thrombocy-topenic purpura.VINBLASTINEIt interferes with metabolic pathwaysof amino acids leading from glutamic acidto the citric acid (Krebs) cycle and urea.Vinblastine has an effect on cell energyproduction required for mitosis andinterferes with nucleic acid synthesis.Reversal of antitumour effect by glutamicacid or tryptophan has occurred.It undergoes rapid distribution andextensive tissue binding following IVinjection. It is metabolised in liver.Adverse effects include hepaticfunction impairment, leucopenia,aspermia, nausea, vomiting, hypertensionand alopecia.It is indicated in Hodgkin’s and nonHodgkin’s lymphoma, testicularcarcinoma, mycosis fungoides and Kaposi’ssarcoma.VINORELBINEIt is semisynthetic vinca alkaloid. Itinterferes with microtubules, in mioticspindle fibres leading to cell cycle arrest
Chemotherapy of Malignancy377in metaphase.It is used for the treatment of non smallcell lung carcinoma, breast carcinoma,Hodgkin’s disease, ovarian carcinoma,squamous cell carcinoma of the head andneck, cervical squamous cell carcinoma,renal cell cancer and Kaposi’s sarcoma.TAXANESPACLITAXELIt is an alkaloid ester derived from thewestern yew Taxus brevifolia.It is a diterpenoid compound and is anatural product with antitumour activity.It binds specifically to the βββββ-tubulinsubunit of microtubule and appears toantagonise the disassembly of thiscytoskeletal protein i.e. enhancespolymerization of tubulin. Arrest in mitosisfollows. The cell killing is dependent onboth drug concentration and duration ofcell exposure.It is indicated in metastatic ovarian andbreast cancer.Adverse effects include bone marrowdepression, hypersensitivity reactions, chestpain, bradycardia, sensory neuropathy,nausea, vomiting, diarrhoea, alopecia andimpaired liver function tests.Docetaxel (DOXOTEL), a related drug,used in metastatic breast cancer.TOPOISOMERASE-I INHIBITORSIRINOTECANIt inhibits topoisomerase-I, the enzymewhich is involved in DNA replication.It is used in the treatment of metastaticcarcinoma of colon or rectum.Adverse effects include vomiting, di-arrhoea, abdominal discomfort, leukopenia,anemia, neutropenia, haemorrhage, insom-nia and dizziness.TOPOTECANTopotecan also inhibits topoisomerase I.Adverse effects include abdominal dis-comfort, vomiting, diarrhoea, intestinalobstruction, nausea, stomatitis, anorexia,bone marrow suppression (primarily neu-tropenia, anaemia and thrombocytopenia).It is valuable in control of metastaticovarian cancer, including cisplatinresistantneoplasms.HORMONE AND HORMONE ANTAGONISTSThese are not cytotoxic drugs. They act bymodifying the growth of hormonedependent tumours.FOSFESTROL (STILBOESTROL)Fosfestrol is a synthetic non-steroidalestrogen which is activated by the enzymeacid phosphatase to produce stilboestrol.Metabolism occurs primarily in the liver.It is used as palliative treatment of dissemi-nated mammary or prostatic carcinoma.Adverse effects include hepatic cuta-neous porphyria, perineal pain, erythemaand feminising effects in man.ETHINYL ESTRADIOLIt is also indicated in palliative treat-ment of disseminated mammary or pros-tatic carcinoma. The detailed pharmacol-
378ogy is discussed in chapter ‘Oral Contra-ceptives.’MEGESTROL ACETATEIt belongs to group of progesteronewhich are mainly used as second or thirdline therapy in breast and endometrialcancer.Adverse effects include nausea, acne,fluid retention, GI disturbances and weightchanges.TAMOXIFENIt exerts its action by binding toestrogen receptors. Tumours with estrogenreceptors respond.It is given orally, the drug has biphasichalf life and is primarily excreted in bile.Adverse effects include nausea,vomiting, hot flushes, vaginal bleeding,pruritus vulvae and menstrualirregularities.It is used as palliative treatment ofestrogen receptor positive advanced ormetastatic carcinoma of breast.MISCELLANEOUS AGENTSHYDROXYUREAThe primary action is inhibition ofenzyme ribonucleoside diphosphatereductase. The drug is specific for S phaseof the cell cycle and causes cell to arrestat the G1-S interface.After oral administration it is readilyabsorbed from GI tract. Hydroxyureareadily crosses blood brain barrier.It is indicated in treatment of chronicgranulocytic leukaemia, polycythemiavera, essential thrombocytosis, melanoma,metastatic or inoperable carcinoma ofovary. In combination with radiotherapyin carcinoma of cervix, head, neck andlung.Adverse effects include nausea, vom-iting, rash. Bone marrow depression is themajor toxic effect. Alopecia, stomatitis,dysuria; inflammation and increased pig-mentation may occur in areas exposed toradiation. Rarely neurological distur-bances occur.PROCARBAZINEAfter metabolic activation, it depoly-merizes DNA and causes chromosomaldamage and also nucleic acid synthesisinhibition. It is found to be effective inHodgkin’s disease and carcinoma oflungs.Adverse effects include drowsiness,restlessness, anaemia, leucopenia, throm-bocytopenia, bone marrow toxicity anddisulfiram like reaction with alcohol.L-ASPARAGINASEIt destroys essential amino acid(asparagine) hence leukaemic cells aredeprived of amino acid and leads to celldeath. It is given by parenteral route.Adverse effects include nausea, vom-iting, headache, fever, abdominal pain,hyperglycemia leading to coma, hypersen-sitivity, renal damage, coagulation defects,thrombosis, CNS depression or hyperex-citability and acute haemorrhagic pancre-atitis.It is used in the treatment of malignantlymphoma and acute leukaemia.
Chemotherapy of Malignancy379CISPLATINIt acts by cross-linking of DNA. It alsohas radiomimetic property. It is bound toplasma proteins and is excreted slowlyunchanged in urine. It is effective inmetastatic testicular and ovariancarcinoma, advanced bladder carcinomaand refractory squamous cell head and neckcarcinoma.Adverse effects include nausea, vomit-ing, fever, anaphylactic reactions, hypokale-mia, hypomagnesaemia, haemolysis, renaldamage, sterility, teratogenesis, ototoxicity,peripheral neuropathy, Raynaud’s diseaseand bone marrow depression.INTERFERON ALFAIt is highly purified protein containing165 amino acids and is manufactured byrecombinant DNA technology.Mechanism of action is not clearlyunderstood but direct antiproliferativeaction against tumour cells and modulationof the host immune response may playimportant roles.It exhibits half life of 3.7-8.5 hours.Alpha interferons are filtered through theglomeruli and undergo rapid proteolyticdegradation during tubular reabsorption.It is indicated in hairy cell leukemia,AIDS related Kaposi’s sarcoma (thedetailed pharmacology and its use asantiviral agent is discussed in chapter‘Antiviral agents’).Adverse effects include GI haemor-rhage, leukopenia and elevation in liverenzyme levels.Recently introduced interferon a-2b isused in chronic myeloid leukaemia, chronichepatitis B and C.IMMUNOSUPPRESSANTSThe drugs like azathioprine andcyclosporine A are used chiefly to preventtransplant rejection and in the treatmentof autoimmune diseases. They are used toprevent graft rejection after kidney, liver,lung, pancreas transplant or bone marrowtransplantation.AZATHIOPRINEIt is a purine antimetabolite which hasmarked effect on T-lymphocytes, suppressescell mediated immunity (CMI). It selectivelyaffects differentiation and functions of Tcells and inhibits cytolytic lymphocytes. It isused primarily as immunosuppressant inorgan transplantation, progressive rheuma-toid arthritis and some other autoimmunediseases.CYCLOSPORINEIt is a cyclic polypeptide with 11 aminoacids. It selectively inhibits T-lymphocytesproliferation, IL-2 and other cytokine pro-duction. It is the most effective drug forprevention and treatment of graft rejec-tion reaction. It is used in cardiac, hepatic,renal, bone marrow transplantation andas second line drug in rheumatoid arthri-tis, inflammatory bowel disease, dermato-myositis, bronchial asthma and certainother autoimmune diseases.Mycophenolate mofetil, a semisyntheticderivative of mycophenolic acid, isolatedfrom the mould Penicillium glaucum is usedin kidney and liver transplant patient.Another newer compound mizoribine isused in kidney transplantation.
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Vitamins and TraceElementsSection 10Section 10
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(Mode of Action of Drugs)PharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsChapter1. 4Chapter10.1Vitamins and TraceElementsVitamins are exogenous chemicalsubstance required by the body in very smallamount for the various metabolic functionsof the body and categorized as essentialnutrients. They do not yield energy butenable the body to use other nutrients andare primarily used in the prevention andtreatment of certain deficiency diseases.Vitamins are vital for normal metabo-lism in body. They vary in their chemicalstructure and are supplied in very smallquantity in diet, because they are not syn-thesized in body or their rate of productionis not sufficient for maintenance of health.Vitamin deficiency leads to development ofdeficiency symptoms. Different vitaminpreparations are available for treatment andprophylaxis. Most of the vitamins are non-toxic but on chronic administration cancause toxicity especially vitamin A and D.Vitamins are classified into two maingroups:I. Fat soluble vitamins, includesvitamin A, D, E and K.II. Water soluble vitamins, includes B-complex group and vitamin C.The fat soluble vitamins are stored in thebody and excessive administration of fatsoluble vitamins can cause toxicity, whilewater soluble vitamins are rapidly excretedin the urine and cause very less toxicity.The different market preparationavailable for vitamins are given in table10.1.1 and the deficiency diseases whichoccur with deficient supply of variousvitamins are listed in table 10.1.2.Table 10.1.1: Classification of various preparationsof vitamins.Vitamin A (ROVIGON)Vitamin D (CALCIROL)Vitamin E (EVION)Alfacalcidol (ALCIDOL)Vitamin B complex groupVitamin B1 (Thiamine; BENALGIS)Vitamin B2 (Riboflavin; LIPABOL)Vitamin B5 (Calcium pantothenate; SIGMAPANTOTHENATE)Vitamin B6 (Pyridoxine; PYRICONTIN)Vitamin B12 (Cyanocobalamin/Mecobalamin;METHYCOBAL)Folic acid (FOLVITE)Vitamin C (Ascorbic acid; CELIN)Multivitamins preparationsB1 + B6 + B12 (NEUROBION)B complex (B1, B2, B3, B5, B6, B12 + folic acid;BECOSULE)Vitamins and TraceElements
Section 10/ Vitamins and Trace Elements384FAT SOLUBLE VITAMINSVITAMIN AVitamin A is widely distributed in plantand animal foods. In plants, the mainsource of vitamin A is green leafyvegetables e.g. spinach and amaranth. Thedarker the green leaves, the higher thecarotene present. Vitamin A is also presentin green & yellow vegetables and fruits e.g.pumpkin, papaya and mango, and in rootse.g. carrots (richest source among plantsource). The most important carotenoid isbetacarotene which has the highest vitaminA percentage. Carotenes are converted tovitamin A in the small intestine.In animal foods, vitamin A is present inliver, eggs, butter, cheese, milk, fish and meat.Fish liver oil are the richest source of retinol.It is vital for the functioning of retina.Vitamin A is essential for differentiationand growth of epithelial tissue. It enhancesfunction of immune system and protectagainst development of certain malignan-cies. Different forms of vitamin A mediatedifferent functions.Table 10.1.2: Diseases due to deficient supply of vitamins.Vitamins Deficiency1. Vitamin A Night blindness (inability to see in dim light), conjunctivalxerosis (dry and non-wettable conjunctiva), corneal xerosis(dry and non-wettable cornea and become opaque), kerato-malacia (cornea becomes soft and burst open and vision islost), Bitot’s spots, growth retardation, dry and rough skin,sterility due to faulty spermatogenesis.2. Vitamin D Rickets (reduced calcification of growing bones).3. Vitamin E Axonal degeneration, ophthalmoplegia (however, vitamin Edeficiency does not occur clinically).4. Vitamin K Decreased prothrombin content of blood and blood clotting timeis prolonged.5. Vitamin B1 (Thiamine) Beriberi (characterized by nerve involvement – peripheral neu-ritis), Wernicke’s encephalopathy (characterized by ophthalmo-plegia, polyneuritis and mental disorientation).6. Vitamin B2 (Riboflavin) Angular stomatitis (occurs in malnourished children).7. Vitamin B3 (Niacin or Nicotinic acid) Pellagra (characterized by diarrhoea, dermatitis and dementia).8. Vitamin B5 (Pantothenic acid) Clinical deficiency is not known (has role in biosynthesis ofcorticosteroids).9. Vitamin B6 (Pyridoxine) Peripheral neuritis, mental confusion, impairs the optimalutilization of pyridoxine [INH (anti TB drug) is a recognisedantagonist].10. Vitamin B12 (Cyanocobalamin) Megaloblastic anaemia (pernicious anaemia), demyelinatingneurological lesions in the spinal cord & infertility.11. Vitamin C (Ascorbic acid) Scurvy12.Folic acid Megaloblastic anaemia and gastrointestinal disturbances suchas diarrhoea, distension and flatulence. Severe folate deficiencycauses infertility or even sterility.
Vitamins and Trace Elements385Retinoids: They influence a wide varietyof biological activities including cellularproliferation, cellular differentiation,immune function, inflammation. e.g.tretinoin, isotretinoin, etretinate.Isotretinoin is a retinoid, recentlyapproved for use in capsule form (10-20 mg).It decreases the amount of sebum thatsebaceous glands produce. Isotretinoin exhibitsantiproliferative and antiandrogenic effects onthe sebaceous glands. It also interacts with theformation of androgens in sebaceous glands.It is indicated in the treatment of severenodular acne, acne conglobata and recalcitrantacne. It is available in International marketunder the brand name ‘ACCUTANE’ byRoche pharmaceuticals.Deficiency symptoms: Bitot’s spots,xerosis, night blindness, keratomalacia,diarrhoea, follicular hyperkeratosis,papular eruptions, drying of epidermis,urinary calculi, degeneration of testis,impaired spermatogenesis, sterility,abortion, impairment of smell and taste.It is indicated in night blindness, vitaminA deficiency (in infants, in pregnancy,lactation, malabsorption syndrome), forprophylaxis of vitamin A deficiency, acne,ichthyosis, psoriasis, xerophthalmia, Bitot’sspots (especially children).Dosage:Severe deficiency withxerophthalmia: 50,000 IU per day for threedays followed by 50,000 IU per day for twoweeks.Severe deficiency: 100,000 IU per dayfor three days followed by 50,000 IU perday for two weeks.Children: 5,000 to 10,000 IU per dayfor two weeks.VITAMIN DThe term vitamin D is used for a rangeof compounds which possess the propertyof preventing or curing rickets. They includeergocalciferol (calciferol, vitamin D2), chole-calciferol (vitamin D3), dihydrotachysterol,alfacalcidol (1α-hydroxycholecalciferol) andcalcitriol (1,25-dihydroxycholecalciferol).It plays an important role in calciummetabolism. It regulates calciumhomeostasis and maintains normal levels ofplasma calcium and phosphate.Deficiency symptoms: Rickets occursin patients who are having deficiency ofvitamin D. The bones are unusually softand due to stress and strain of weightbearing produce characteristic deformities.It is indicated in prophylaxis andtreatment of rickets, postmenopausalosteoporosis, Fanconi syndrome andhypoparathyroidism.Adverse effects include headache,weakness, nausea, vomiting, dry mouth,muscle pain, constipation, somnolence,ectopic calcification, hypertension,nephrocalcinosis and weight loss.ALFACALCIDOLIt regulates calcium metabolism byincreasing calcium and phosphateabsorption from the intestinal tract and alsomobilises minerals from the bone.After oral administration it is absorbedin the small intestine and undergoes rapidmetabolism to 1,25 (OH)2 D3 in liver andfurther distribution to bone and intestine isnearly similar to its physiological distribution.
Section 10/ Vitamins and Trace Elements386Adverse effects include hypercalcae-mia and hyperphosphataemia.It is indicated in osteoporosis, hypo-parathyroidism, hyperparathyroidism(with bone disease), renal osteodystrophy,nutritional and malabsorptive rickets,hypophosphataemic vitamin D resistantrickets and osteomalacia.Dosage:Adults: Initially 1 mcg daily adjustedaccording to response. Elderly: Initially 0.5mcg daily adjusted according to response.Children: Over 20 kg: Initially 1 mcgdaily adjusted according to response.Under 20 kg: 0.05 mcg/kg body wt. daily.VITAMIN EIt is an antioxidant vitamin. Itpresumably prevents oxidation ofcoenzyme Q and inhibits generation ofperoxidation products from unsaturatedfatty acids.Vitamin E is a family of eight com-pounds, four tocopherols and fourtocotrienols. Tocotrienols appear to affecta key enzyme in the liver (HMG CoA re-ductase), which plays a key role in the syn-thesis of cholesterol. As such tocotrienolshelp maintain good cardiovascular health.Vitamin E is an antioxidant and preventsthe oxidation of LDL (the bad cholesterol).Vitamin E functions as anticoagulant,which means it delays the clotting of theblood. It can help prevent thrombosis, theformation of blood clots in the arteries.Deficiency symptoms: In vitamin Edeficiency in experimental animals themanifestations are seen in several systemsincluding cardiovascular, reproductive andhaematopoietic.The clinical manifestations are axonaldegeneration, gait disturbances, ophthal-moplegia, hyporeflexia and necrotizingmyopathy.Adverse effects include nausea,fatigue, headache, blurred vision, diarrhoea.It is indicated in premature infantsexposed to high concentration of oxygen,correction of established vitamin E defi-ciency, in patients at risk of developingvitamin E deficiency, nocturnal musclecramps, intermittent claudication,fibrocystic breast disease, coronary arterydisease and as an antioxidant.Dosage:Adults:– Nocturnal muscle cramps: 400 mg dailyfor 8 to 12 weeks.– Intermittent claudication: 400 mg dailyfor 12 to 18 weeks.– Fibrocystic breast disease: 600 mg dailyfor 2 to 6 months.Children: 200 mg daily.WATER SOLUBLE VITAMINSVITAMIN B GROUPVitamin B1 (Thiamine)Vitamin B1 is the first member of the Bcomplex.Thiamine pyrophosphate is a coenzymeand the active form of vitamin B1. It func-tions as coenzyme in decarboxylation of α-keto acid and in hexose monophosphateshunt.Deficiency symptoms: In severevitamin B1 deficiency beriberi develops.
Vitamins and Trace Elements387It is indicated in wet beriberi, dryberiberi, Wernicke’s encephalopathy,prophylaxis of thiamine deficiency,hyperemesis gravidarum, Korsakoff’ssyndrome, chronic alcoholics, multipleneuritis, toxic and confusional states,delirium tremens and anorexia nervosa.Dosage: Mild chronic deficiency: 10-25mg daily; severe deficiency, 200-300 mgdaily.VITAMIN B2 (RIBOFLAVIN)It carries its physiological function inits active forms, flavin mononucleotide(FMN) and flavin adenine dinucleotide.These coenzymes are involved in variousbiochemical reactions.Deficiency symptoms: It is character-ized by glossitis, dermatitis of trunk andextremities, angular stomatitis, cheilosis,anaemia, neuropathy, cataract formationand vascularization of cornea.It is indicated in arteriosclerosis, asadjunct in treatment of hypertension,diabetes and obesity.VITAMIN B3 (NIACIN)Niacin was initially called pellagrapreventing factor.It is converted to coenzymes,nicotinamide adenine dinucleotide (NAD)or nicotinamide adenine dinucleotidephosphate (NADP). These coenzymes arebound to hydrogenases, function asoxidants by accepting hydrogen andelectrons from substrates and becomereduced.Deficiency symptoms: In niacindeficiency, pellagra develops. The mainfeatures of this condition are diarrhoea,dermatitis and dementia. Nausea, vomiting,stomatitis, dizziness, depression, insomnia,headache develops. In severe deficiencyhallucinations and dementia occurs.Adverse effects include flushing,activation of peptic ulcer, vomiting,diarrhoea, pruritus, skin rash and transientheadache.It is indicated in pellagra, for prophy-laxis, Hartnup disease, hyperlipoprotein-aemia.VITAMIN B5 (CALCIUMPANTOTHENATE)Pantothenic acid is traditionallyconsidered to be vitamin B substance. It iswidely distributed in meat, legume andwhole grain cereals, egg, milk, vegetablesand fruit.It is a component of coenzyme A whichis essential in the metabolism of carbohy-drate, fat and protein.Deficiency symptoms: Deficiency ofpanthothenic acid is unlikely in manbecause of its widespread distribution infood, though it has been administered bymouth as a nutritional supplement as thecalcium salt and usually in conjunctionwith other vitamins of the B group.Dosage: 50 to 100 mg per day.VITAMIN B6 (PYRIDOXINE)It is involved as a coenzyme (pyridoxalphosphate) in metabolism of tryptophan,in several metabolic transformations ofamino acids including transamination,decarboxylation and racemization.Deficiency symptoms: Peripheralneuritis, seizures, stomatitis, anaemia,