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Alkylating Agents Presented by : Clinical Pharmacist: Heba Sabry,Reem Ahmed,Dina redda,Dalia El-Magraby and Heba Othman. Pharm-D 4 (2009) Group 1. Alkylating Agents Contain an alkyl group (highly reactive chemical group which allow them to form irreversible covalent bond with other molecules specially at the cross link of DNA). In DNA, the N-7 position of guanine is especially susceptible to alkylation, it interferes with separation of the strands and prevent mitosis. COMMON STRUCTURE CH2CH2Cl CH2CH2Cl or R N Ar N CH2CH2Cl CH2CH2Cl CH2CH2Cl Ar N + CH2CH2 - Ar CH2CH2Cl N -- Nu Enzyme, proteins DNA, RNA CH2CH2Cl CH2CH2 Nu Ar N CH2CH2Cl Alkylating Mechanism of Mechlorethamine With Guanine Base O N HN NH2 O HN + N N Alkylation bischloroethyl group N CH2CH2Cl e.g. NH2 N R N N CH2CH2Cl DNA Strand B N DNA Strand A O 1 HN 2 NH2 N7-N7 Biguanyl DNA cross link 6 CH2CH2 5 3 4 N Cl N 7 N DNA Strand A CH2CH2 Cl N O NH N DNA Strand B NH2 1. Attachment of the alkyl groups to DNA bases. 2-Formation of cross bridges, bonds between atoms in the DNA. 3-Induction of mispairing of the nucleotides leading to mutations. Classification of alkylating agents Nitrogen Mustard Nitrosourea Ethylenamines Melphalan Carmustine Chlorambucil Lomustine Ifosfamide Cyclophosphamide Thiotepa Alkylsulfonate Triazine Busulfan DTIC Metal salts Cisplatin Carboplatin Oxatiplatin Nitrogen Mustard Cyclophosphamide Trade name Ifosfamide Endoxan® cytoxan® Structure CH2CH2Cl O N P Holoxane® N P N CH2CH2Cl Well absorped orally. Absorption Distribution Widely BBB Vd Metabolism PPB O O distributed. Cross.(brain tumour) 0.35-1.2 L/Kg. 10% - 56% minimal. CH2CH2Cl N H CH2CH2Cl No oral form Widely BBB Vd PPB distributed. Cross. 0.35-0.85 L /Kg. Negligible. Prodrugs metabolised by Cytochrome p450 to active metabolites in the liver (acrolein and phosphoramide mustard which is a potent alkylator) . (4-OH cyclophosphamide and aldophosphamide) Elemination Unchanged 25% of oral and IV, active metabolite 62% in the urine for 48 hours. Renally: 70-86%, 61% unchanged after high dose (5 gm/m2), 18% unchanged Metabolism of Ifosfamide Generation of CAA may explain differing antitumoral activities of IFO and cyclophosphamide and Suppression of CAA metabolic pathway , although it may be beneficial as a means of reducing neurotoxic responses, may also be associated with a reduction in antitumor effect. Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite, 4carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide have been shown to interact with DNA. Cyclophosphamide Dialysis Dialyzable. Administer the dose post hemodialysis. Ifosfamide Not dialysable. IV over 30-60 min, continuous IV infusion Administration •PO. 1 hour before meal . •IV Push over 3 to 5 min. •Bolus infusion over 15-30 min, slow infusion 1-24 hours. Adverse effects (Dose related) •Heamorrhagic cyctitis, Hematuria. . •Myelosuppression. •Hyperurecemia. •Gastrointestinal side effects. •Pulmonary toxicity (interstitial pneumonitis). •Nervous system toxicity , and nephrotoxicity with ifosfamide.(Somnolence, confusion to sever encephalopathy). Drug interaction •Microsomal enzyme inducer (phenobarbital , phenytoin) •Microsomal enzyme inhibitor ( chloramphenicol, chloroquin.) •Inc. sedative effect of succynylcholine . •Nephrotoxic drugs eg. Cisplatin •Cyclophosphamide potentiate cardiac toxicity of anthracyclines. Cyclophosphamide Ifosfamide Indication Cancer of the bladder, bones, cervix, endometrium, breast, lungs, prostate, adrenal cortex, ovaries Soft tissue sarcomas . Thymoma, brain tumour Wilms' tumour Recurrent testicular cancer and germ cell tumors Sarcomas (soft-tissue, osteogenic sarcoma, Ewing's sarcoma) Non-Hodgkin's lymphoma Hodgkin's disease Non-small cell and small cell lung cancer Bladder cancer Head and neck cancer Cervix cancer Doses 40-50mg/Kg in divided doses over 2-5 day. CAF : 500mg/m2 FEC: 600mg/m2 1.2-2.5g/m2 for 3-5 days. Drug Reconstitutio Final n concentration Dilution Cyclophospha mide 1000 mg SWI 1000 mg: 50 mL 2000 mg: 100 mL Signs of melting is yellowish viscous liquid. < 1 g: 100 NS* > 1 g: 250 NS* high dose in BMT: may need 500 NS* NS,10 D5W, D5NS, D5-Ringer’s, Lactated Ringer’s, Sodium Chloride 0.45%, Sodium Lactate. 6d in ref, 24h at Rt. 2000 mg (BMS) (RT)53 no preservative 20 mg/mL 48 h F, 24 h RT Ifosfamide 1000 m g 3000 mg (Baxter) (RT) no preservative 1000 mg: 20 mL SWI109 3000 mg: 60 mL SWI shake well 50 mg/mL 48 h F 0.6–20 mg/mL 500–1000 mL*NS, D5W, D5-NS, D5-1/2NS, Lactated Ringer’s 72h. In ref. 24 h F, RT when mixed with mesna10 D5W or Lactated Ringer’s when mixed Prophylaxis against hemorrhagic cystitis Against hemorrhagic cystitis, hyperhydration and mesna given. IV dose of mesna is 20% given at 0, 4, 8 hours or (1mg/mg drug). May be given orally at 4, 8 hours at 40% of the drug dose diluted in water or juice. Patients are encouraged to: - drink plenty of water ( fluids) during therapy( most adults will require at least 2L/day ) . -Void frequently . - Avoid taking the drug at night . Mesna react with acrolein and urotoxic metabolites to form nontoxic metabolites . Oral absorption of mesna is 50% bioavailability so oral dose should be double that of IV dose. Mesna Upon entering the bloodstream mesna is immediately converted to an inactive disulfide form, dimesna (dithiodiethanesulfate) which is subsequently filtered and secreted by the kidneys, where the enzymes thiol transferase and glutathione reductase reduce dimesna back to mesna. The free sulfhydryl (thiol) groups of mesna combine directly with a double bond of acrolein and with other urotoxic 4droxyoxazaphosphorine metabolites (4-hydroxycyclophosphamide and 4-hydroxyifosfamide) to form stable nontoxic compounds. The metabolite acrolein has been implicated as the major causative agent in oxazaphosphorine-induced urothelial toxicity Chlorambucil Trade name Leukeran® 2 mg tab. Uses CLL , Hodgkin and non Hodgkin lymphomas ,other uses as Behcet syndrome ,nephrotic syndrom and autoimmune haemolytic anemia. Doses 0.1-0.2 mg/kg /day. Absorption Rapid and complete . Melphalan Alkeran® either 2 mg tab . or 50 mg vial Multiple myeloma,ovarian cancer, breast cancer,melanoma, certain sarcomas,preperative BMT regimens and other uses as amyloidosis. Oral: 0.1-0.5 mg/kg/day (duration and interval according to the indication). IV: 10-140 mg /m2: Oral: Incomplete and variable food reduces the absorption (spacing). Distribution Widely distributed. Vd 0.14-0.24L/Kg PPB 99% Widely distributed. Vd 0.5-0.6L/Kg , PPB 60- 90% Metabolism Hepatic microsomal enzyme oxidation. Active metabolite : phenylacetic acid mustard. In plasma through hydrolysis to mono,dihydroxy products Chlorambucil Melphalan Renally excreted. Elimination Urinary excretion is low. If BUN = 30 mg/dl or more :50 %reduction Administration One time with food. On an empty stomach . Reconstitute with 10 ml diluent and dilute in NS ,IV infusion over 15 min. May intraarterial,intraperitoneal or by regional isolation perfusion (melanoma) Adverse reactions Seizures.(high risk in children and with high doses) Haematologic: anemia,leukopenia and thrombocytopenia may need dose reduction. Bronchopulmonary dysplasia. May Mutagenic,carcinogenic infertility Drug interaction arterial or venous thrombus. and teratogenic . NSAID,anticoagulant : risk of bleeding ↑ Local:extravasation and phlebitis. Dermatologic: :rash,dermatitis and allergy. Mutagenic,carcinogenic and teratogenic infertility . ↑ :pulmonary toxicity NSAID,anticoagulant : risk of bleeding ↑ Cyclosporine:nephrotoxicity Carmustine ETHYLENAMINE DERIVATIVES Thiotepa 15 and 30 mg vials Uses Bladder,breast and ovarian cancer Carcinomatous meningitis, soft tissue sarcoma, Hodgkin , NHL and in preperative BMT regimens. Polyfunctional alkylating agent. (cytotoxic effect of Thiotepa and its metabolite Tepa). Absorption Poorly absorbed, unstable in acidic medium ( no oral form ) Distribution Rapid and extensive to tissues. Vd 0.25-1.6L/Kg. BBB crossing and reaches CSF. PPB About 40% . Thiotepa Metabolism In liver by oxidative desulfuration to triethylenephophoramide(TEPA). Elimination 60% of IV dose excreted in urine within 72 hours . Administration and doses Reconstitute with sterile water to reach 10 mg/ml, and further dilution with NS (1 mg/ml). IV push (the doses range from 20 mg/m2 to 1000 mg/m2) Intrathecal (carcinomatous meningitis) Intravesical (bladder irrigation) 60 mg in 60 ml NS and retained for 2 hrs. Adverse reactions Haematologic. Drug interaction Intravesicular injection may cause abdominal pain and hematuria. Decreases pseudocholinesterase activity, prolonged apnea when administered with succinylcholine. - With mivacurium : risk of respiratory deppression. Metals salts Trade Name Structure Cisplatin Carboplatin Oxaliplatin Platinol® Paraplatin® Eloxatin® O NH3 Cl Pt NH3 Cl NH3 NH3 Pt O •Cyclic rings increase chemical stability so they have less side effects and less reactivity. •Ring structure hydroxylated in water to form active moeity ,this reaction is slower in carboplatin than in cisplatin so carboplatin dose is 4-6 times that of cisplatin to produce the same cytotoxic effect. Cisplatin Carboplatin Oxaliplatin •Seminoma cancer •Ovarian cancer •Testicular cancer •Bladder cancer •Head and neck cancer •Cervical cancer •NSCLC •SCLC •Brain cancer •Neuroblastoma •Wilm’s tumor •retinoblastoma •Colorectal cancer CALVERT FORMULA = Total dose(mg)= Target AUC×(GFR+25) 85 mg/m2 in a combination therapy Indications •Seminoma cancer •Ovarian cancer •Testicular cancer •Bladder cancer •Head and neck cancer •Cervical cancer •NSCLC •SCLC •Eesophageal cancer •Brain cancer •Melanoma •Neuroblastoma Doses 50-100 mg/m2 as a single IV infusion every 34 weeks or 15-20 mg/m2 as a daili inf. For 5 days every 3-4 weeks Cisplatin Carboplatin Oxaliplatin Side effect •Nephrotoxicity •Ototoxicity •Neurotoxicity •Ematogenesis •Anaphylaxsis •Hypomanesemia and hypocalcemia Stability Further diluted in dextrose 5% or sodium chloride and protected from light •Hematological toxicity(thrombocytopenia ,leukopenia) •Anaphylaxsis Further diluted in dextrose 5% or sodium chloride but dextrose is preferable as after 24 hrs in saline there is 4-5% loss of carboplatin •Anaphylaxsis •neuropathy Further diluted in dextrose 5% only Cisplatin Carboplatin Oxaliplatin I.V within 2-6 h (1 mg/min) or 24 h infusion . It has been proposed that a longer infusion time of 6-8 hours may decrease gastrointestinal and I.V within 15' (short infusion). I.V within 2 h. Administration renal toxicities. Hydration • Only required for cisplatin Pretreatment hydration: Patients should be adequately hydrated before and for 24 hours after administration of cisplatin to ensure good urinary output and minimise nephrotoxicity. Hydration may be achieved by IV infusion of 2 litres of either sodium chloride IV infusion 0.9% or glucose-saline (eg glucose 4% in one-fifth sodium chloride IV infusion 0.9%) over a 2 hour period. During the last 30 minutes of the pretreatment hydration or after the hydration, 375 mL of 10% mannitol injection may be administered via a side-arm drip. Post-treatment hydration: Adequate hydration and urinary output must be maintained during the 24 hours following infusion. It has been suggested that IV hydration continue after treatment with the aim to administer 2 litres of sodium chloride IV infusion 0.9% or glucose-saline over a period of 6-12 hours. Radiation and Platinum Drug Interaction Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects. The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or Recommendations for minimizing Nephrotoxicity include: Prepare cisplatin in saline containing vehicles. Infusion rate of cisplatin. Vigorous hydration(2 L glucose and normal saline) + KCl + MgSO4 before cisplatin administrarion. Simultaneous administration of either mannitol or furosemide. Maintaining urine output 100-150 ml/hr for 24 hours after cisplatin administration. Avoid other nephrotoxic agents (aminoglycosides,amphotericin…etc.). Triazine Structure Dacarbazine(DTIC) •Acts as an antimetabolite inhibiting purine bases. •Dimethyl triazinoimidazole Carboxamide. Distribution Localized in liver. BBB minimal. Vd 0.63L/Kg PPB minimal . CONH2 N N N N N CH3 Metabolism Through liver enzyme. Elimination •Renal 50% unchanged, 10 – 20% as its metabolite. Administration Infused within 30-120 mins. with light protection as this compound unstable under light . CH3 Dacarbazine(DTIC) Adverse effects •Extravasation(irritant not vesicant). •Photosensitivity. •Hepatotoxicity. •Myelosuppression. Drug interaction •Microsomal enzyme inducer Phenobarbitane ,carbamazepine. •Microsomal enzyme inhibitor amiodarone, ciprofloxacin ,ketoconazole…etc. •Inc. effect of allopurinol due to inhibition of xanthine oxidase. Triazine Structure Dacarbazine(DTIC) Acts as an antimetabolite inhibiting purine bases. Dimethyl triazinoimidazole Carboxamide. CONH2 N N N N N CH3 CH3 Distribution Localized in liver. BBB minimal. Vd 0.63L/Kg PPB minimal . Metabolism Through liver enzyme. Elimination Renal Administration Infused within 30-120 mins. with light protection as this compound unstable under light . 50% unchanged, 10 – 20% as its metabolite. Dacarbazine(DTIC) Adverse effects Extravasation(irritant not vesicant). Photosensitivity. Hepatotoxicity. Myelosuppression. Drug interaction Microsomal enzyme inducer Phenobarbitane ,carbamazepine. Microsomal enzyme inhibitor amiodarone, ciprofloxacin ,ketoconazole…etc. Inc. effect of allopurinol due to inhibition of xanthine oxidase. Procarbazine Trade name Matulane®, Natulane Alkyl Sulphonate Structure Absorption 1-methyl-2-benzyl derivative of hydrazine completely absorbed from the GI tract. Distribution distributes widely throughout the body tissues, concentrating in the liver, intestinal wall, skin, and kidneys. Procarbazine crosses the blood-brain barrier . Metabolism extensive metabolism by the liver. Some metabolites have cytotoxic activity. Elimination Both Administration orally unchanged drug and its metabolites are excreted in the urine. Seventy percent of a dose can be found in the urine in the first 24 hours after a dose.. Procarbazine Adverse Effects principal toxic effect is bone marrow depression, resulting in leukopenia, anemia, and thrombocytopenia. In patients with preexisting renal, hepatic, or bone marrow impairment, severe toxicity may occur. Procarbazine therapy should be discontinued if the leukocyte count is reduced to 4000/mm3 or less, or if the platelet count falls to 100,000/mm3 or less Drug interaction CNS Depressants Concomitant administration of CNS depressants such as barbiturates, antihistamines, opiates, hypotensive agents, should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by procarbazine. •Other Drugs and Food Patients receiving procarbazine should not drink alcohol since a disulfiram-like reaction may result. Since procarbazine hydrochloride possesses some monoamine oxidase inhibitory activity, sympathomimetic drugs (including those in nose drops and cough preparations), local anesthetics, tricyclic antidepressants, and other drugs and foods with known high tyramine content such as cheese, bananas, yogurt, tea, coffee, wine and cola drinks, and cigarettes should be avoided. Busulfan Administartion Orally taken anytime during the day with large amount of fluids before or shortly after meal. IV infusion over 2 hours through central venous catheter. Adverse effects Skin Drug interaction Phenytoin.(induction hyperpigmentation. Seizures. Hepatic veno- occlusive disease. of glutathione S-transferase). Acetaminophen.(reduction of glutathione level) Itraconazole. NSAID and anticoagulant…..etc. Succinylcholine. NITROSOUREA Carmustine Trade name BCNU – BiCNU Structure Distribution O NO C NHCH2CH2Cl N CH2CH2Cl not absorbed orally Highly Vd BBB PPB Metabolism CCNU -CeeNU O ON Absorption Lomustine lipid soluble 2.6-3.3L/Kg crossing 80% NH C N CH2CH2Cl Absorbed orally. Highly lipid soluble, extensive tissue distribution. Vd no information found BBB crosing and reaches CSF PPB moderate 50% Hepatic microsomal enzyme oxidative system. Alkyl Sulphonate Trade name Busulfan Myleran®, Busulfex® O Structure CH3 S O OCH2CH2CH2CH2O O 1,4-Butanediol dimethanesulfonate Absorption Highly absorbed. Distribution Rapidly Vd BBB PPB S CH3 O distributed and eliminated from the plasma. 0.6-1L/Kg crosses. minimal. Metabolism Slowly , in the liver conjugated with glutathione. Elimination Renally ( 1% excreted unchanged ) . Carmustine Lomustine Elimination Renally: 60% to 70% of a dose is excreted in urine after 4 days as metabolites, 10% in respiration as CO2 . Renally: slowly 60% of a dose excreted after 48 hours with 50% excreted in the 1st 12 h. Administration IV administration over a period of 1-2 hours (to prevent irritation at injection site, burning with rapid infusion), reconstituted with alc. Orally on empty stomach with much water as single dose . Adverse reactions Vesicant.,Phelibitis Delayed Delayed Toxicity Pulmonary toxicity Reversible hepatotoxicity Nephrotoxicity GIT toxicity,confusion… hematological toxicity. Hepatotoxicity. Pulmonary toxicity. Drug interaction Amphotericin B. Hematologic Phenobarbital increase Carmustine The recommended dose as single agent •150 to 200 mg/m² intravenously every 6 weeks. Lomustine •130 mg/m2 as a single oral dose every 6 weeks repeat course of should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³, leukocytes above 4,000/mm³), and this is usually in 6 weeks Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose Uses Brain tumour,Non-Hodgkin's lymphomas,Hodgkin’sdisease,multiple myloma Carmustine Lomustine Elimination Renally: 60% to 70% of a dose is excreted in urine after 4 days as metabolites, 10% in respiration as CO2 . Renally: slowly 60% of a dose excreted after 48 hours with 50% excreted in the 1st 12 h. Administration IV administration over a period of 1-2 hours (to prevent irritation at injection site, burning with rapid infusion), reconstituted with alc. Orally on empty stomach with much water as single dose . Adverse reactions Vesicant. Disorientaion, Delayed hematological toxicity. Hepatotoxicity. Pulmonary toxicity. Drug interaction Amphotericin B. Microsomomal enzyme inducers. ataxia. Other alkylating agents : Temozolomide Trade name Uses Temodar® (cap.5,10,100 and 250 mg) Refractory astrocytoma. Absorption Completely absorped. Is a prodrug and by hydrolysis in the body turn into the active molecule Metabolism By liver ,cytochrome P450. Elimination Renal elimination ,dose reduction may be Administration and doses Side effects Drug interactions necessary in renal impaairment (no guidelines) Orally, once daily. Doses:150-200 mg/m2 for 5 days each 28 days cycle. Haematologic Severe nausea and vomiting Teratogenic. Valproic acid may reduce its clearance by 5 %. Other alkylating agents : Streptozocin Trade name Zanosar® (1 gm vial) Uses Pancreatic islet cell carcinoma and carcinoid tumour. Absorption Not absorped from GIT. Metabolism By liver Elimination Renal elimination. If crcl 10-50 ml/min:give 75 % of the dose. If less than 10 ml/min : give 50% of the dose. Administration and doses Direct IV injection or infusion.. Doses:500 mg/m2 IV /day for 5 days (every 6 weeks). 1-1.5 gm /m2 IV as a single dose (every week). Reconstitute 1 gm with 9.5 ml NS or D5%, may further dilution with NS or D5% and administered over 15 min ti 6 hrs. Side effects Nephrotoxicity in 25 -75 % of patients. Haematologic Severe nausea and vomiting. May induce DM in animals. Teratogenic. Drug interactions -Avoid using with other nephrotoxic drugs. Doxorubicin: it prolong doxorubicin half life so dose of doxorubicin should be reduced. -Phenytoin may diminish the cytotoxic effect.of streptozocin.