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PBL AMAC (PHARMACOLOGICAL TREATMENT (ADME (METHOTREXATE (Absorption…

- - - - Absorption
        
        Rapidly absorbed from the GI tract at low doses, higher doses are less well absorbed. Rapidly and completely absorbed after IM doses. Peak plasma concentrations after 1-2 hr (oral), 30-60 min (IM).
      - Metabolism
        
        Partly by intestinal flora. Does not undergo significant metabolism at low dose therapy; 7-hydroxy metabolite is detected at high-doses.
      - Excretion
        
        Primarily via urine; small amounts in bile, faeces. Some evidence of enterohepatic recirculation. Interindividual variation exists, patients with delayed clearance are at an increased risk of toxicity.
      - Distribution
        
        Tissues and extracellular fluids; crosses the blood-brain barrier and placenta; enters breast milk. Small amounts in saliva and breastmilk. 50% bound to plasma proteins. Bound as polyglutamate conjugates, bound drug may remain in the body for several mth, particularly in the liver .
    - - Absorption
        
        Unpredictable (oral); small amounts (topical).
      - Distribution
        
        Body tissues and fluids, including blood-brain barrier.
      - Metabolism
        
        Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive.
      - Excretion
        
        7% to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver.
    - - Distribution
        
        Widely distributed in the tissues, crosses the blood-brain barrier and placenta; enters breast milk.
        Volume of distribution: 30-50 L.
        Plasma protein binding: Approx 20%; >60% (some metabolites).
      - Metabolism
        
        Undergoes hepatic metabolism and converted to active metabolites acrolein, 4-aldophosphamide, 4-hydroperoxycyclophosphamide and nor-nitrogen mustard.
      - Absorption
        
        Well absorbed from the GI tract.
        Bioavailability: >75%.
        Time to peak plasma concentration: Approx 1 hr (oral); 2-3 hr (IV as metabolites).
      - Excretion
        
        Via urine (10-20% as unchanged drug); faeces (4%).
        Mean half-life: 4-8 hr.
  - - - Malignancies
    - - Acute lymphoblastic leukemias in children
      - Psoriasis chemotheraphy
      - Antineoplastic chemotherapy
        
        Alone or in combination in management of breast cancer, epidermoid cancers of head & neck
    - - Palliative treatment of malignant tumours : colorectal, breast, stomach, pancreatic, cervical, ovarian, uterine , bladder, & primary liver carcinoma
  - - - a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR).
      - inhibition of synthesis of tetrahydrofolate (THF), the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine - DNA, RNA, and key cellular proteins
    - - 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP)
        
        forms a covalently bound ternary complex with the enzyme TS and the reduced folate 5,10-methylenetetrahydrofolate
        
        5-fluorodeoxyuridine-5′-triphosphate (FdUTP),
        
        subsequently incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function
      - inactive in parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites
      - 5-fluorouridine-5′-triphosphate (FUTP)
        
        interferes with RNA processing and mRNA translation
    - - transfer of their alkyl groups to various cellular constituents.
      - intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent
      - major site of alkylation within DNA is the N7 position of guanine
      - interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups.
      - result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues.
      - DNA strand breakage through scission of the sugar-phosphate backbone of DNA.
  - - - 40 mg/m&sup2 IV; days 1 and 8 every 4 weeks
    - - IV inj. 12mg/kg once daily for 4 successive days
      - 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs
      - give a maintenance dose of 10–15mg/kg per week as a single dose
    - - 600 mg/m² intravenously (IV) with other antineoplastics
- - - - This drug may cause visual impairment and dizziness, if affected, do not drive or operate machinery.
    - - Methotrexate may cause birth defects if either parent is taking it during the time of conception or if the woman takes it during pregnancy
      - After treatment is stopped, women should wait at least one menstrual cycle and men should wait at least three months before trying to conceive.
      - Breast feeding is not recommended because the it can passed to the child through the mother's milk and it may be harmful to the child
    - - Do not breast feed while taking Fluorouracil
      - Do not take aspirin or products containing aspirin unless your doctor specifically permits this
  - - - METHOTREXATE
        
        Common
        
        Low blood count
        
        Mouth sores
        
        Loss of appetite
        
        Less common
        
        Skin rash
        
        Kidney toxicity
        
        Alopecia
        
        Skin photosensitivity
        
        Nausea and vomiting
        
        Darkening of the skin where previous radiation treatment has been given
      - 5-FLUOROURACIL
        
        Common
        
        Photosensitivity, watery eyes
        
        Metallic taste in mouth during infusion
        
        Discoloration along vein through which the medication is given
        
        Low blood count
        
        Less common
        
        Hair thinning
        
        Discoloration and loss of nails
        
        Darkening of the skin where previous radiation treatment has been given
        
        Dry, cracking and peeling skin
        
        Palmar-plantar erythrodysesthesia
      - CYCLOPHOSPHAMIDE
        
        Common
        
        Nausea and vomiting
        
        Poor appetite
        
        Discoloration of skins or nails
        
        Hair loss
        
        Less Common
        
        Loss of fertility
        
        Diarrhea
        
        Mouth sores
        
        Hemorrhagic cystitis
  - - - Blood tests and chest x-rays may be needed to check for unwanted effects.
      - Some men and women may become infertile
      - Increases the chance of getting an infection
        
        can lower the number of white blood cells in your blood
      - May make the skin more sensitive to sunlight. Use a sunscreen when in outdoors. Avoid sunlamps and tanning beds.
      - Using this medicine with radiation therapy may increase risk of tissue or bone problems, such as tissue or bone not receiving enough blood.
      - Hepatic or renal impairments, bone marrow depression, elderly, neonates
      - Ulcerative disorders of the Gi tract
      - Monitor haematological, renal and hepatic functons and Gi toxicity regugarly
      - DRUG INTERACTION
        
        Decreased effectiveness with folic acid and its derivatives
        
        Potentially fatal
        
        Increase toxicity with with NSAIDs and salicylates,probenecid, some penicilins,aminiglycosides,neomycin and paramomycin
        
        Synergistic enhancement of effects with Fluorouracil
        
        Increased serum concentration with Omeprazole
        
        Reduced serum concentration with colestyramine
    - - DRUG INTERACTION
        
        With levoleucovorin(IV) increases the risk of toxicity of fluorouracil
        
        Increase in warfarin effects
        
        Possibility of generalized infection with live vaccines and reduce in response to vaccines
      - Regular monitoring of blood count
      - History with heart disease, hepatic or renal insufficiency, weak or malnourished patient
      - Pt with history of high- dose pelvic radiation or use of alkylating agent
      - Pt with wide spread metastases to the bone marrow
    - - After cyclophosphamide treatment, do not have any immunizations (vaccines) without doctor's approval
      - Cyclophosphamide may lower body's resistance and vaccine may not work as well or might get the infection which vaccine is meant to prevent it.
      - Cause temporary loss of hair in some people
      - Avoid people with infections
        
        temporarily lower the number of white blood cells in blood which increasing the chance of getting an infection.
      - Reduce the risk of bleeding
        
        lower number of platelets
      - DRUG INTERACTION
        
        Allopurinol appears to increase systemic exposure of CYC's toxic metabolites by altering liver metabolism or renal excretion
        
        CYC reduces plasma pseudocholinesterase activity; thus, coadministration or subsequent use of succinylcholine may lead to prolonged neuromuscular blockade
        
        Drugs that induce hepatic microsomal enzymes including CYP2B6 (eg, carbamazepine, barbiturates, phenytoin, rifampin) may accelerate the metabolism of CYC into its active metabolites and thus increase both the pharmacologic and toxic effects
        
        drugs which inhibit the hepatic microsomal enzymes (eg, clopidogrel, desipramine, paroxetine, sertraline) slow the conversion of CYC to active metabolites, and thus may decrease both therapeutic and adverse effects.
  - - - Methotrexate Injection USP (preservative-free) and Methotrexate Injection USP (Pharmacy Bulk Vial, preservative-free): store single-use vials between 15°C and 25°C. Protect from light and freezing. Discard unused portion.
        Methotrexate Injection USP (with benzyl alcohol as preservative): store multidose vials between 15°C and 25°C. After the vials are punctured, the vials should be stored between 2°C and 8°C for a maximum of four weeks (30 days).
    - - Solutions of 5-fluorouracil are expected to be stable in solution 7 days at 37 °C, several weeks at 25 °C, and at least 4 months at 0-4 °C. It is recommended to store 5-fluorouracil in airtight containers protected from light.
    - - Store it at room temperature and away from excess heat and moisture