Doxorrubicin

Doxorubicin (INN, pronounced /ˌdɒksəˈruːbəsɪn/; trade name Adriamycin; also known as hydroxydaunorubicin) is a drug used in cancer chemotherapy. It is ananthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA.

Doxorubicin is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas.

Doxorubicin's most serious adverse effect is life-threatening heart damage.

The drug is administered intravenously, in the form of hydrochloride salt. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.^[2]Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.

The molecule was originally isolated in the 1950s from bacteria found in soil samples taken from Castel del Monte, an Italian castle

History

The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. A new strain ofStreptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic was produced from this bacterium that was found to have good activity againstmurine tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color.^[3] Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity.^[4]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain ofStreptomyces was mutated using N-nitroso-N-methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.^[5] Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.^[6]

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and it is now estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI).^[3]

Clinical use

Doxorubicin is commonly used to treat some leukemias and Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.^[2] Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere, CA), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine),BEACOPP, CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) and FAC (5-fluorouracil, Adriamycin, cyclophosphamide). Doxil is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.^[7]

Adverse effects

Acute adverse effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including CHF, dilated cardiomyopathy, and death, dramatically increase. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some patients may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain and erythema.^[7]

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"^[12] or "red death."^[13]

Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception

Mechanism of action

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation.^[23] Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis.^[24] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures

DABIGATRAN

The etexilate dabigatran is a profarmac of small molecule lacking of farmacologic activity, after his oral administration, it is absorbed quickly and transformated in dabigatran by hydrolisis mediated for plasma and liver esterases. Dabigatran is a direct competitive and reversible inhibitor of trombin. Because trombin allows the conversion of fibrinogen to fibrine in the coagulation cascade, his inhibition blocks clots formation. Dabigatran also inhibits free trombin, protein linked trombin and platelet agregation initiated by trombin. Meals doesn't affect his biodisponibility, but delay 2 hours the time required for yield maximum concentrations. Protein link of dabigatran is low (34-35%) it is eliminated principally by kidney (85%), while fecal elimination is about 6%. Dabigatran is conjugated and form active acyl-glucuronids. Dabigatran is eliminated principally in urine in a rate aproximately of 100ml/min.

Indications:Primary prevention of tromboembolism in patients intervened in surgery of total replace of hip or knee.

Dosification: It is administrated VO 220mg day, divided in two takes of 110mg. It is recomended initiate with the administration of the farmac 1-4 hours after surgery. It is continuated for 28-35 days. In CRF is recomendated two takes of 75mg/day.

Contraindication: CRF, pregnancy, lactation, liver failure

There is a posibility of amplify the indications frame.

Esmolol

Esmolol is an ultra-short–acting B₁-selective adrenoceptor antagonist. The structure of esmolol contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol to a metabolite that has a low affinity for receptors. Consequently, esmolol has a short half-life (about 10 minutes). Therefore, during continuous infusions of esmolol, steady-state concentrations are achieved quickly, and the therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol may be safer to use than longer-acting antagonists in critically ill patients who require a -adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients

It must be diluted to 10-20mg/ml before use it. Beware of dilute with sodium bicarbonate solutions. In Supra ventricular Taquicardia: response i often acquired with doses of 50-200mcgs/kg/min now that higher doses doesn't yield a better response and augment the adverse reactions risk. Initiate treatment with 500mcg/kg/min for a minute and then continue with a mantenance dose of 50 mcg/kg/min for 4 minutes. In case of enought quantity, repeat the squeme: load 500mcg/kg/min and menteinance dose 150mcgs/kg/min for 4 minutes. When desired effect is acquired continue with 200 mcgs/kg/min.

Methyl-Dopa

Methyldopa

Methyldopa was widely used in the past but is now used primarily for hypertension during pregnancy. It lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output.

Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent on posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume-depleted patients. One potential advantage of methyldopa is that it causes reduction in renal vascular resistance.

Methyldopa (L --methyl-3,4-dihydroxyphenylalanine) is an analog of L -dopa and is converted to -methyldopamine and -methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa illustrated before. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. However, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa's antihypertensive effect, because the -methylnorepinephrine released is an effective agonist at the adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa's antihypertensive action appears to be due to stimulation of central adrenoceptors by -methylnorepinephrine or -methyldopamine.

Pharmacokinetics & Dosage

Pharmacokinetic characteristics of methyldopa are listed below. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4–6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation.

Toxicity

The most common undesirable effect of methyldopa is sedation, particularly at the onset of treatment. With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa. This toxicity is probably mediated by inhibition of dopaminergic mechanisms in the hypothalamus.

Other important adverse effects of methyldopa are development of a positive Coombs test (occurring in 10–20% of patients undergoing therapy for longer than 12 months), which sometimes makes cross-matching blood for transfusion difficult and rarely is associated with hemolytic anemia, as well as hepatitis and drug fever. Discontinuation of the drug usually results in prompt reversal of these abnormalities.

Usual dose: 1g/d.

Allopurinol

Allopurinol

The preferred and standard-of-care therapy for gout in the intercritical period (the period between acute episodes) is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.

Chemistry

The structure of allopurinol, an isomer of hypoxanthine

Pharmacokinetics

Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. Like uric acid, allopurinol is itself metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

Pharmacodynamics

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid . Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased.

Indications

Treatment of patients in the intercritical period of gout with allopurinol, as with uricosuric agents, is begun with the expectation that it will be continued for years if not for life. Allopurinol is often the first urate-lowering drug used. When starting allopurinol, colchicine or an NSAID should also be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL. Thereafter colchicine or the NSAID can be stopped, while allopurinol is continued. Aside from gout, allopurinol is used as an antiprotozoal agent (see Chapter 52) and is indicated to prevent the massive uricosuria following therapy of blood dyscrasias that could otherwise lead to renal calculi.

Adverse Effects

See above for protection against an acute attack during the initial use of allopurinol.Gastrointestinal intolerance, including nausea, vomiting, and diarrhea, may occur. Peripheral neuritis and necrotizing vasculitis, depression of bone marrow elements, and, rarely, aplastic anemia may also occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pruritic maculopapular lesions occurs in 3% of patients. Isolated cases of exfoliative dermatitis have been reported. In very rare cases, allopurinol has become bound to the lens, resulting in cataracts.

Interactions & Cautions

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration. Safety in children and during pregnancy has not been established.

Dosage

The initial dosage of allopurinol is 100 mg/d. It may be titrated upward until serum uric acid is below 6 mg/dL; this level is commonly achieved at 300 mg/d but is not restricted to this dose.

As noted above, colchicine or an NSAID should be given during the first weeks of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur