Rifampin

Rifampin

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 10⁶ and are rapidly selected out if rifampin is used as a single drug, especially in a patient with active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine.

Antimycobacterial Activity, Resistance, & Pharmacokinetics

Rifampin binds to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Clinical Uses

Mycobacterial Infections

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only, who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

Other Indications

Rifampin has other uses. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors, contraceptives, and a host of others. Administration of rifampin results in significantly lower serum levels of these drugs.

Alendronic Acid

Alendronic acid (INN) or alendronate sodium (USAN, sold as Fosamax by Merck) is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D (2,800 U and 5600 U, under the name Fosamax+D). Merck's U.S. patent on alendronate expired in 2008 and Merck lost a series of appeals to block a generic version of the drug from being certified by the U.S. Food and Drug Administration (FDA).

On February 6, 2008, the US FDA approved the first generic versions of alendronate, which were marketed by Barr Pharmaceuticals and Teva Pharmaceuticals USA. Teva Pharmaceuticals manufactures generic alendronate in 5-milligram, 10-milligram, and 40-milligram daily doses, and in 35-milligram and 70-milligram weekly doses, while Barr made generic alendronate in 70-milligram tablets, which were taken once weekly. ^[1]Barr pharmaceuticals were subsequently acquired by Teva in July 2008

Pharmacokinetics

As with all potent bisphosphonates, the systemic bioavailability after oral dosing is low, averaging only 0.6–0.7% in women and in men under fasting conditions. Intake together with meals and beverages other than water further reduces the bioavailability. The absorbed drug rapidly partitions, with approximately 50% binding to the exposed bone surface; the remainder is excreted unchanged by the kidneys. Unlike most drugs, the strong negative charge on the two phosphonate moieties limits oral bioavailability, and, in turn, the exposure to tissues other than bone is very low. After absorption in the bone, alendronate has an estimated terminal half-life of 10 years.^[2]

[edit]Pharmacology

Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates, it is chemically related to inorganic pyrophosphate, the endogenous regulator of bone turnover. Whereas pyrophosphate and the first bisphosphonate, etidronate, are capable of inhibiting both osteoclastic bone resorption as well as the mineralization of the bone newly formed by osteoblasts, alendronate and the other potent N-containing bisphosphonates such as risedronate, ibandronate, and zoledronate specifically inhibit bone resorption without any effect on mineralization at pharmacologically achievable doses. Its inhibition of bone-resorption is dose-dependent and approximately 1,000 times stronger than the equimolar effect of etidronate. Under therapy, normal bone tissue develops, and alendronate is deposited in the bone-matrix in pharmacologically inactive form. For optimal action, enough calcium and vitamin D are needed in the body in order to promote normal bone development. Hypocalcemiashould, therefore, be corrected before starting therapy.

[edit]Clinical data

Treatment of post-menopausal women with Fosamax has demonstrated normalization of the rate of bone turnover, significant increase in BMD (bone mineral density) of the spine, hip, wrist and total body, and significant reductions in the risk of vertebral (spine) fractures, wrist fractures, hip fractures, and all non-vertebral fractures. In the women with the highest risk of fracture (by virtue of pre-existing vertebral fractures) in the Fracture Intervention Trial, treatment with Fosamax 5 mg/day for two years followed by 10 mg/day for the third year (plus calcium and vitamin D) resulted in approximately 50% reductions in fractures of the spine, hip, and wrist compared with the control group taking placebos plus calcium and vitamin D.^{[citation needed]}

[edit]Uses

§ Prophylaxis and treatment of female osteoporosis

§ Treatment of male osteoporosis

§ Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D

§ Paget's disease

[edit]Contraindications and precautions

§ Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)

§ Clinically manifest osteomalacia

§ Certain malformations and malfunctions of the esophagus (strictures, achalasia)

§ Inability to stand, walk, or sit for 30 minutes after oral administration

§ Renal impairment with a creatinine clearance below 30ml/min

§ Hypersensitivity to alendronate or another ingredient

§ Hypocalcemia

§ Pregnancy and breastfeeding

§ Patients below 18 yrs. of age, as no clinical data exists

[edit]Side-effects

§ Gastrointestinal tract: ulceration of the esophagus; this may require hospitalization and intensive treatment. Gastric and duodenal ulceration may also occur. December 31, 2008, the FDA reported alendronate and related drugs may carry an increased risk for esophageal cancer.^[3]

§ General: infrequent cases of skin rash, rarely manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis, eye problems (uveitis, scleritis) and generalized muscle, joint, and bone pain ^[4] (rarely severe) have been seen. In laboratory tests decreased calcium and phosphate values may be obtained but reflect action of the drug and are harmless.

§ Osteonecrosis of the Jaw - Deterioration of the Temporomandibular Joint (TMJ) may occur while on this drug, if dental work of any kind is carried out.^[5] Although osteonecrosis is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.^{[citation needed]}

§ Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.^[6]

§ Bone: Alendronate has been linked in long-term users to the development of low-impact femoral fractures.^[7] Further, studies suggest that users of alendronate have an increase in the numbers of osteoclasts and develop giant, more multinucleated osteoclasts; the significance of this development is unclear.^[8] People who have taken Fosamax has been linked to a rare type of leg fracture that cuts straight across the upper thigh bone after little or no trauma. (Subtrochanteric fractures) ^[9] This is because Fosamax makes the thigh bone more brittle and stops the cells in the body that remodel the bone. Studies are showing that people who have taken Fosamax for more than five years are at risk for developing these kind of fractures. In some cases, patients have reported that, after weeks or months of unexplained aching, their thigh bones simply snapped while they were walking or standing. One doctor reports that a 59-year old previously healthy woman visiting New York City was riding a subway train one morning when the train jolted. She shifted all her weight to one leg, felt a bone snap, and fell to the floor of the train. An x-ray in a local emergency room revealed a comminuted spiral fracture involving the upper half of the right femur. She had been taking Fosamax for 7 years. ^[10] On Oct. 13, 2010 the Food and Drug Administration issued a warning about these fractures. ^[11]

[edit]Interactions

§ Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminium (antacids): the resorption of alendronate is decreased. At least half an hour should pass after intake of alendronate before taking the supplement or drug.

§ Highly active vitamin D analogues or fluorides: no data is available. Concomitant treatment should be avoided.

§ The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen. The combination is therefore possible.

§ Intravenous ranitidine increases the oral bioavailability of alendronate. No clinical consequences are known.

§ The combination of NSAIDs and alendroate may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

[edit]Dosage

§ Prophylaxis of osteoporosis in women: 5-10 mg daily or 35-70 mg weekly.

§ Therapy of osteoporosis in women and men : 10 mg daily or 70 mg weekly.

§ Osteoporosis under corticosteroids: 5-10 mg daily or 35-70 mg weekly in men and premenopausal women or those receiving concomitant HRT. In postmenopausal women not receiving HRT, the recommended dose is 10 mg daily or 70 mg weekly.

§ Paget's Disease: 40 mg daily for 6 months.

The drug is to be taken only upon rising for the day with three swallows of water, not to exceed 6-8 oz. Stand, walk, or sit, and remain fasting for 30-45 minutes afterwards, then eat breakfast. Lying down or reclining after taking the drug and prior to eating breakfast may cause gastroesophageal reflux and esophageal irritation. At least 30 minutes should be allowed to pass before meals or other beverages than water are taken in.

Alendronic acid 35 MG (as alendronate sodium 45.7 MG) Oral Tablet

On December 31, 2008, a letter in the New England Journal of Medicine cited a finding by the U.S. Food and Drug Administration that 23 cases of esophageal cancer, possibly linked to the use of the drug, have been seen since Fosamax's 1995 market debut.^[12]

[edit]Dosage forms

§ Fosamax solution 70 mg/75ml

§ Fosamax tablets 5 mg, 10 mg, 35 mg, 40 mg, and 70 mg

[edit]Litigation

By 2000, the FDA had received 139 spontaneous reports through the MedWatch system of osteonecrosis of the jaw (ONJ) in cancer patients treated with intravenous (IV) bisphopshonates, either IV pamidronate (Aredia) or IV zolendronate (Zometa).

At the 2004 ODAC meeting the number of spontaneous reports had increased since 2000, and although almost all of the reports remained in cancer patients treated with one of the IV bisphosphonates 13 of the reports were in patients taking oral alendronate or risedronate, most of which were reported on September 24, 2004, in the Journal of Oral and Maxillofacial Surgery. Although this small number of reports does not remotely indicate causality, given the millions of patients who have been treated with alendronate and risedronate, in order to be cautious the FDA asked the manufacturers of the oral bisphosphonates to issue a warning to healthcare professionals of the potential that bisphosphonates might increase the risk of ONJ.

Despite the fact that no data links the oral bisphosphonates causally to ONJ, product liability attorneys immediately filed suit maintaining that their claimants' ONJ is a direct result of the use of alendronate. Merck has stated the "underlying cause" of osteonecrosis of the jaw is "uncertain", though it might be triggered by a traumatic event like tooth extraction or oral surgery. As of May 13, 2007, hundreds of cases had been filed against Merck alleging Fosamax-induced ONJ. The first case is set to be tried in late 2008.

[edit]Bis-phossy jaw

The term given by scientists to the link between bisphosphonates and jaw necrosis is 'bis-phossy jaw.' This is derived from the 19th-century term phossy jaw, given its name after workers in match factories working with white phosphorus developed osteonecrosis of the jaw

Hydralazine

Hydralazine

Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients.

Pharmacokinetics & Dosage

Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. It is metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population (see Chapter 4). As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, possibly due to avid binding to vascular tissue.

Usual dosage ranges from 40 mg/d to 200 mg/d. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodilation and may be used if necessary. Dosing two or three times daily provides smooth control of blood pressure.

Toxicity

The most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence—chiefly in persons who slowly acetylate the drug—of a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects

ABCIXIMAB

Abciximab (previously known as c7E3 Fab), is a glycoprotein IIb/IIIa receptor antagonist manufactured by Centocor and distributed by Eli Lilly under the trade nameReoPro, is a platelet aggregation inhibitor mainly used during and after coronary artery procedures like angioplasty to prevent platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery. It is a glycoprotein IIb/IIIa inhibitor.^[1]

While Abciximab has a short plasma half life, due to its strong affinity for its receptor on the platelets, it may occupy some receptors for weeks. In practice, platelet aggregation gradually returns to normal about 96 to 120 hours after discontinuation of the drug.^{[citation needed]}

Abciximab is made from the Fab fragments of an immunoglobulin that targets the glycoprotein IIb/IIIa receptor on the platelet membrane

Indications for use

Abciximab is indicated for use in individuals undergoing percutaneous coronary intervention (angioplasty with or without stent placement). The use of abciximab in this setting is associated with a decreased incidence of ischemic complications due to the procedure^[3] and a decreased need for repeated coronary artery revascularization in the first month following the procedure.^[4] Research also shows that this drug can be of use for patients with diabetes and chronic renal insufficiency. It is not the appropriate drug of choice if a patient is scheduled for an emergency surgery (ie:heart surgery) because bleeding time may take about 12 hours to normalize.

[edit]Pharmacokinetics

Abciximab has a plasma half life of about ten minutes, with a second phase half life of about 30 minutes. However, its effects on platelet function can be seen for up to 48 hours after the infusion has been terminated, and low levels of glycoprotein IIb/IIIa receptor blockade are present for up to 15 days after the infusion is terminated.

[edit]Side effects

Many of the side effects of abciximab are due to its anti-platelet effects. This includes an increased risk of bleeding. The most common type of bleeding due to abciximab is gastrointestinal hemorrhage.

Thrombocytopenia is a rare but known serious risk. Abciximab-induced thrombocytopenia can typically be treated with transfusion of platelets. Abciximab induced thrombocytopenia can last for seven days after initial drug administration. Transfusing platelets is the only known treatment and may have limited effectiveness as the drug may also bind to the new platelets. Platelet counts which should average 250,000-400,000 can effectively drop to zero

Vancomycin

Vancomycin

Vancomycin is an antibiotic produced by Streptococcus orientalis and Amycolatopsis orientalis. With the single exception of flavobacterium, it is active only against gram-positive bacteria, particularly staphylococci. Vancomycin is a glycopeptide of molecular weight 1500. It is water soluble and quite stable.

Mechanisms of Action & Basis of Resistance

Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide (Figure 43–5). This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.

Resistance to vancomycin in enterococci is due to modification of the D -Ala-D -Ala binding site of the peptidoglycan building block in which the terminal D -Ala is replaced by D -lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC 16 mcg/mL), which have acquired the enterococcal resistance determinants. The underlying mechanism for reduced vancomycin susceptibility in vancomycin-intermediate strains (MICs 4–8 mcg/mL) of S aureus is not known. However these strains have altered cell wall metabolism that results in a thickened cell wall with increased numbers of D-Ala-D-Ala residues, which serve as dead-end binding sites for vancomycin. Vancomycin is sequestered within the cell wall by these false targets and is unable to reach its site of action.

Antibacterial Activity

Vancomycin is bactericidal for gram-positive bacteria in concentrations of 0.5–10 mcg/mL. Most pathogenic staphylococci, including those producing lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis strains that do not exhibit high levels of aminoglycoside resistance.

Pharmacokinetics

Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15–30 mcg/mL for 1–2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur (Table 43–2). In functionally anephric patients, the half-life of vancomycin is 6–10 days. A significant amount (roughly 50%) of vancomycin is removed during a standard hemodialysis run when a modern, high-flux membrane is used.

Clinical Uses

The main indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin-resistant staphylococci. However, vancomycin is not as effective as an antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus (ie, MIC > 1 mcg/mL). The recommended dosage is 30 mg/kg/d in two or three divided doses. A typical dosing regimen for most infections in adults with normal renal function is 1 g every 12 hours. The dosage in children is 40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportional to creatinine clearance, and the dosage is reduced accordingly in patients with renal insufficiency. For functionally anephric adult patients, a 1-g dose administered once a week is usually sufficient. Patients receiving a prolonged course of therapy should have serum concentrations checked. Recommended trough concentrations are 10–15 mcg/mL.

Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat antibiotic-associated enterocolitis caused by C difficile. Because of the emergence of vancomycin-resistant enterococci and the selective pressure of oral vancomycin for these resistant organisms, metronidazole had been preferred as initial therapy over the last two decades. However, recent clinical data suggest that vancomycin is associated with a better clinical response than metronidazole for more severe cases of C difficile enterocolitis. Therefore, oral vancomycin may be used as a first line treatment for severe cases or for cases that fail to respond to metronidazole.

Adverse Reactions

Adverse reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. Among the more common reactions is the so-called "red man" or "red neck" syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours.

HYDROXYUREA

Hydroxycarbamide (INN) or hydroxyurea (brand names include Hydrea and Droxia) is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia. It is also used to reduce the rate of painful attacks in sickle-cell disease and has antiretroviral properties in diseases such as AIDS.

Mechanism of action

One mechanism of action is thought to be based on its reduction of production of deoxyribonucleotides[1] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.[2]

In the treatment of sickle-cell disease, hydroxycarbamide increases the concentration of fetal hemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gammaglobulin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).[2][3]

[edit]Uses

Hydroxycarbamide is used for the following indications:

Myeloproliferative disease (primarily polycythemia vera and essential thrombocytosis[4])

Sickle-cell disease[5] (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)

AIDS as an adjunct to ddI in combination antiretroviral therapies[6]

Second line treatment for psoriasis[7] (slows down the rapid division of skin cells)

Biochemical research as a DNA replication inhibitor[8] that causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair)

Treatment for systemic mastocytosis[citation needed]

[edit]Dose

The dose depends on the indication, but tends to be 500 milligrams once a day when treatment is initiated. In myeloproliferative disease, further increases are determined by the response of the cell count and whether myelosuppression (decreased production of other blood cells) develops.[citation needed]

In sickle-cell disease, the initial daily dose is 15 mg per kilogram body weight (or less in reduced kidney function); after two weeks, a fall in the hemoglobin and platelet count and an increase in MCV (mean corpuscular volume) (size of the red blood cells) is to be expected. The dose is then increased every two weeks with monitoring of the full blood count until the dose is either 35 mg/kg or cytopenias develop.[2]

[edit]Side effects

Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (which may take 7–21 days to recover after the drug has been discontinued), alopecia (hair loss), skin changes, abnormal liver enzymes, creatinine and blood urea nitrogen.[9]

Due to its effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function, uric acid and electrolytes, as well as liver enzymes, are commonly checked.[citation needed]

Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.[2]

[edit]Contraindications

Contraindications are: severe anemia, neutropenia.[citation needed]

[edit]Use in pregnancy

Category D - investigational or post-marketing data show risk to the fetus. However, potential benefits may outweigh the potential risk. Generally this rating is reserved for drugs with no safer alternatives.[9]

[edit]Synthesis

Hydroxyurea was first synthesized in 1869 by Dresler and Stein from hydroxylamine and hydrogen cyanide; the industrial process is analogous.[10] Hydroxyurea may also be synthesized by reaction of ethyl carbamate with hydroxylamine; hydroxylamine displaces the ester to give the amide.[11]

Labetalol

Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent blocker. Labetalol has a 3:1 ratio of B:alpha antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via blockade) without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies

Emergency hypertension: 40-80mg every 10 minutes

Labetalol

Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent blocker. Labetalol has a 3:1 ratio of B:alpha antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via blockade) without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies

Protamine

Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in the patient, 1 mg of protamine sulfate is given intravenously; the rate of infusion should not exceed 50 mg in any 10-minute period. Excess protamine must be avoided; it also has an anticoagulant effect. Neutralization of LMW heparin by protamine is incomplete. Limited experience suggests that 1 mg of protamine sulfate may be used to partially neutralize 1 mg of enoxaparin. Protamine will not reverse the activity of fondaparinux. Excess danaparoid can be removed by plasmapheresis

Piperacillin/Tazobactam

Piperacillin/tazobactam

Antibiotic Class:

Beta-lactam/beta-lactamase inhibitor

Antimicrobial Spectrum:

Staphylococcus aureus (methicillin susceptible), Coagulase negative Staphylococci, Streptococcus pneumoniae (penicillin susceptible), Streptococcus spp., Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitides, Neisseria gonorrhoeae, Enterobacteriaceae, E. coli, Pseudomonas aeruginosa

Mechanism of Action:

The beta-lactamase inhibitors are recognized as substrates for the beta-lactamases produced by bacteria. This allows the actual beta-lactams to attack the bacterial cell wall by binding to penicillin binding proteins

Pharmacodynamics:

Time dependent killer (Time > MIC)

Pharmacokinetics:

(of the tazobactam)

Dose 200mg: Cmax: 29 mcg/L; Protein binding: 20-23%; Volume of distribution: 0.18-0.33L/kg; Table 5

Adverse Effects:

No new adverse effects are seen as a result of adding beta-lactamase inhibitors to beta-lactam antibiotics. The adverse reactions would remain the same for the parent compound

Dosage:

IV: Complete listing on Table 6

Dosing in adults:

Mild/Moderate: 2.25-3.375g q6h

Severe: 3.375-4.5g q6h

Dosing in pediatrics:

Not indicated in children < 12 years of age

Table 8

Disease state based dosing:

Renal failure: CrCl > 40mL/min: 3.375g q4-6h

CrCl 20-40mL/min: 2.25g q6h

CrCl < 20mL/min: 2.25g q8h

Hepatic failure: Dosage adjustment not necessary

Table 9

Dosing during Continuous Renal Replacement Therapy

CVVH (Continuous venovenous hemofiltration): 2.25g IV q6h

CVVHD (Continuous venovenous hemodialysis): 2.25-3.375g IV q6h

CVVHDF (Continuous venovenous hemodiafiltration) 2.25g-3.375g IV q6h

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which combine dialysis with fluid removal.

Contraindications/Warnings/Precautions:

Precautions: hypersensitivity to penicillins, history of gastrointestinal disease, particularly colitis, renal impairment

Drug Interactions:

Live Typhoid Vaccine - decreased immunological response to the typhoid vaccine

Methotrexate – increased methotrexate toxicity

Probenecid - increased piperacillin levels

Vecuronium - enhanced and/or prolonged neuromuscular blockade which may lead to respiratory depression and paralysis

Pregnancy:

Category B: No evidence of risk in humans but studies inadequate.

Monitoring Requirements:

Therapeutic: Culture and sensitivities, serum levels, signs and symptoms of infection, white blood cell count

Toxic: Urinalysis, BUN, SCr, AST and ALT, skin rash, Neutropenia and leukopenia,

Brand names/Manufacturer: Zosyn/Wyeth pharmaceuticals

Cisplatin

Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. In terms of clinical pharmacology, cisplatin and the other platinum analogs are extensively cleared by the kidneys and excreted in the urine. As a result, dose modification is required in the setting of renal dysfunction

Cisplatin has a number of side-effects that can limit its use:

Nephrotoxicity (kidney damage) is a major concern. The dose is reduced when the patient's creatinine clearance (a measure of renal function) is reduced. Adequate hydration and diuresis is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen species and in animal models can be ameliorated by free radical scavenging agents (e.g., amifostine). Nephrotoxicity is a dose-limiting.

Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before and after treatment.

Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics (ondansetron, granisetron, etc.) in combination with corticosteroids. Aprepitant combined with ondansetron and dexamethasone has been shown to be better for highly emetogenic chemotherapy than just ondansetron and dexamethasone.

Ototoxicity (hearing loss): unfortunately there is at present no effective treatment to prevent this side effect, which may be severe. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to melanin in the stria vascularis of the inner ear or the generation of reactive oxygen species.

Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin