ANEMIA AND ITS TREATMENT

Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells provide oxygen to body tissues.

Causes, incidence, and risk factors 

While many parts of the body help make red blood cells, most of the work is done in the bone marrow. Bone marrow is the soft tissue in the center of bones that helps form blood cells.

Healthy red blood cells last between 90 and 120 days. Parts of your body then remove old blood cells. A hormone called erythropoietin made in your kidneys signals your bone marrow to make more red blood cells.

Hemoglobin is the oxygen-carrying protein inside red blood cells. It gives red blood cells their red color. People with anemia do not have enough hemoglobin.

Possible causes of anemia:

Certain medications

Chronic diseases such as cancer, ulcerative colitis, or rheumatoid arthritis

Genetics: Some forms of anemia, such as thalassemia, can be inherited

Kidney failure

Blood loss (for example, from heavy menstrual periods or stomach ulcers)

Poor diet

Pregnancy

Problems with bone marrow such as lymphoma, leukemia, or multiple myeloma

Problems with the immune system that cause the destruction of blood cells (hemolytic anemia)

Surgery to the stomach or intestines that reduces the absorption of iron, vitamin B12, or folic acid

Too little thyroid hormone (underactive thyroid, or hypothyroidism)

Testosterone deficiency

Symptoms

Possible symptoms include:

Chest pain

Dizziness or light-headedness (especially when standing up or with activity)

Fatigue or lack of energy

Headaches

Problems concentrating

Shortness of breath (especially during exercise)

Some types of anemia may have other symptoms, such as:

Constipation

Problems thinking

Tingling

Signs and tests

Pale skin

Rapid heart rate

Heart murmur

Blood tests used to diagnose:

Blood levels of vitamin B12, folic acid, and other vitamins and minerals

Red blood count and hemoglobin level

Reticulocyte count

Ferritin level

Iron level

Iron deficiency Anemia

Iron deficiency anemia occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin, which contains iron, cannot be formed.The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Iron deficiency anemia can be caused by parasitic infections, such as hookworms. Intestinal bleeding caused by hookworms can lead to fecal blood loss and heme/iron deficiency. Chronic inflammation caused by parasitic infections contributes to anemia during pregnancy in most developing countries.Iron deficiency anemia is an advanced stage of iron deficiency.Iron deficiency ranges from iron depletion, which yields little physiological damage, to iron deficiency anemia, which can affect the function of numerous organ systems.

Hemolytic Anemia

Hemolytic anemia occurs when the bone marrow is unable to increase production to make up for the premature destruction of red blood cells and the abnormal breakdown of red blood cells  either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications such as gallstones and pulmonary hypertension.

Megaloblastic anemia

Megaloblastic anemia is a disorder of the bone marrow. There is a presence of erythroblasts in the bone marrow with delayed nuclear maturation because of defective DNA synthesis.

In megaoblastic anaemia Erythrocytes are larger and have higher nuclear-to-cytoplasmic ratios compared to normoblastic cells. Neutrophils can be hypersegmented, and megakaryocytes are abnormal. Risk Factors for Megaloblastic anaemia are Vitamin B12 deficiency ,Folic acid deficiency and Conditions with neither B12 nor folate deficiency, e.g. orotic aciduria, where there is a defect in pyrimidine synthesis, therapy with drugs interfering with DNA synthesis and myelodysplasia. 

Anemia of chronic disease

Anemia of chronic disease is a form of anemia seen in chronic illness e.g. from chronic infection, chronic immune activation, or malignancy.In Anemia of chronic disease,In response to the inflammatory cytokines (IL-6) the liver produces increased amounts of hepcidin. Hepcidin in turn stops ferroportin from releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin.Anemia of chronic disease may also due to the neoplastic disorder and non infectious inflammmatory diseases. Neoplastic disorder include Hodgkin’s disease lung and breast carcinoma and non infectious inflammmatory diseases include Rheumatoid arthritis and systemic lupus erythematosus.

Anemia of chronic disease is often a mild normocytic anemia, but can sometimes be more severe, and can sometimes be a microcytic anemia.

ANEMIA PHARMACOLOGY 

ANDROGENS (eg, oxymetholone): Anabolic steroids are synthetic derivatives of testosterone. These drugs enhance the production and urinary excretion of erythropoietin in patients with anemias due to bone marrow failure and often stimulate erythropoiesis in anemias due to deficient red cell production. The actions of anabolic steroids are similar to those of male sex hormones, therefore the possibility of causing serious disturbances of growth and sexual development in young children does exist.

COMPLEMENT INHIBITOR (eg, eculizumab): Eculizumab is a monoclonal antibody which binds with high specificity and affinity to the complement protein C5. When bound to C5, eculizumab prevents the protein from cleaving into C5a and C5b and inhibits the formation of the terminal complement complex C5b-9. This action inhibits the terminal complement-mediated intravascular hemolysis of abnormal red blood cells (RBCs) found in paroxysmal nocturnal hemoglobinuria (PNH). PNH patients are deficient in terminal complement inhibitors which make PNH RBCs susceptible to continuous terminal complement-mediated destruction.

ERYTHROPOIESIS-STIMULATING AGENTS (ESAs): Erythropoietin is a glycoprotein that stimulates red blood cell production. Endogenous production of erythropoietin is normally regulated by the level of tissue oxygenation. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis. 

Recombinant erythropoietin (eg, epoetin alfa) and erythropoiesis-stimulating proteins (darbepoetin alfa) stimulate red blood cell production by the same mechanism of action as endogenous erythropoietin. Darbepoetin alfa differs in that it has a longer circulatory survival (half-life: 21hours) than recombinant erythropoietin (half-life: 4–13hours).

Sufficient time should be allowed to determine a patient's responsiveness to ESAs before adjusting the dose. Because of the time required for erythropoiesis and the RBC half-life, an interval of 2-6 weeks may occur between the time of a dose adjustment and a significant change in hemoglobin.

GONADOTROPIN-RELEASING HORMONE (GnRH) ANALOGUES: Leuprolide acetate is a long-acting GnRH analogue that is used in combination with iron therapy to treat anemia caused by acute or chronic blood loss associated with uterine leiomyomata. Repeated dosing of leuprolide acetate causes reduced secretion of pituitary gonadotropins leading to inactivity of dependent tissues and functions. This effect has been shown to reduce uterine and fibroid volume and excessive vaginal bleeding, thereby alleviating anemia caused by uterine leiomyomata.

HEMATINICS: 

Iron supplements: Iron is essential for the maintenance of normal hemoglobin synthesis and erythropoiesis. Treatment of iron deficiency anemias can generally be managed with oral iron supplementation. Oral iron supplements are available as carbonyl iron [elemental iron (eg, Ferralet 90)] or as various salt formulations which are similar in absorption and bioavailability, but differ in their percentage of elemental iron. 

Ferrous fumarate - 33% elemental iron

Ferrous gluconate - 12% elemental iron 

Ferrous sulfate - 20% elemental iron

Ferrous sulfate; exissicated - 32% elemental iron

Proper dosing of these supplements is based on the elemental iron content. Liquid formulations of iron may stain teeth.

Parenteral therapy is used when oral iron therapy is not feasible, cannot be tolerated, or iron losses are large. Preparations for parenteral therapy include iron dextran, iron sucrose, and sodium ferric gluconate. Use caution when administering parenteral iron therapy as acute hypersensitivity and anaphylactic reactions may occur; iron sucrose and sodium ferric gluconate have a lower incidence of these reactions. Of these agents, sodium ferric gluconate has the fastest onset of action but may require more frequent dosing. 

Vitamins: Vitamin B12 (eg, cyanocobalamin) is a vitamin essential for erythropoiesis. Rapidly dividing cells (eg, bone marrow and myeloid cells) have the highest requirement for Vitamin B12. Cyanocobalamin is available as an injection and as topical nasal preparations for the treatment of pernicious anemia and other megaloblastic anemias due to Vitamin B12 deficiency.

Folic acid and folic acid derivatives: Folic acid, which is necessary for the maintenance of normal erythropoiesis, is reduced by dihyrofolate reductase to tetrahydrofolic acid. Tetrahydrofolic acid is involved in the formation of thymidylates of nucleic acids and subsequently DNA synthesis. Folic acid deficiency impairs this process, resulting in megaloblastic and macrocytic anemias. Leucovorin is a folic acid derivative composed of a mixture of active tetrahydrofolic acid derivatives that do not require enzymatic reduction. Caution should be used if megaloblastic and pernicious anemias due to Vitamin B12 deficiency are suspected as folic acid and its derivatives may mask the signs of this condition.

SUBSTITUTED UREA (eg, hydroxyurea): Although the exact mechanism of action of hydroxyurea in treating sickle cell anemia is unknown, it is believed that the agent causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid. Known pharmacologic effects of hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

by

Akshaya Srikanth, Dr.Chandra Babu*

Pharm.D Intern, *Asst.Prof of Medicine

RIMS Medical College, Kadapa, A.P

INDIA

Peripartum cardiomyopathy

HEART FAILURE DURING PREGNANCY was recognized as early as 1849, but it was first described as a distinctive form of cardiomyopathy only in the 1930s.1 In 1971, Demakis et al2 described 27 patients who presented during the puerperium with cardiomegaly, abnormal electrocardiographic findings, and congestive heart failure, and named the syndrome peripartum cardiomyopathy. 

The European Society of Cardiology3 recently defined peripartum cardiomyopathy as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within 5 months of delivery.

Peripartum cardiomyopathy is defined on the basis of four criteria:

  1-  Development of cardiac failure in the last month of pregnancy or within five months of delivery

  2-  Absence of an identifiable cause for the cardiac failure 

  3-  Absence of recognizable heart disease prior to the last month of pregnancy

 4-  Left ventricular systolic dysfunction demonstrated by classic echocardiographic criteria, such as depressed  shortening fraction or ejection fraction

The true incidence of PPCM is unknown; estimates proposed over the last several decades range from 1 per 1300 to 1 per 15,000 live births.

Unknown etiology

No hormonal disorder has been identified in patients with PPCM, even though estrogen, progesterone, and prolactin have significant effects upon the cardiovascular system

Inflammatory cytokines may play a role in PPCM ( TNF, IL6, Fas receptor, ….)

Myocarditis , evidence by endomyocardial biopsies

A maternal immunologic response to a fetal antigen has been proposed as another potential etiology of PPCM 

Familial or genetic etiology can not be excluded 

Risk Factors

Age greater than 30 years 

Multiparity

Women of African descent 

Pregnancy with multiple fetuses 

A history of preeclampsia, eclampsia, or postpartum hypertension

Association with maternal cocaine abuse or selenium deficiency 

Long term (>4 weeks) oral tocolytic therapy with beta adrenergic agonists such as : Terbutaline.

Diagnosis    

The development of CHF signs and symptoms

EKG: sinus tachy, a-fib, low voltages , prolong PR/QRS, non specific ST-T wave changes

CXR: enlargement of the cardiac silhouette with evidence of pulmonary venous congestion and/or interstitial edema, pleural effusions.

The echocardiogram and Doppler usually reveal left ventricular enlargement with significant global reduction in overall performance without LVH  

The role of endomyocardial biopsy remains unclear. 

Viral and bacterial cultures, as well as selected viral titers (eg, Coxsackie B) should also be considered.

Management

Heart failure treatment during pregnancy

When considering tests or treatments in pregnancy, the welfare of the fetus is always considered along with that of the mother. Coordinated management with specialists (an obstetrician and maternal-fetal medicine team) is essential, with fetal heart monitoring.

• Angiotensin-converting enzyme (ACE) inhibitors and ARBs are contraindicated in pregnancy because they can cause birth defects, although they are the main treatments for postpartum women with heart failure. The teratogenic effects occur particularly in the second and third trimester, with fetopathy characterized by fetal hypotension, oligohydramnios-anuria, and renal tubular dysplasia. However, a recent study suggested a risk of malformations even after first trimester exposure to ACE inhibitors.
• Digoxin, beta-blockers, loop diuretics, and drugs that reduce afterload such as hydralazine and nitrates have been proven to be safe and are the mainstays of medical therapy of heart failure during pregnancy.Beta-blockers have strong evidence of efficacy in patients with heart failure, but they have not been tested in peripartum cardiomyopathy. Nevertheless, beta-blockers have long been used in pregnant women with hypertension without any known adverse effects on the fetus, and patients taking these agents prior to diagnosis can continue to use them safely.
• Heart failure treatment postpartum
• After delivery, the treatment is identical to that for nonpregnant women with dilated cardiomyopathy. ACE inhibitors and ARBs. The target dose is one-half the maximum antihypertensive dose.

Diuretics are given for symptom relief

Spironolactone or digoxin is used in patients who have New York Heart Association class III or IV symptoms. The goal with spironolactone is 25 mg/day after dosing of other drugs is maximized. The goal with digoxin is the lowest daily dose to obtain a detectable serum digoxin level, which should be kept at less than 1.0 ng/mL. In the Digitalis Investigation Group trial,55 serum digoxin levels of 0.5 to 0.8 ng/mL (0.6–1.0 nmol/L) were most beneficial, and levels of 1.1 to 1.5 ng/mL (1.4–1.9 nmol/L) were associated with an increase in deaths related to heart failure.

Beta-blockers are recommended for peripartum cardiomyopathy,44 as they improve symptoms, ejection fraction, and survival. Nonselective beta-blockers such as carvedilol (Coreg) and selective ones such as metoprolol succinate (Toprol XL) have shown benefit. The goal dosage is carvedilol 25 mg twice a day (50 mg twice a day for larger patients) or metoprolol succinate 100 mg once a day.

Anticoagulation treatment

During pregnancy, the risk of thromboembolic complications increases due to higher concentrations of coagulation factors II, VII, VIII, and X, and of plasma fibrinogen. The risk may persist up to 6 weeks postpartum.1 Cases of arterial, venous, and cardiac thrombosis have been reported in women with peripartum cardiomyopathy, and the risk may be related to the degree of chamber enlargement and systolic dysfunction and the presence of atrial fibrillation.

Patients with evidence of systemic embolism, with severe left ventricular dysfunction or documented cardiac thrombosis, should receive anticoagulation. Anticoagulation should be continued until a return of normal left ventricular function is documented.

We await the results of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial, which should determine which drug will best prevent death or stroke in patients with ejection fractions of less than 35%.

Warfarin can cause spontaneous fetal cerebral hemorrhage in the second and third trimesters and therefore is generally contraindicated during pregnancy. However, guidelines from the American College of Cardiology and the American Heart Association on the management of patients with heart valve disease say that “warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation.” The guidelines also say warfarin is “relatively safe” during the second and third trimesters but must be stopped and switched to a heparin several weeks before delivery. Unfractionated heparin or low-molecular-weight heparin can be used during pregnancy. However, should warfarin be needed for any reason, we believe a cesarian section should be performed to reduce the risk to the infant.

by

Akshaya Srikanth, Dr. Archana

Pharm.D Intern, Asst.Prof. of Obs & Gyn

RIMS Medical College, Kadapa

India

Overdose Prevention Programs Using Opioid Antagonist

Naloxone, an opioid antagonist, is being used by at least 188 overdose prevention programs in the United States, but many states with high death rates due to heroin or other opioid overdose do not include naloxone distribution in their programs, according to research published in the Feb. 17 issue of the US Centers for Disease Control and Prevention's Morbidity & Mortality Weekly Report. 

Eliza Wheeler, MPA, of the Harm Reduction Coalition in Oakland, CA, and colleagues compiled a report based on surveys regarding naloxone distribution and overdose reversal that were completed by 48 US programs representing 188 local programs.

The researchers found that, since 1996, when naloxone was first distributed by a prevention program, the programs completing the survey indicated that they provided training and distributed naloxone to more than 53,000 people and reversed overdoses in 10,171. However, 19 of 25 states with higher than median drug overdose fatalities did not have a program that distributes naloxone, and 43.7% of programs that do distribute the agent reported difficulty in obtaining the drug.

"Providing opioid overdose education and naloxone to persons who use drugs and to persons who might be present at an opioid overdose can help reduce opioid overdose mortality, a rapidly growing public health concern," the authors write.

Full text can be available at

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6106a1.htm?s_cid=mm6106a1_w

by

Akshaya Srikanth,

Pharm.D Intern

Hyderabad, India

DRUGS USED IN BACTERIAL INFECTIONS - A BRIEF REVIEW

Antiinfectives should never be given casually for mild infections. Ideally, a culture & sensitivity should be done before administering the antiinfective of choice. Antibiotics are ineffective against viruses. The product labeling should be consulted for specific information about organism sensitivity and resistance and for detailed microbiological indications. Advise patients to continue taking medication until course of treatment is finished (usually 7–10 days) unless severe allergic reactions occur. When selecting antibiotics for the prevention of bacterial endocarditis, the physician or dentist should read the full joint statement of the American Heart Association and the American Dental Association. Treatment of strep infections usually requires at least 10 days of therapy.

Interactions: Antibiotics may reduce efficacy of oral contraceptives. Bactericidal drugs are primarily active against actively dividing cells. Therefore, bacteriostatic antibiotics (eg, tetracyclines) may interfere with the action of bactericidal antibiotics (eg, penicillins).

Adverse Reactions: Pseudomembranous colitis may occur following the administration of antibacterial agents. This may range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhea subsequent to antibiotic therapy. Mild cases usually respond to discontinuing the drug; more severe cases may need supportive care and/or therapy with an agent effective against Clostridium difficile. Anti-motility drugs should be avoided since they may precipitate toxic megacolon. Also, overgrowth of nonsusceptible organisms, including fungal overgrowth (superinfection) may occur with the prolonged use of antibiotics.

AMINOGLYCOSIDES: The aminoglycosides (eg, gentamycin, tobramycin, streptomycin, amikacin) bind to the 30S ribosomal subunit of bacteria resulting in decreased protein synthesis and misreading of mRNA. These agents exert concentration-dependent bactericidal effects and demonstrate a post-antibiotic effect to persistently suppress bacterial growth after concentrations fall below the MIC. Aminoglycosides are active against gram-negative aerobic and facultative bacilli, including Pseudomonas aeruginosa. Aminoglycosides have limited activity against gram-positive organisms when used alone; however, when combined with a cell wall-active agent (eg, penicillins, vancomycin), in vitro synergistic bactericidal activity against enterococci and staphylococci is observed. Aminoglycosides are not active against anaerobes or atypicals.

β-LACTAMS: β-lactam antibiotics inhibit bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins to exert time-dependent bactericidal activity. The β-lactam antibiotics can be divided into penicillins, cephalosporins, carbapenems, and monobactams, which are further divided into different groups according to spectra of activity.

Penicillins are primarily active against gram-positive cocci and some gram-negative bacilli. These agents can be subdivided into 5 distinct groups: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, and ureidopenicillins. β-lactamase inhibitors (eg, clavulanic acid, sulbactam sodium) may be formulated in combination with penicillins to restore the spectrum of activity of the corresponding β-lactam to include pathogens that were resistant due to their production of β-lactamases. 

Natural penicillins (eg, penicillin G, penicillin V) are active against non-β-lactamase-producing gram-positive bacteria, anaerobes, and select gram-negative cocci. Penicillinase-resistant penicillins (eg, nafcillin, oxacillin) are semi-synthetic penicillins stable against staphylococcal penicillinase. 

Aminopenicillins (eg, ampicillin, amoxicillin) have a spectrum of activity similar to penicillin G with added activity against gram-negative cocci and Enterobacteriaceae that do not produce β-lactamase. 

Carboxypenicillins (eg, ticarcillin) have an expanded spectrum of activity against non-β lactamase-producing gram-negative aerobic bacilli. 

Ureidopenicillins (eg, piperacillin) have a broader spectrum of activity compared to carboxypenicillins. Relative to carboxypenicillins, piperacillin offers activity against Enterococcus faecalis and Klebsiella and has greater efficacy against Pseudomonas. In addition, piperacillin has excellent activity against non-β-lactamase-producing anaerobic cocci and bacilli.

Cephalosporins

Cephalosporins are divided into 4 different generations based on microbiologic activity. In general, gram-positive activity diminishes while gram-negative activity increases moving from the first- to third-generations. Fourth-generation cephalosporins demonstrate similar activity to first-generation agents against gram-positive cocci and are also active against most gram-negative bacilli (including Pseudomonas). All cephalosporins are considered inactive against methicillin-resistant staphylococci, enterococci, Listeria, Legionella, Chlamydia, Mycoplasma, and Acinetobacter species. 

First-generation cephalosporins (eg, cefazolin, cephalexin, cefadroxil, cephradine) are most often used as alternatives to penicillins for infections caused by methicillin-sensitive staphylococci and streptococci.

Second-generation cephalosporins can be further subdivided into true cephalosporins and the cephamycins. True cephalosporins (eg, cefuroxime, cefprozil, cefaclor) have similar activity against staphylococci and noneterococcal streptococci compared to first-generation agents but have increased activity against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria. The cephamycins (eg, cefotetan and cefoxitin) have reduced activity against gram-positive pathogens but enhanced activity against certain Enterobacteriaceae and are active against anaerobes, especially Bacteriodes fragilis. 

Third-generation cephalosporins (eg, ceftriaxone, cefotaxime, cefixime, cefdinir) have enhanced activity against gram-negative bacilli that are resistant to other β-lactams. 

Fourth-generation cephalosporins (eg, cefepime) have the widest activity spectrum. Cefepime has enhanced activity against Enterobacter, Citrobacter, and Serratia and is active against Pseudomonas while maintaining potency against gram-positive cocci.

Carbapenems

The carbapenems (eg, imipenem, meropenem, ertapenem, doripenem) are primarily active against gram-positive cocci, gram-negative bacilli, and anaerobes. These agents are not active against atypicals.

Monobactams

Aztreonam is active only against gram-negative aerobic bacilli. Because of structural differences, aztreonam can be safely given to patients with immediate hypersensitivity reactions to other β-lactams.

FLUOROQUINOLONES: Fluoroquinolones (eg, ciprofloxacin, levofloxacin, moxifloxacin) exert concentration-dependent bactericidal activity. These agents inhibit bacterial DNA synthesis and promote cleavage of DNA leading to bacterial cell death. These agents inhibit the activity of DNA gyrase and topoisomerase IV to prevent uncoiling of DNA strands and decatenation of daughter DNA strands during the replication process, respectively. In general, fluoroquinolones primarily inhibit DNA gyrase in gram-negative bacteria, whereas topoisomerase IV is the main target in gram-positive bacteria. Fluoroquinolones are most active against aerobic gram-negative bacilli and gram-negative cocci and have some activity against atypicals but provide poor anaerobic coverage.

FOLATE SYNTHESIS INHIBITORS: Sulfonamides (eg, sulfamethoxazole, sulfisoxazole), trimethoprim, and pyrimethamine are bacteriostatic agents that inhibit microbial synthesis of folate, a necessary component of bacterial nucleotide synthesis. Only bacteria which must self-synthesize folic acid are susceptible to these agents. Sulfonamides and trimethoprim/pyrimethamine exert their inhibitory effects at different stages of the folate synthesis pathway. Sulfonamides competitively inhibit dihydropteroate synthase which acts to incorporate para-aminobenzoic acid (PABA) into dihydropteroic acid, the precursor to folic acid. Trimethoprim and pyrimethamine inhibit dihydrofolate reductase, which is responsible for the conversion of dihydrofolic acid to the active tetrahydrafolic acid. Thus, the combination of sulfonamides with trimethoprim or pyrimethamine acts synergistically to reduce intracellular folate and subsequently inhibit nucleotide synthesis and bacterial cell growth.

Sulfonamides and trimethoprim are active against gram-positive and gram-negative bacteria, Actinomyces, Nocardia spp., Chlamydia, Plasmodium, and Toxoplasma. Trimethoprim is 20100 times greater in potency than a sulfonamide, making the synergistic combination of sulfisoxazole/trimethoprim more effective therapy than a sulfonamide alone. Pyrimethamine is highly selective against Plasmodium and Toxoplasma gondii; its activity against Toxoplasma is enhanced when combined with a sulfonamide.

GLYCOPEPTIDES: Vancomycin exerts time-dependent bactericidal activity by inhibiting cell wall synthesis. Vancomycin forms stable complexes with cell wall precursor units to prevent polymerization (transglycosylaton) of precursor units for the formation of a functional cell wall. Vancomycin is active only against gram-positive organisms. Vancomycin is not absorbed when given orally and is not appropriate for treatment of systemic infections. However, it achieves high concentration within the gastrointestinal tract and therefore is used for the treatment of pseudomembranous colitis caused by C. difficile or pseudomembranous enterocolitis caused by Staphylococcus aureus.

GLYCYLCYCLINES: Glycylcyclines (eg, tigecycline) are derivatives of minocycline that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis to exert bacteriostatic activity against gram-positive and gram-negative organisms, atypicals, and anaerobes.

KETOLIDES: Ketolides (eg, telithromycin) are derivatives of erythromycin that bind to the 50S subunit of bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria, similarly to macrolides. Telithromycin differs from macrolides in that it is more acid stable and demonstrates a higher binding affinity for the ribosome, which may contribute to its improved activity against macrolide-resistant pathogens. Telithromycin is bacteriostatic and has improved activity against gram-positive aerobic bacteria compared to macrolides. It is also active against gram-positive and gram-negative bacteria, atypicals, and some anaerobes.

LICOPEPTIDES: Daptomycin is a lipopeptide antibiotic that exerts concentration-dependent bactericidal activity. Daptomycin binds to the cell membrane of gram-positive bacteria in a calcium-dependent manner, resulting in loss of cell membrane depolarization. This action results in inhibition of protein, DNA, and RNA synthesis, leading to cell death. Daptomycin has a spectrum of activity that resembles that of vancomycin while maintaining activity against pathogens with reduced susceptibility to vancomycin (eg, vancomycin intermediate S. aureus and vancomycin-resistant enterococci).

LINCOSAMIDES: Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis through interactions with the 50S bacterial ribosomal subunit. Clindamycin primarily exhibits bacteriostatic activity against anaerobes and gram-positive organisms; it has been shown to be bactericidal against Streptococcus pneumoniae, Streptococcus pyogenes, and S. aureus.

MACROLIDES: Macrolides (eg, erythromycin, clarithromycin, azithromycin) bind to the 50S subunit of the prokaryotic bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria to exert bacteriostatic effects. Macrolides are active against gram-positive cocci and bacilli and atypicals and have some activity against gram-negative bacteria.

NITROIMIDAZOLES: Nitroimidazoles (eg, metronidazole) are prodrugs that exert their antibacterial actions by interfering with DNA synthesis to induce apoptosis; they are amebacidal, bactericidal, and trichomonacidal. By passive diffusion, these agents cross bacterial cell membranes and undergo nitro reduction to form free radicals. These reactive intermediates exert their cytotoxic effects via damage to nucleic acids and proteins. Metronidazole is active against anaerobic cocci, anaerobic gram-negative bacilli, anaerobic spore-forming gram-positive bacilli and microaerophilic pathogens. Due to its excellent penetration, metronidazole is used for the treatment of brain abscess or other central nervous system infections, as well as anaerobic infections involving the bones and joints, soft tissues, oral cavity, head and neck. 

OXAZOLIDINONE: Linezolid is an oxazolidinone that binds to the 50S ribosomal subunit of the 30S unit to prevent the formation of the 70S initiation complex. Linezolid is generally bacteriostatic, however it is bactericidal against some strains of S. pneumoniae and S. pyogenes. It is active against gram-positive pathogens including gram-positive anaerobic cocci, as well as mycobacteria. Linezolid lacks activity against most gram-negative aerobes and anaerobes. In addition to its antibiotic effects, linezolid is also a weak monoamine oxidase inhibitor, thus concomitant use with adrenergics, serotonergics, or consumption of tyramine-rich foods may lead to palpitations, headache, hypertensive crisis, fever, and mental status changes.

RIFAMYCINS: Rifamycins (eg, rifampin and rifaximin) are broad-spectrum antibacterials. These agents bind to DNA-dependent RNA polymerase, resulting in a drug-enzyme complex. Formation of this complex inhibits activity of the RNA polymerase, preventing the initiation of chain formation in the synthesis of RNA, but not chain elongation. Rifamycins are most active against gram-positive organisms, but are also active against gram-negative pathogens. Additionally, rifampin is moderately active against slow-growing mycobacteria and has some activity against Legionella.

STREPTOGRAMINS: Quinupristin and dalfopristin are streptogramins that bind to the 50S ribosomal subunit of the 70S unit in the elongation phase of protein synthesis. Quinupristin acts at the same site as macrolides and causes protein synthesis termination at a later phase, whereas dalfopristin directly blocks the addition of amino acids into the peptide chain to inhibit early polypeptide elongation. The streptogramins are active against most gram-positive aerobic pathogens. Available as combination therapy, the synergistic activity of quinupristin/dalfopristin accounts for its bactericidal activity; it is bacteriostatic against Enterococcus faecium.

TETRACYCLINES: Tetracyclines (eg, tetracycline, doxycyline, minocycline) are bacteriostatic antibiotics that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis. Tetracyclines primarily exhibit activity against atypicals and have some activity against gram-positive and gram-negative bacteria.

OTHER CLASSES: Fosfomycin exerts its antibacterial effect by inhibiting the enzyme enolpyruvyl transferase to irreversibly block an initial step in bacterial cell wall synthesis and, additionally, decreasing bacteria adherence to uroepithelial cells. Fosfomycin has a broad spectrum of activity against gram-positive and gram-negative pathogens.

Nitrofurantoin is used exclusively for prophylaxis against recurrent urinary tract infections (UTI); and treatment of uncomplicated cystitis or uncomplicated UTIs. Nitrofurantoin is rapidly eliminated and thus only achieves adequate concentrations in the urine. Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA; the antibacterial activity of nitrofurantoin is enhanced in the presence of acidic urine. Macrocrystalline preparations of nitrofurantoin (eg, Macrodantin, Macrobid) are absorbed and excreted more slowly than microcrystalline preparations (eg, Furadantin).

Feel free to share your comments and suggestions

by

Akshaya Srikanth, 

Pharm.D Intern,

Hyderabad, India.

Antidotes for Toxicological Emergencies

Introduction

Poisoning is a leading cause of morbidity and mortality in the United States; in fact, it is the second leading cause of injury-related mortality, and its incidence is rising. The American Association of Poison Control Centers' National Poison Data System receives reports of more than 2.4 million human poison exposures and approximately 1300 poisoning-related deaths annually. However, it is likely that the associated mortality is much higher than those statistics would indicate, as it is estimated that only about 5% of U.S. poisoning deaths are reported to poison control centers. 

Antidotes play a critical role in the care of poisoned or overdosed patients. Recently issued national consensus guidelines include a recommended list and the quantities of antidotes that should be readily available in hospitals that provide emergency care. Some of the anti-dotes should be available for immediate administration on a patient's arrival, which requires stocking in the emergency department (ED) at most hospitals; other antidotes should be available within 60 minutes and can be stocked in the hospital pharmacy provided that prompt delivery to the ED can be assured.

Antidotes for Toxic-alcohol Poisoning

The use of ethanol or, preferably, fomepizole for alcohol dehydrogenase (ADH) inhibition is a mainstay in the management of toxicity due to ingestion of methanol, ethylene glycol, or diethylene glycol. The toxicity of methanol and of ethylene glycol is well described, and each year in the United States there are about 5000 exposures that require treatment and 20–30 associated deaths reported to poison centers. Methanol and ethylene glycol, as parent compounds, are relatively nontoxic. However, they are metabolized by ADH to toxic metabolites that can cause end-organ damage and death. Methanol is metabolized via ADH to formic acid, which results in anion-gap metabolic acidosis and ocular toxicity. Retinal toxicity secondary to methanol poisoning is usually irreversible. Ethylene glycol is metabolized via ADH to glycolic acid, which results in anion-gap metabolic acidosis, and oxalic acid, which results primarily in renal toxicity due to the formation of calcium oxalate crystals. Both can produce irreversible CNS toxicity.

Poisoning by diethylene glycol (historically and tragically used as a glycerin substitute and also in household products such as wallpaper stripper and Sterno brand heating fuel) is less common but associated with very high morbidity and mortality. Diethylene glycol is metabolized via ADH to hydroxy-ethoxyacetic acid and diglycolic acid and causes anion-gap metabolic acidosis, bilateral cortical necrosis, and sensorimotor polyneuropathy.

Ethanol

For many years, ethanol has been used to inhibit ADH and limit the metabolism of methanol and ethylene glycol to their respective metabolites.The dose of ethanol needed to competitively inhibit ADH depends on the comparative affinity of the specific toxic alcohol for ADH. Most authorities recommend using a dose of ethanol sufficient to achieve and maintain a serum ethanol concentration of 100–150 mg/dL. In the presence of ethanol, the half-lives of ethylene glycol (in patients with normal renal function) and methanol are approximately 17.5 and 45 hours, respectively.

Ethanol can be administered intravenously or orally. However, a commercial i.v. preparation of ethanol is no longer available, and extemporaneous preparation is too time-consuming to be considered satisfactory. A loading dose is necessary to quickly achieve the desired serum concentration of 100–150 mg/dL; then a maintenance dose is administered, using serum ethanol concentrations to maintain the desired target. Repeat evaluations of the serum ethanol concentration are required to ensure that the target level is achieved and maintained. Individual differences in ethanol metabolism occur due to pharmacogenetics and whether the patient is induced or becomes induced secondary to chronic ethanol exposure.

The risks associated with ethanol administration include central nervous system (CNS) depression, hypoglycemia (due to decreased gluconeogenesis), nausea, and vomiting. Intravenous administration of ethanol poses an additional risk of phlebitis and hypertonicity with hyponatremia. Frequent assessment of the serum ethanol concentration and monitoring of venous blood glucose are required.

Fomepizole

Fomepizole competitively inhibits ADH and is an effective and safe antidote for both ethylene glycol and methanol toxicity. In the presence of fomepizole, the half-lives of ethylene glycol (in patients with normal renal function) and methanol are 14.5 and 40 hours, respectively.

The Food and Drug Administration (FDA)-approved regimen of fomepizole is an i.v. loading dose of 15 mg/kg over 30 minutes followed by a dose of 10 mg/kg every 12 hours, with the frequency of dosing increased to every 4 hours during hemodialysis. Fomepizole induces its own metabolism, presumably through the cytochrome P-450 2E1 isoenzyme; therefore, after 48 hours of drug administration, the fomepizole dose should be increased to 15 mg/kg every 12 hours.

Fomepizole is generally well tolerated. Adverse events reported with the use of fomepizole include mild irritation at the i.v. infusion site, headache, nausea, dizziness, drowsiness, and a bad or metallic taste in the mouth.

Although there are no head-to-head comparisons of fomepizole versus ethanol for the management of toxic-alcohol poisoning, the former's ease of administration and relative lack of serious adverse effects have elevated it to preferred status. The clinical advantages of fomepizole over ethanol are a much higher potency of ADH inhibition (K i = 0.1μmol/L, a 1000-fold higher affinity than that of ethanol), better maintenance of therapeutic blood concentrations, and fewer adverse effects; moreover, the administration of fomepizole is less labor-intensive.

Additional and Supportive Therapy

In addition to antidote administration, hemodialysis should be considered in all toxic-alcohol exposures in which toxic metabolites have already formed, as evidenced by anion-gap metabolic acidosis or end-organ damage, and for patients with toxic serum methanol or ethylene glycol concentrations whose elimination of parent or toxic metabolites is expected to be inordinately prolonged (e.g., cases involving significant methanol exposure or ethylene glycol ingestion by a patient with renal impairment). Empiric hemodialysis is recommended if the serum methanol concentration is >25 mg/dL and if the serum ethylene glycol concentration is >50 mg/dL with renal insufficiency. Hemodialysis also should be considered in cases of severe isopropyl alcohol poisoning in patients with hemodynamic instability.

Intravenous administration of 50 mg of folic acid every six hours enhances methanol elimination and has been shown to prevent retinal toxicity in animal models. Also, urinary alkalinization (i.e., a urine pH of >8) with i.v. sodium bicarbonate enhances formate elimination and may reduce the distribution of formic acid to the eye.

Theoretically, the use of i.v. thiamine hydrochloride 100 mg and i.v. pyridoxine hydrochloride 50 mg every six hours should shunt the metabolism of ethylene glycol away from production of oxalic acid to production of less toxic metabolites'[26,27] though there are no data from studies of humans to support this practice, these agents are well tolerated and the potential benefits outweigh any risks.

Implications for the Pharmacist Methanol or ethylene glycol toxicity should be suspected in a patient with anion-gap metabolic acidosis in whom laboratory testing reveals a low (or no) ethanol concentration, no ketones, and a normal lactic acid concentration (clinicians need to be aware that some test results can be skewed by glycolic acid, the toxic metabolite of ethylene glycol). Fomepizole and adjuvants that act as cofactors should be used as soon as toxic alcohols are included in the differential diagnosis. Fomepizole should be continued until the patient is no longer acidemic and the toxic-alcohol serum concentration is presumed or confirmed to be <25 mg/dL. The availability of testing for toxic alcohols is limited.

by

Akshaya Srikanth, 

Pharm.D Intern,

Hyderabad, India

Molar Pregnancy

Molar pregnancies are an uncommon and very frightening complication of pregnancy. The formal medical term for a molar pregnancy is "hydatidiform mole." Simply put, a molar pregnancy is an abnormality of the placenta (afterbirth), caused by a problem when the egg and sperm join together at fertilization. The following is a brief review of this complicated subject. 

Types of Molar Pregnancy

There are two types of molar pregnancy, complete and partial. Complete molar pregnancies have only placental parts (there is no baby), and form when the sperm fertilizes an empty egg. Because the egg is empty, no baby is formed. The placenta grows and produces the pregnancy hormone, called HCG, so the patient thinks she is pregnant. Unfortunately, an ultrasound (sometimes called a sonogram) will show that there is no baby, only placenta. A partial mole occurs when 2 sperm fertilize an egg. Instead of forming twins, something goes wrong, leading to a pregnancy with an abnormal fetus and an abnormal placenta. The baby has too many chromosomes and almost always dies in the uterus. Thus, molar pregnancies are "accidents of nature" that are not anyone’s fault. They are not caused by behavior, but they are more common in older women and in certain geographic locations. Also, although most molar pregnancies occur after a miscarriage, some occur after an ectopic (tubal) pregnancy or even a normal delivery.

Risk Factors

The incidence of molar pregnancy varies depending on where one lives. For example, in the US about 1 out of every 1000 pregnancies is a molar pregnancy. In Southeast Asia the incidence is 8 times higher. Interestingly, women from Mexico, Southeast Asia, and the Philippines have higher rates than white US women, who themselves have higher rates than black US women. Age over 40 is a risk factor for molar pregnancy, as is having a prior molar pregnancy. In fact, the chance of having another molar pregnancy is about 1 out of 100. The reasons for the geographic and age differences are currently unknown.

Symptoms and Diagnosis

Women with a molar pregnancy usually feel pregnant and complain of vaginal spotting or bleeding. Many women with molar pregnancies develop nausea and vomiting. Some even develop rare complications like thyroid disease or very early preeclampsia (toxemia). Preeclampsia occurring earlier than 20 weeks is very worrisome for a molar pregnancy. The doctor or midwife more than likely will check them for a possible miscarriage, and may order or perform an ultrasound (sonogram). The pelvic exam may reveal a larger, or smaller, than expected uterus. It may also reveal enlarged ovaries, caused by non-cancerous ovarian cysts stemming from abnormally high amounts of the pregnancy hormone HCG. The ultrasound will often show a "cluster of grapes" appearance or a "snowstorm" appearance, signifying an abnormal placenta. If a baby is present it’s a possible partial mole, while if the baby is absent it’s probably a complete mole. Treatment consists of a D&C (dilation and curettage) of the uterus, where a small vacuum device is inserted into the uterus, under anesthesia, to remove the molar pregnancy. This must be done very carefully or excessive bleeding and blood clots to the lungs can occur. The placental tissue is sent to the pathologist, who looks under the microscope to make the final diagnosis. An HCG level, and sometimes a thyroid level, are also obtained. In unusual cases, where the patient has completed her childbearing, a hysterectomy may be preferable. Although most cases of molar pregnancy occur after a miscarriage, some occur after ectopic pregnancies or a normal pregnancy. Therefore, women with abnormal bleeding or a persistent cough (especially if it produces blood) should see their doctor for an HCG level to make sure they do not have a molar pregnancy.

Follow-up

After evacuating a molar pregnancy it is critically important that the patient see her doctor frequently, as molar pregnancies can recur. Follow-up usually consists of a baseline chest x-ray, review of the pathology specimen, physical examination of the vagina and uterus every 2 weeks until the uterus returns to normal then every 3 months for a year, contraception like the pill or shot with no attempt to become pregnant for 1 year, and, most importantly, weekly HCG blood levels until zero then every month for a year. As one can see, this involves a lot of trips to the lab and the doctor’s office! This is important because molar pregnancies can "come back" even after a thorough D&C. When they come back the patient may need chemotherapy to prevent the microscopic placental cells from spreading to other organs like cancer. Fortunately, this only occurs in about 20% of complete molar pregnancies; it is even more uncommon with partial molar pregnancies. Many women are frustrated when their doctor recommends waiting one year to become pregnant. This is actually important, because a rise in HCG levels may indicate a normal pregnancy when the patient is trying to get pregnant, or a recurrent molar pregnancy, which requires chemotherapy. To avoid this confusion we ask for a 1 year period without becoming pregnant.

Treatment for recurrent molar pregnancy

When the HCG levels drop then increase again it means that the molar pregnancy has grown from microscopic cells in the wall of the uterus to larger cells. These cells can act like a cancer, and metastasize (spread) to other organs, like the lungs, brain, bones, and vagina. Treatment for recurrent molar pregnancy, called gestational trophoblastic neoplasia, or GTN, in medical terms, usually consists of a chemotherapy medication called methotrexate(Drug information on methotrexate). Fortunately, methotrexate is a pretty "easy" chemotherapy on the system, and can be given as an intramuscular shot. Sometimes only 1 shot is necessary. In other cases, multiple shots, or even the addition of other medications, is necessary. Also, when GTN is suspected, the patient usually gets a CT scan of the brain, lungs, and abdomen, and a battery of blood tests. Again, weekly HCG tests are obtained until they fall to zero, then careful follow-up is undertaken for a year. Patients can expect an almost 100% cure rate using chemotherapy.

Future Pregnancy

Fortunately, the risk of having another molar pregnancy is about 1% (1 in 100). Most doctors will perform an ultrasound to make sure the pregnancy is normal when a patient has had a prior molar pregnancy. It is also a good idea to send the placenta to the pathologist after the delivery just to make sure there are not abnormal areas.
by
Akshaya Srikanth, Dr.Archana*
Pharm.D Intern, *Asst.Prof of Obs&Gyn
RIMS Medical College, Kadapa
India

Medication and high blood pressure

High blood pressure is typically treated with a combination of lifestyle changes and medication. Since people experience different levels of success in lowering their blood pressure level with lifestyle changes, medication(s) may be added to help lower blood pressure to an acceptable level. And if the pressure is still high despite the use of one medication, then the dose of the medication may be increased or another medication may be added until the target blood pressure level is achieved.

Doctors often prescribe medication because it is a very effective way of lowering high blood pressure and reduces a person's risk of developing complications related to hypertension. However, medication is only effective when it is taken as prescribed by a doctor. Treating other conditions such as diabetes or high cholesterol with medication and lifestyle changes in order to decrease the risk of heart attack and stroke may also be necessary in some cases.

Medications for long-term use

Long-term use of a medication requires commitment to lead a longer, healthier life. Although taking medications for a long period of time may seem like a chore, research has proven that many antihypertensive (blood pressure lowering) medications provide effective, long-term treatment for people with hypertension. The blood-pressure-lowering effects of these medications help to decrease the risk of death and disability from the complications associated with hypertension.

Medication types

Many different medications have been developed to treat hypertension. Because they work to decrease blood pressure, they are called antihypertensives. This group of medications is then divided into other groups or classes by how they work in the body.

The main classes of prescribed medications include:

diuretics

angiotensin-converting enzyme (ACE) inhibitors

beta-blockers

calcium channel blockers

angiotensin II receptor blockers

alpha-blockers

direct renin inhibitors

To determine what kind of medication you have been prescribed, go to the related medication page for a listing of medications by class.

Diuretics: This class of medications increases the amount of salt removed by the kidneys. In turn, the body gets rid of more water (in the form of urine) and the volume of water in the blood is lowered, which helps lower the blood pressure. You can think of your blood vessels as balloons filled with water. If the balloons are not filled as full, there is less pressure on the sides of the balloon.

Diuretics are often the first type of medication prescribed. Combination products are available containing two diuretics; these are intended to increase the likelihood of staying with the therapy, to lower blood pressure even more, and to decrease some side effects. Diuretics are also combined with other antihypertensive medications called ACE inhibitors, beta blockers, and angiotensin II receptor blockers (see below). Side effects of diuretics may include dizziness, increased blood sugar, and decreased potassium levels.

Others may have told you their pharmacist said to eat a banana or drink orange juice to maintain their potassium levels while taking a diuretic. While this is good advice for them to heed, it doesn't apply to all diuretics, so check with a health care professional before changing your diet.

ACE inhibitors: These medications reduce the amount of a chemical in the blood that is responsible for causing blood vessels to narrow or tighten. This results in relaxation of the blood vessels and subsequently lower blood pressure. The heart uses less effort to circulate the blood.

ACE inhibitors are often used by people with diabetes and certain types of kidney disease, and have shown kidney-protecting effects. Common side effects associated with using ACE inhibitors are dizziness, swelling, headache, and dry cough. The dry cough causes many people to stop using ACE inhibitors. The cough is usually nothing more than an inconvenience and goes away when the ACE inhibitor is stopped. Talk to your doctor before stopping any medication.

Beta-blockers: This type of medication works to lower high blood pressure by slowing down the rate of the heart and decreasing the strength of each beat. This means blood is pumped through the vessels with less force, which lowers blood pressure. It is recommended that people with diabetes who use beta-blockers monitor their blood glucose levels more frequently, since beta-blockers can hide the symptoms of low blood sugar. Side effects of this type of medication may include dizziness upon rising, exercise intolerance, sexual dysfunction, and drowsiness. Caution is recommended when beta-blockers are combined with certain other medications that can directly affect the heart rate.

Angiotensin II receptor blockers: These medications work by blocking the action of a chemical in the blood that normally tightens blood vessels. Although they can be used as first therapy, they are also commonly given in some cases when other choices have intolerable side effects. The side effects of angiotensin II receptor blockers can include dizziness, rash, headache, and swelling.

Calcium channel blockers: These medications lower blood pressure by relaxing blood vessels. Some calcium channel blockers also decrease heart rate and the force of contraction of the heart, and it is necessary to be cautious when combining these with beta blockers. Interactions with grapefruit and grapefruit juice can occur with some of these medications, so it is best to avoid this fruit and its juice when taking calcium channel blockers. Some of the side effects associated with calcium channel blocker use are constipation, headache, flushing, and swelling (especially in the ankles and feet).

Alpha-blockers: This class of medication works to lower blood pressure by causing dilation or widening of the blood vessels. Alpha-blockers are not recommended as the first therapy for treating hypertension - they are generally only used to add to another therapy when the other therapy has not lowered blood pressure levels enough. There tends to be more side effects associated with alpha blockers than with other choices. Common side effects include lightheadedness upon rising, dizziness, drowsiness, headache, and swelling. Sometimes a diuretic is added to keep the body from retaining fluids. This type of medication can also be used to help treat a condition known as benign prostatic hypertrophy in men.

Direct renin inhibitor: This is a new class medication that reduces the amount of a chemical in the blood that is responsible for causing blood vessels to narrow or tighten. Currently only one medication (aliskiren) is available in Canada. This medication can be used alone or in combination with diuretics, ACE inhibitors, or calcium channel blockers to treat mild to moderate hypertension. Some common side effects include diarrhea, dizziness, swelling, rash, and cough.

Combination medications

There are many combination products that contain more than one medication in a single pill. Once the right dosage of each medication is found, then a tablet that contains both medications can be prescribed. There are a number of benefits associated with this single-tablet format, including:

1) convenience: not having to remember to take two separate pills

2) potentially reduced costs: only one prescription needs to be dispensed

The possibilities and different combinations are extensive, considering the number of possible medications available to treat hypertension. Not all antihypertensive medications are available in a single-tablet format, however. If you are taking more than one blood pressure medication, check with your doctor to see whether a combination medication could be an option for you.

by

Akshaya Srikanth

Pharm.D Intern

Hyderabad, India

Hepatitis C Bigger Killer than HIV

More Americans now die from hepatitis C infection than from HIV, researchers from the Centers for Disease Control and Prevention reported. 

The rate of HIV deaths has been falling while the rate for hepatitis C has been rising and the two curves crossed each other in 2007, according to Kathleen Ly, MPH, and colleagues.

In that year, they wrote in the Feb. 21 issue of Annals of Internal Medicine, 12,734 deaths were blamed on HIV, compared with 15,106 attributed to hepatitis C.

The analysis, based on death certificates from 1999 through 2007, also showed that the death rate for hepatitis B has been falling slightly, although it was the underlying or contributing cause of 1,815 deaths in 2007.

The figures probably represent "only a fraction of a larger burden of morbidity and mortality from viral hepatitis," Ly and colleagues argued, noting that chronic hepatitis infection -- both B and C -- is most prevalent among people born from 1945 through 1965.

Most of those with the disease do not know they are infected and they are now reaching the age where they are at risk for hepatitis-related diseases and death, they noted.

Indeed, in 2007, 73.4% of hepatitis C-related deaths were among people ages 45 through 64, while 59.4% of hepatitis B-related deaths occurred in that age group, they found.

Ly and colleagues cautioned that someone other than the primary physician often completes death certificates, so that they may not be completely accurate. But the effect of that bias, they noted, should be roughly the same over time and so should not affect the trends.

Also, they noted, viral hepatitis was often not detected and thus not reported as a cause of death.

The findings come at a time when the treatment picture for hepatitis C is changing rapidly, as a range of new direct-acting agents is approved and comes to the clinic.

Before 1990, HCV infection had only a 10% cure rate with early interferon monotherapy. In 2011, HCV-specific protease inhibitors combined with pegylated interferon and ribavirin, achieved close to 70% sustained virologic response rates for patients with genotype 1 infections.

Within five years, it may be possible to achieve 90% cure rates using combinations of the new agents, according to Harvey Alter, MD, and Jake Liang, MD, both of the National Institutes of Health in Bethesda, Md.

"What is currently lacking in this optimistic perspective is a national 'find-and-treat' policy" to reduce the burden of the disease, they argued in an accompanying editorial.

Preventing the long-term consequences of hepatitis C – liver disease and cancer – "is now achievable if our collective will can evolve as rapidly as our pharmacologic skill."

One possible step forward would be a change in screening policy for hepatitis C, according to David Rein, PhD, of the social science research organization NORC at the University of Chicago in Atlanta, and colleagues.

Currently, the CDC recommends antibody screening for people with such risk factors or indicators as a history of injection-drug use or elevated alanine aminotransferase levels.

But one-time screening and then treating people based on birth cohort – specifically those born from 1945 through 1965 – would be cost-effective, Rein and colleagues argued in a companion study in the journal.

Their analysis showed that birth-cohort screening identified an extra 808,580 cases of chronic infection, compared with the status quo, at a cost of $2,874 per case.

Depending on the form of subsequent treatment, the screening would prevent between 82,300 and 121,000 deaths, with an incremental cost-effectiveness ratio per quality-adjusted life year gained ranged from $15,700 to $35,700, Rein and colleagues calculated.

ORIGINAL ARTICLE: 

Ly KN, et al "The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007" Ann Intern Med 2012; 156: 271-278.

by

Akshaya Srikanth

Pharm.D Intern

Hyderabad, India