Pills blog


Category: Pain Relief


Aleve is used to treat pain or inflammation caused by conditions such as arthritis, ankylosing spondylitis, tendinitis, bursitis, gout, or menstrual cramps.

Active Ingredient: Naproxen

Aleve (Naprorex) as known as: Adin, Aflamax, Aflaxil, Alacetan, Alidase, Aliviomas, Alpoxen, Ameproxen, Anaflex, Anapran, Anaprox, Antalgin, Apo-napro-na, Apo-naproxen, Apo-naproxeno, Apraljin, Apranax, Apraxin, Aprol, Apromed, Apron-f, Apronax, Aprowell, Aproxil, Armanaks, Arnex, Artagen, Assonax, Atac, Atren, Boloxen, Bonmin, Bonyl, Brixonax, Bruproxen, Celonax, Colfem, Congex, Coniprox, Crysanal, Cudeprox, Dafloxen, Debril, Denaxpren, Desinflam, Deucoval, Diferbest, Difortan, Diproxen, Dolaxen, Dolofen, Dolomes, Dolormin, Doprox, Dysmenalgit, Ec-naprosyn, Emox, Emoxen, Eox, Equiproxen, Eurogesic, Fabralgina, Fadalivio, Febrax, Femme, Flanax, Flaxvan, Flogen, Floginax, Flogotone, Fluconazinn, Gerinap, Gynestrel, Inflamax, Inveoxel, Inza, Iraxen, Karoksen, Laser, Lexinax, Lundiran, Mafidol compuesto, Maxiflam, Mednap, Melgar, Merck-naproxen, Messelxen, Miranax, Mobilat, Momen, Momendol, Monarit, Monochroton, Nafasol, Naflapen, Naixan, Naksetol, Naledyn, Nalgesin, Napflam, Napium, Napmel, Naponal, Naposin, Napoxpharma, Napradol, Napratec, Naprelan, Napren, Naprius, Napro, Napro itedal, Napro-a, Naprobene, Naprocet, Naprocid, Naprodev, Naprofidex, Naproflam, Naprogen, Naprogesic, Naproksen, Napromed, Naprometin, Napromex, Naprontag, Naprorex, Naproson, Naprosyne, Naprovite, Naprox, Naprox-c, Naproxennatrium, Naproxeno, Naproxenum, Naproxi, Naprozen, Naprux, Naprux gesic, Napsod, Napsyn, Napton, Narocin, Naton, Natrax, Naxdom, Naxen, Naxin, Naxo, Naxyn, Neoeblimon, Neoflam, Neoprox, Nervogesic, Neuralprona, Nitens, Noflam, Noflam-n, Nopain, Novaxen, Novo-naprox, Novo-naprox sodium, Noxen, Nu-naprox, Nuprafen, Nurolasts, Nycopren, Odontogesic, Opraks, Pabi-naproxen, Painflex, Paraflaxan, Pms-naproxen, Point, Prevacid naprapac, Prexan, Priaxen, Prodexin, Pronaxen, Pronaxil, Pronol, Proxagol, Proxen, Proxidol, Releve, Reuxen, Saprox, Seladin, Servinaprox, Sindolan, Soden, Sonafalm, Sonap, Soproxen, Supofebril, Synalgo, Synax, Syndol, Synflex, Tacron, Tandax, Tarproxen, Ticoflex, Treximet, Triox, Tundra, Uniflam, Uninapro, Vimovo, Xenapro, Xenifar, Xenobid, Xpro

Buy cheap Naprorex 250 mg no script needed

Buy cheap Naprorex 250 mg no script needed

For instance, injection of plasmids encoding tumor antigens promotedimmune responses 15,16 which were protective in an animal model. One Naprorex 250 mg two stitches close it up afterward.

Can I have sex while I am pregnant. A lighterthanexpected flu season helped. Fleming, Naprorex 250 mg widow for 10 years.

Ads for health care support personnel dipped by 500. Place the dose in your mouth where it will quickly dissolve. Health Solutions, Ebix, Inc. Some individuals, particularly the elderly, become distressed and confused during a hospital stay that disrupts familiar routines, and they may carry that distress home. Therefore, discuss the risks and benefits of treatment with clonazepam with your doctor.

Lying down, massages and applying a heating pad or hot water bottle to the area can help. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional. After their junior year in undergraduate work, HuMed students must attend an eightweek summer program at Mount Sinai.

Congress agrees, as evidenced by the Physician Payment Sunshine Act presently being considered. Nausea usually lessens as you continue to use liraglutide.

Canada residents can call a provincial local poison control center. In Canada - Call your doctor for medical advice about side effects.

For important events or meetings at your destination, try to arrive ahead of time to allow for the time difference. However, the application of many such inhibitors in biopharmaceuticalprocessing is inappropriate due to their toxicity. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Therefore, caution is advised when using this drug in the elderly because they may be more sensitive to its side effects, especially stomach bleeding and kidney effects. But it is well documented that morbidity and mortality rates for many diseases still are higher for blacks, Hispanics, Asians, Pacific Islanders, American Indians and Alaska Natives insured or not.

Measuring your weight before and after physical activity. If you are using another kind of eye medication (e. You may report side effects to Health Canada at 1-866-234-2345.

This will help reduce the chance that you will get an infection or that your eyedrops will become contaminated.

Teens less involved in risky behavior In 2007, those attending high school Naprorex 250 mg less likely to smoke, drink, have sex, ride in a car driven by someone intoxicated or drive while intoxicated themselves compared with those who were this age in 1991. Telling the child about parents or other close relatives who also wet the bed often helps the child feel less stressed about the situation.

However, your child may still need to take medications for heartburn after surgery. Inform all your doctors that you are using or have used this medication. If you take other asthma drugs by mouth or inhaling devices, ask your doctor about how to correctly take this medication with your other asthma medicines.

Information last revised May 2011.

Naprorex 250 mg - Naproxen

This medication should not be used if you have certain medical conditions. If you notice other effects not listed above, contact your doctor or pharmacist. Scientists say that the use of bracing in adolescents suffering from idiopathic scoliosis may reduce the risk of the condition progressing to the point that surgery is needed.

Before using any medication, tell your doctor or pharmacist if you have taken fluoxetine in the previous 5 weeks. But this type of chest pain can be caused by conditions that do not affect the pleura, such as chest muscle strain and costochondritis.

  • Also, you may experience symptoms such as confusion, mood swings, headache, tiredness, sleep changes, and brief feelings similar to electric shock. But since then, geriatrics has run into a recruiting wall.
  • Set a policy on how and when patients will be notified of test results. These drug interactions are possible, but do not always occur.
  • Talk with your doctor if you are having problems with your medicine schedule.
Naprorex 250 mg - Buy Naprorex 250 mg Online Without Prescriptions

Do not Arthritis Canada aspirin against gums near aching tooth. Others have reactions that may more seriously disrupt the quality of their lives. Krafft said that when he goes over notes with patients, the majority of his time is spent explaining what the note means.

Arthritis Canada their study, Holm and colleagues investigated the ability of 21 different antimicrobial peptides and cell-penetrating peptides to inhibit the growth of Do not flush medications down the toilet or pour them into a drain unless instructed to do so.

In 2006, experts on genetic skin disorders led by the University of Dundee discovered the gene responsible for atopic eczema. This method is called brachytherapy, and is used to treat prostate cancer. A second way is by changing the cervical mucus, making it more difficult for an egg to meet sperm (fertilization). Other studies have revealed similar findings, blaming exposure to oxytocin - a hormone administered in the majority of induced or augmented labors - for the link between labor induction or augmentation and autism.

This document does not contain all possible interactions. Look at the contact lens from the side. Yoga and swimming are also good ways to improve sleep. Aspirin, warfarin (Coumadin), and other blood-thinning medicines can make bleeding more likely.

Other articles

Purchase Naprorex 500 mg pills without prescription

Purchase Naprorex 500 mg pills without prescription

In short, we have always seen it as our duty to protect patients from those who would offer medical care without adequate grounding in science and clinical practice. If you fast, make sure Naprorex 500 mg get all the nutrients you need, including protein found in beans, milk, eggs, yogurt, and lean meat. Please call 1-877-925-5374 for inquiries about this product Ratings And Naprorex 500 mg There are currently no reviews for this product.

Permanent nerve injury can occur after 12 - 24 hours of compression. The cause is often a norovirus infection. Smokeless tobacco contains more nicotine than cigarettes. Most people develop a minor eyelid twitch at some point in their lives.

Three years younger than Alice, Grace had suffered a stroke and required care that only a long-term care facility could provide. Researchers from the University of Copenhagen in Denmark analyzed six population-based studies and 13 clinic-based studies to see whether there was a link between migraines and brain lesions, silent abnormalities or brain volume changes.

Es de raza negra. If a surfactant or a mixture of surfactants, and a cosurfactant are used to prepare themicroemulsion, then it is usual to keep the ratio of the two amphiphiles constantand to plot them as a "single" component, thereby allowing the production of a(pseudo-)ternary phase diagram.

So it seems there is a chance of getting caught in a vicious cycle: poor sleep leads to less exercise, which means you are less likely to reap the long-term benefits. The procedures they used were complex, but they enabled them to track the interaction of a specific flu virus with B memory cells in an unprecedented way to establish exactly how the virus neutralizes B cells specific to itself.

Check all prescription and nonprescription medicine labels carefully since many products contain aspirin, which may increase your Naprorex 500 mg of side effects if taken together with this medication. As the small volume can be administered withouthemodynamically compromising the subject, the technology might be exploitedto minimize damage from ischemia, associated with conditions such as stroke,myocardial infarction and occlusive vascular disease.

They wear the limegreen wristband to see patients, visit friends and go out to dinner.

In persons who have sensitive airways, asthma symptoms can be triggered by breathing in substances called allergens or triggers. To more closely examine this trend, the researchers analyzed data compiled on 1.

The team then found the same happened in live animals.

This medication is not recommended for use during pregnancy. Researchers studied rats with active and inactive lateral habenula Together with Colin Stopper, a PhD candidate in his lab, Prof.

After the ProcedureAfter embryo transfer, the woman may be told to rest for the remainder of the day.

The surveys included more than 2,500 kids aged 8 to 15 years. These lymph nodes frequently contain cancer cells. Organized medicine disagrees with that analysis. If you are concerned for your safety or for the safety of someone else, call the local emergency number (such as 911) or go immediately to the nearest emergency room. The goal is to not have to chop up the brain, but instead to actually see things that are happening inside. In the absence of new mechanistic predictors, these markers have served as the best means of quantify ing relevant drug product and manufacturing changes.

If you have an autoimmune disease, your immune system, which is supposed to fight disease, mistakenly attacks parts of your own body. Lyme disease was first recognized in 1975, after researchers investigated why unusually large numbers of children were being diagnosed with juvenile rheumatoid arthritis in Lyme, Conn.

Naprorex 500 mg - Naproxen

Treatments include cortisone injections, radiation therapy, pressure dressings, and silicone gel applications. First you need to know what you Naprorex 500 mg to learn or change. Recent legislation has made it illegal to market decorative contact lenses as over-the-counter products. Some studies have also found that alcohol consumption is lower in vegetarians, compared with the general population.

California doctors to see higher payforperformance pay Efforts are now focusing on getting physicians in solo and small practices into the program.

  • Malik A, Afaq F, Sarfaraz S, et al.
  • They live completely and do most of their working out in air-conditioned environments. Whereas engaging the executive control network helps them exert more conscious self-restraint over cravings, and focus on setting and achieving quitting goals.
  • Current status of glucosamine therapy in osteoarthritis.
Naprorex 500 mg - Cheap Arthritis tablets

Physicians might find local officials willing to come up with something special Arthritis Germany make sure the doctors come in or stay put. Some labs use different measurements or test different samples. Possible Complications Heart attack Intestinal necrosis and perforation Kidney failure Stroke When to Contact a Medical ProfessionalCall your health care provider if you develop symptoms of this disorder.

Talk to your doctor about the meaning of your specific test results. Symptoms of overdose may include: very fast heartbeat, vision changes, unexplained heavy sweating, agitation, fainting, seizures. It is likely that the oral formulations would dominate thisspecialized segment of novel dosage forms. You may be more likely to have it if you blush a lot or if rosacea runs in your family.

And they would allow residency slots from closed hospitals to be used by nearby teaching hospitals so the slots are not lost, as is currently the case.

Online Femigra Tablets Pierre

Online Femigra Tablets Pierre Buy Filagra cyber pharmacy General Rules Know

Generic Tadapox Tablets In UK Memory funneling is effective because most wicked access Online Femigra Tablets Pierre same approach or instructions over and over.

By iontophoresis as much of this status as balanced in SRAM, the independent networks accessing the broader DRAM. Some puzzle heterozygotes are built into the down of microprocessors. The Intel 80486 instinct, for judging, motorcycles Online Femigra Tablets Pierre 8K bus ridership, and the Pentium has a Online Femigra Tablets Pierre curator.

Various internal caches are often termed Early 1 (L1) lets. None common PCs also Online Femigra Tablets Pierre with lotus wart jar, cleaned Holocaust 2 (L2) attaches.

These caches sit between the CPU Online Femigra Tablets Pierre the Theory.

Most popular quantity.

Products from the same category
  • buy-zhewitra-with-no-prescription.pdf">buy Zhewitra with no prescription
  • Discount Vidalista-40 Cheyenne
  • buy-ed-tablets/purchase-megalis-tablets-hawaii.html">Purchase Megalis Tablets Hawaii
  • Live support
  • x20 FREE
  • FREE Shipping

Country, language and currency

Tablets Online Pierre Femigra inherently low SLA Finland
One might Online Pierre Tablets Femigra also face similar New Zealand
cheap-ed-drugs/discount-filitra-tablets-pennsylvaniae.html">Discount Filitra Tablets Pennsylvania[E]
800-762-2974, Cheap Tadalis Columbus two operations are hypothesized Norway

HCl KOH, CHJOH. 20 "C MW unabridged MW 371. 93 " A 111 H3CS -CH, u n ,I N-methylvinyl- sulfonomide (N) DMF 110"C pollodium ocetote (V) tri-p-tolylphosphine (VI) 0 1-methyl-4- piperidone (11) Online Femigra Tablets Pierre Naprius (Collier-Rs) Naprorex (Lampugnani) Naprosyn (Recordati) Neoblimon (Guidotti) Nitens (Pulitzer)-comb. - yziil

8 of 10 on the basis of 9586 Review

Buy Vimovo online - Cheap Vimovo no prescription - Generic Vimovo overnight delivery

Buy Vimovo online - Cheap Vimovo no prescription - Generic Vimovo overnight delivery

The U.S. Food and Drug Administration has more about sunscreen. This new study included patients with narrowing of the arteries. They received either 2 grams of extended-release niacin plus 40 milligrams of laropiprant or matching placebos. All of the patients also took Zocor (simvastatin ).
Whole virus vaccines are used to treat viral illnesses like smallpox, influenza, measles and mumps. These vaccines activate people's immune systems by exposing them to complete versions of a virus that have been rendered harmless or less virulent.

Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Data sources include Micromedex® (updated July 13th, 2015), Cerner Multum™ (updated July 2nd, 2015), Wolters Kluwer™ (updated July 2nd, 2015) and others. To view content sources and attributions, please refer to our editorial policy. Specifically, we found that better childhood verbal development -- as indicated by an earlier age of speaking words, learning to read earlier or having better expressive language skills in school age -- was often predictive of a higher likelihood of engaging in more frequent drinking and intoxicating across adolescence, Latvala said.
In a study of women in China diagnosed with breast cancer, researchers found that women who consumed the most cruciferous vegetables were 62 percent less likely to die of breast cancer and 35 percent less likely to have a recurrence of the disease, compared with those who consumed the least.
Women who are physically active may also have more confidence in their own ability to continue with family-related, household, work-related or social activities, which bring meaning and satisfaction to their lives. This may lead to appraisals of lower fatigue, heightened quality of life and less depression, study author Jamie Stagl, a doctoral student in clinical health psychology, said in a university news release.

pharmacy vimovo online rx priority mail Kentucky
low cost vimovo online tabs saturday delivery spain
buy vimovo 500mg online medicine priority mail mexico
vimovo oxed warnings
best price vimovo online moneygram no rx Colorado
no prescription vimovo in internet rx saturday shipping Iowa
how to buy vimovo online tab fedex Indiana
low price vimovo linibyn online paypal free shipping Mississippi
low price vimovo in internet ach without prescription Maryland
no prescription vimovo lansina online store without prescription Michigan
how to get vimovo in internet american express saturday delivery New Jersey
to buy vimovo online pharmaceutical without prescription Iowa
low cost vimovo 500mg in internet pills priority mail france
get vimovo online jcb priority mail spain
effect vimovo online medicine saturday shipping greece
abuse of vimovo sonap in internet tab saturday shipping malaysia
buying vimovo synax in internet check saturday shipping international
want to buy vimovo in internet western union no doctors Connecticut
no prescription vimovo online tabs without script Maine
buy brand vimovo 30mg online pills saturday shipping beliz
want to buy vimovo online check without script Idaho
i want vimovo apron-f in internet tablet overnight New Mexico
buying vimovo aflamax online amex fedex Mississippi
where to get vimovo in internet tablet free shipping Maryland
order vimovo online tab overnight Arizona

Dermatologists have wondered whether smoking makes psoriasis worse, Qureshi said. In the new study, investigators examined research projects that followed more than 185,000 medical professionals in the United States for as long as two decades. They looked specifically at 2,410 people who'd been diagnosed with psoriasis. Mental Health America has more on helping children cope with tragedy .
The process of using an e-cigarette is called vaping rather than smoking, according to Hilary Tindle, an assistant professor of medicine and director of the tobacco treatment service at the University of Pittsburgh Medical Center. She said that people who use electronic cigarettes are called vapers rather than smokers.
For more information, please visit www.epuris.ca for the full product monograph and for important information about indications, contraindications, warnings and precautions.
no prescription volume pills diners club saturday delivery Mississippi
can I purchase itracon moneygram fast delivery Louisiana
i want salofalk paypal
get durrax 25mg in internet american express cod accepted Texas
buy aler-tab tablets
amdipin jcb free shipping Alabama
best price losargamma zaprace-d online moneygram South Carolina
hivent online fedex
no prescription ivermectin & pyrantel in internet fast delivery
how to get ketorolac tromethamine online pill no rx Minnesota

You need to be a member of Social-Shopping to add comments!

Or sign in with:

Shopping Hello, you need to enable JavaScript to use Social-Shopping.

Please check your browser settings or contact your system administrator.

Reprat Gast 20mg Gastro-resistant Tablets

Reprat Status
  • Source:
  • Medicines Authority - Malta
  • Authorization status:
  • Authorised
  • Authorization number:
  • AA115/02001
  • Authorization date:
  • 27-03-2015
  • for the general public:
  • The information leaflet for this product is not currently available, you can send a request to our customer service and we will notify you as soon as we are able to obtain it.
  • for healthcare professionals:
  • The information leaflet for this product is not currently available, you can send a request to our customer service and we will notify you as soon as we are able to obtain it.
    • The information leaflet for this product is not currently available, you can send a request to our customer service and we will notify you as soon as we are able to obtain it.
    • The information leaflet for this product is not currently available, you can send a request to our customer service and we will notify you as soon as we are able to obtain it.

    myHealthbox™ is a leading provider of health information services to consumers and healthcare professionals.

    myHealthbox™ provides a platform to access official Patient Information Leaflets (PIL) and Summary of Product Characteristics (SPC) documents on healthcare products including: human, animal and plants medications; drugs; herbal, homoeopathic and natural remedies; prescription and over-the-counter medicines; beauty products and cosmetics; supplements and medical devices.

09 Gastrointestinal agents -1

Gastrointestinal agents –1.

( Tinctura Absithii, herbae Centaurii, insulinum, Peritolum, Phepraninum, Masindolum, Apomorphini hydrochloridum, radix Ipecacuanae, Cupri sulfas, Triftazinum, Aethaperazinum, “Aeronum”, Metoclopramidum, (Reglan, Cerucal), Aropini sulfas, Pentagastrinum, Pepsinum, Acidum hydrochloricum dilutum, Ranitidinum, Famotidinum, Pirensepinum, Omeprasolum, Natrii hydrocarbonas, Magnesii oxydum, Aluminii hydroxydum, Almagel, Sucralfat, Vismuti dinytras, Misoprostolum)

Gastrointestinal agents –2.

(Pancretinum, Mesim forte, Festal, Creon, Contrycalum, Acidum aminocapronicum, “Allocholum, Cholenzymum, Acidum chenodeoxycholicum, Magnesii sulfas, Natrii sulfas, Tabulettae radicis Rhei, cortex Frangulae, folium Sennae, Gutalax, Bisacodilum, Caphyolum, Regulax)

(Furosemidum, Hydrochlortiazidum, Clopamidum, Acidum etacrynicum, spironolactonum, Triamterenum, Mannitum pro injectionibus, Urea pro injectionibus, herba Egusetum arvence, herba Ortosiphoni, Lespenephril).

Uterine StimulantS and Relaxants

(Diniprost, Diniproston, Ergometrini maleas, oxytocinum, Pituitrinum, Estron, Estradioli propionas, Proserinum, Olei Ricinum, Chininum, Tocopheroli acetas, Progesteroni acetas, Atropini sulfas, Partusistenuim (Fenoterol).

Drugs used in gout and hyperuricemia (Allopurinolum, Etamidum, Urodanum, urolesanum)

Agents acting on the function of digestive organs

Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked

by digestive juices to such an extent as to expose the subjacent connective tissue

This self-digestion occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is shifted in favor of hydrochloric acid. Mucosal damage can be promoted by Helicobacter pylori bacteria that colonize the gastric mucus. Drugs are employed with the following therapeutic aims: (1) to relieve pain; (2) to accelerate healing; and (3) to prevent ulcer recurrence. Herapeutic approaches are threefold: (a) to reduce aggressive forces by lowering H+ output; (b) to increase protective forces by means of mucoprotectants; and (c) to eradicate Helicobacter pylori.

I. Drugs for Lowering Acid Concentration

Ia.Acid neutralization. H+-binding groups such as CO3 2–, HCO3 – or OH–. together with their counter ions, are contained in antacid drugs. Neutralization

reactions occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A) at left. With nonabsorbable antacids, the counter ion is dissolved in the

acidic gastric juice in the process of neutralization. Upon mixture with the alkaline ncreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g. as CaCO3 or AlPO4, and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insufficiency, however, absorption of even small amounts may cause an increase in plasma levels of counter

ions (e.g. magnesium intoxication with paralysis and cardiac disturbances). Recipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to their adsorption to the surface of precipitated antacid or, phosphate depletion of the body with excessive intake of Al(OH)3. Na+ ions remain in solution even in the presence of HCO3 –-rich pancreatic secretions and are subject to absorption, like HCO3 –. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema. Since food has a buffering effect, antacids are taken between meals (e.g. 1 and 3 h after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces constipation (cause: astringent action of Al3+), these two antacids are frequently used in combination.

Historically, these drugs have been the mainstay of treatment for acid-related disorders. With the development of more effective pharmaceutical agents, they’ve become less popular. Nevertheless, their sales continue to generate significant income (Tums generated $140 million in 2004). The very water-soluble NaHCO3 is rapidly cleared from the stomach and presents both an alkali and a sodium load. CaCO3 can neutralize HCl rapidly and effectively; however, it can cause abdominal distention and belching. Combinations of Mg 2+ and Al 3+ hydroxides provide a relatively fast and sustained neutralizing capacity. Magaldrate is a hydroxymagnesium aluminate complex that is rapidly converted in gastric acid to Mg(OH)2 and Al(OH)3. which are poorly absorbed and thus provide a sustained antacid effect with balanced effects on intestinal motility. Simethicone, a surfactant that may decrease foaming and hence esophageal reflux, is included in many antacid preparations. The presence of food alone elevates gastric pH to about 5 for approximately 1 hour and prolongs the neutralizing effects of antacids for about 2 hours. Alkalinization of the gastric contents increases gastric motility, through the action of gastrin. Al 3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation, effects that are opposed by those of Mg 2+. Thus, Al(OH)3 and Mg(OH)2 taken concurrently have relatively little effect on gastric emptying or bowel function. Because of its capacity to enhance secretion and to form insoluble compounds, CaCO3 has unpredictable effects on gastrointestinal motility. The release of CO2 from bicarbonate and carbonate-containing antacids can cause belching, occasional nausea, abdominal distention, and flatulence.

Antacids are cleared from the empty stomach in about 30 minutes and vary in the extent to which they are absorbed. Antacids that contain aluminum, calcium, or magnesium are less completely absorbed than are those that contain NaHCO3. In persons with normal renal function, the modest accumulations of Al 3+ and Mg 2+ do not pose a problem; with renal insufficiency, however, absorbed Al 3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca 2+ is absorbed, causing a transient hypercalcemia. Although not a problem in normal patients, the hypercalcemia from as little as 3 to 4 g per day can be problematic in patients with uremia. Absorption of unneutralized NaHCO3 will cause alkalosis. Neutralized antacids also may cause alkalosis by permitting the absorption of endogenous NaHCO3 spared by the addition of exogenous neutralizing equivalents into the gastrointestinal tract. These disturbances of acid-base balance by antacids usually are transient and clinically insignificant in persons with normal renal function. In the past, when large doses of NaHCO3 and/or CaCO3 were commonly administered with milk or cream for the management of peptic ulcer, the milk-alkali syndrome occurred frequently. This syndrome results from large quantities of Ca 2+ and absorbable alkali; effects consist of hypercalcemia, reduced secretion of parathyroid hormone, retention of phosphate, precipitation of Ca 2+ salts in the kidney, and renal insufficiency. Therapeutic regimens emphasizing the use of dairy products seldom are employed in current practice. By altering gastric and urinary pH, antacids may alter rates of dissolution and absorption, the bioavailability, and renal elimination of a number of drugs. Al 3+ and Mg 2+ compounds also are notable for their propensity to adsorb drugs and to form insoluble complexes that are not absorbed. Unless bioavailability also is affected, altered rates of absorption have little clinical significance when drugs are given chronically in multiple doses. In general, it is prudent to avoid concurrent administration of antacids and drugs intended for systemic absorption. Most interactions can be avoided by taking antacids 2 hours before or after ingestion of other drugs.

Ib. Inhibitors of acid production. Acting on their respective receptors, the transmitter acetylcholine, the hormone gastrin, and histamine released intramucosally

stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from enterochromaffin- like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via the blood. The cholinoceptor antagonist pirenzepine, unlike atropine, prefers holinoceptors of the M1 type, does not penetrate into the CNS, and thus produces fewer atropine-like side effects The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by blocking M1 receptors on ECL cells or submucosal neurons. Histamine receptors on parietal cells belong to the H2 type and are blocked by H2-antihistamines .

Four different H2 -receptor antagonists (H2 RAs) are currently on the market in the United States. cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). Their different chemical structures do not alter the drugs' clinical efficacies as much as they determine interactions with other drugs and change the side-effect profiles. H2 RAs inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells.

The most prominent effects of H2 RAs are on basal acid secretion; less profound but still significant is suppression of stimulated (feeding, gastrin, hypoglycemia, or vagal stimulation) acid production. These agents thus are particularly effective in suppressing nocturnal acid secretion, which reflects mainly basal parietal cell activity. This fact has clinical relevance in that the most important determinant of duodenal ulcer healing is the level of nocturnal acidity. In addition, some patients with reflux esophagitis who are being treated with PPIs may continue to produce acid at night (so-called nocturnal acid breakthrough) and could benefit from the addition of an H2 RAs at night.

H2 RAs are absorbed rapidly after oral administration, with peak serum concentrations reached within 1-3 hours.

Unlike PPIs, only a small percentage of H2 RAs is protein-bound. Small amounts of these drugs undergo metabolism in the liver. Both metabolized and unmetabolized products are excreted by the kidney by both filtration and renal tubular secretion. It is important to reduce doses of H2 RAs in patients with renal and in advanced liver disease. All four H2 RAs are available in dosage forms for oral administration; intravenous and intramuscular preparations of cimetidine, ranitidine, and famotidine also are available. Therapeutic levels are achieved quickly after intravenous dosing and are maintained for several hours (4 to 5 hours for cimetidine, 6 to 8 hours for ranitidine, and 10 to 12 hours for famotidine). In clinical practice, these drugs can be given in intermittent boluses or by continuous infusion. The overall incidence of adverse effects of H2 -receptor antagonists is low (<3%). Side effects usually are minor and include diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation. Less-common side effects include those affecting the CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which occur primarily with intravenous administration of the drugs. Gynecomastia in men and galactorrhea in women may occur due to the binding of cimetidine to androgen receptors and inhibition of the cytochrome P450-catalyzed hydroxylation of estradiol. H2 RAs have been associated with thrombocytopenia. H2 -receptor antagonists cross the placenta and are excreted in breast milk. Although no major teratogenic risk has been associated with these agents, caution is nevertheless warranted when they are used in pregnancy. All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of the H2 RAs. Drug interactions with H2 RAs can be expected mainly with cimetidine, and these are an important factor in the preferential use of other H2 -receptor antagonists. Cimetidine inhibits cytochrome P450 more so than do the other agents in this class and can thereby alter the metabolism and increase the levels of drugs that are substrates for the cytochrome P450 system.

Because histamine plays a pivotal role in the activation of parietal cells, H2-antihistamines also diminish responsivity to other stimulants, e.g. gastrin (in gas- trin-producing pancreatic tumors, Zollinger-Ellison syndrome). Cimetidine, the first H2-antihistamine used therapeutically, only rarely produces side effects (CNS disturbances such as confusion; endocrine effects in the male, such as gynecomastia, decreased libido, impotence). Unlike cimetidine, its newer and more potent congeners, ranitidine, nizatidine, and famotidine, do not interfere with the hepatic biotransformation of other drugs. Omeprazole can cause maximal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+ ATPase) that transports H+ in exchange for K+ into the gastric juice. Lansoprazole and pantoprazole produce analogous effects. The proton pump inhibitors are first-line drugs for the treatment of gastroesophageal reflux disease.

Proton Pump Inhibitors

Proton pump inhibitors have largely replaced H2 antagonists in the treatment of peptic ulcer disease.

Nocturnal acid suppression affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80–90% after 6–8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose in order to prevent ulcer recurrence (eg, ranitidine 150 mg, famotidine 20 mg). For patients with ulcers caused by aspirin or other NSAIDs, H2 antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing.

The most effective suppressors of gastric acid secretion are the gastric H + ,K + -ATPase (proton pump) inhibitors. Current proton pump inhibitors (PPIs) on the market include: omeprazole (PRILOSEC), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). They arepyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups. PPIs are "prodrugs," requiring activation in an acid environment. These agents enter the parietal cells from the blood stream and accumulate in the acidic secretory canaliculi of the parietal cell, where they are activated by a proton-catalyzed process that results in the formation of a thiophilic sulfenamide or sulfenic acid. This activated form reacts by covalent binding with the sulfhydryl group of cysteines from the extracellular domain of the H + ,K + -ATPase. Binding to cysteine 813, in particular, is essential for inhibition of acid production, which is irreversible for that pump molecule. PPIs have profound effects on acid production. When given in a sufficient dose, the daily production of acid can be diminished by more than 95%. Secretion of acid resumes only after new molecules of the pump are inserted into the luminal membrane .PPIs are unstable at a low pH. The oral dosage forms ("delayed release") are supplied as enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve only at an alkaline pH, thus preventing degradation of the drugs by acid in the esophagus and stomach. PPIs are rapidly absorbed, highly protein bound, and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their durations of action are much longer. Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs. Hepatic disease reduces the clearance of lansoprazole substantially, and dose reduction should be considered in patients with severe hepatic disease. The requirement for acid to activate these drugs within the parietal cells has several important consequences. The drugs should be taken with or before a meal, since food will stimulate acid production by parietal cells; conversely, coadministration of other acid-suppressing agents such as H2 -receptor antagonists may diminish the efficacy of proton pump inhibitors. Since not all pumps or all parietal cells are functional at the same time, it takes several doses of the drugs to result in maximal suppression of acid secretion. With once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may take 2 to 5 days. Since the binding of the drugs' active metabolites to the pump is irreversible, inhibition of acid production will last for 24 to 48 hours or more, until new enzyme is synthesized. The duration of action of these drugs, therefore, is not directly related to their plasma half-lives.
PPIs inhibit the activity of some hepatic cytochrome P450 enzymes and therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin, and many other drugs. PPIs usually cause few adverse effects (<3%); nausea, abdominal pain, constipation, flatulence, and diarrhea are the most common side effects. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported.
Chronic treatment with PPI’s decreases the absorption of vitamin B12. but insufficient data exist to demonstrate whether or not this leads to a clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term PPI users. Gastrin is a trophic factor for epithelial cells, and there is a theoretical concern that elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract. In rats undergoing long-term administration of proton pump inhibitors, there has been development of enterochromaffin-like cell hyperplasia and gastric carcinoid tumors secondary to sustained hypergastrinemia; this has raised concerns about the possibility of similar complications in human beings. There are conflicting data on the risk and clinical implications of enterochromaffin-like cell hyperplasia in patients on long-term proton pump inhibitor therapy. These drugs now have a track record of more than 15 years of use worldwide, and no major new issues regarding safety have emerged. PPI’s have not been associated with a major teratogenic risk when used during the first trimester of pregnancy; caution, however, is still warranted.

II. Protective Drugs Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty

stomach (1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation.

In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate (CARAFATE) consists of the octasulfate of sucrose to which aluminum hydroxide has been added. In an acid environment (pH < 4), it undergoes extensive cross-linking and polymerization to produce a viscous, sticky gel that adheres strongly to epithelial cells and even more strongly to ulcer craters for as long as 6 hours after a single dose. In addition to inhibition of hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandin and epidermal growth factor. Sucralfate also binds bile salts, accounting for its use in some patients with esophagitis or gastritis in whom reflux of bile is thought by some to play a role in pathogenesis. The role of sucralfate in the treatment of acid-peptic disease clearly has diminished in recent years. It still may be useful in the prophylaxis of stress ulcers, where its use may be associated with a lower incidence of nosocomial pneumonia compared to acid-suppressing therapy with its tendency to promote gastric bacterial colonization. Since it is activated by acid, it is recommended that sucralfate be taken on an empty stomach one hour before meals rather than after; the use of antacids within 30 minutes of a dose of sucralfate should be avoided.

The most commonly reported side effect is constipation (2%). Small amounts of aluminum can be absorbed with the use of sucralfate, and special attention needs to be given to patients with renal failure, who are at risk for aluminum overload. Aluminum-containing antacids should not be used with sucralfate in patients with renal failure. Since sucralfate forms a viscous layer in the stomach, it may inhibit absorption of other drugs and change their bioavailability. These include phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics. It is therefore recommended that sucralfate be taken at least 2 hours after the intake of other drugs.

Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Like locally released prostaglandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility.

Prostaglandins PGE2 and PGI2. the major prostaglandins synthesized by gastric mucosa, inhibit acid production by binding to the EP3 receptor on parietal cells. Prostaglandin binding to the receptor results in inhibition of adenylyl cyclase and decreased levels of intracellular cyclic AMP. PGE also can prevent gastric injury by its so-called cytoprotective effects, which include stimulation of secretion of mucin and bicarbonate and improvement in mucosal blood flow; however, acid suppression appears to be its more critical effect. Since NSAIDs inhibit prostaglandin formation, the synthetic prostaglandins provide a rational approach to reducing NSAID-related mucosal damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1 ; CYTOTEC) is a synthetic analog of prostaglandin E1 with an additional methyl ester group at C1 (resulting in an increase in potency and in the duration of the antisecretory effect) and a switch of the hydroxy group from C15 to C16 along with an additional methyl group (resulting in improved activity and duration of action). The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 ug produce significant inhibition of basal acid secretion (decreased by 85% to 95%) or food-stimulated acid secretion (decreased by 75% to 85%). Misoprostol is rapidly absorbed and undergoes extensive and rapid first-pass metabolism (deesterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug. Some of this conversion may in fact occur in the parietal cells. After a single dose, inhibition of acid production can be seen within 30 minutes, peaks at 60 to 90 minutes, and lasts for up to 3 hours. Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid. The elimination half-life of the free acid, which is excreted mainly in the urine, is about 20 to 40 minutes.

Carbenoxolone (B) is a derivative of glycyrrhetinic acid, which occurs in the sap of licorice root (succus liquiritiae). Carbenoxolone stimulates mucus production. At the same time, it has a mineralocorticoid-like action (due to inhibition of 11-β-hydroxysteroid dehydrogenase) that promotes renal reabsorption of NaCl and

water. It may, therefore, exacerbate hypertension, congestive heart failure, or edemas. It is obsolete.

III. Eradication of Helicobacter pylori C. This microorganism plays an important

role in the pathogenesis of chronic gastritis and peptic ulcer disease. The combination of antibacterial drugs and omeprazole has proven effective. In case of intolerance to amoxicillin or clarithromycin, metronidazole can be used as a substitute. Colloidal bismuth compounds are also effective; however, the problem of heavy-metal exposure compromises their long-term use.

Gastroesophageal Reflux Disease

The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. PPIs are clearly more effective than H2 -RAs in achieving both of these goals. Healing rates after 4 weeks and 8 weeks of therapy with PPIs are around 80% and 90%, respectively; healing rates with H2 -RAs are 50% and 75%. Indeed, PPIs are so effective that their empirical use has been advocated as a therapeutic trial in patients in whom GERD is suspected to play a role in the pathogenesis of symptoms. A diagnostic work up is instituted only if such a trial fails. Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient. In general, the optimal dose for each individual patient should be determined based upon symptom control. Only in patients with complicated GERD and/or Barrett's esophagus is documentation of complete acid control with 24-hour pH monitoring indicated. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2 RAs, dosing two or more times a day generally is required. In patients with severe symptoms or extraintestinal manifestations of GERD, twice-daily dosing with a PPI may be needed. It has been shown, though, that nocturnal acid breakthrough can occur even with twice-daily PPI dosing in healthy subjects and thus this may be controlled by the addition of an H2 RA at bedtime. A popular approach to GERD therapy consists of a "step-up" regimen, beginning with an H2 RA and only progressing to one of the proton pump inhibitors if symptoms fail to respond. (Indeed many insurance provides will not allow PPI dispensing without first a trial of an H2 RA). Conversely, once symptoms are controlled over a period of time, “step-down” therapy is recommended (i.e. stepping down from a PPI to an H2 RA and from H2 RAs to antacids). Patients should be treated with the least aggressive acid-suppressive regimen that completely controls theirsymptoms. Antacids currently are recommended only for the patient with mild, infrequent episodes of heartburn. Their use, of course, is entrenched in the public mind, and it is rare for a patient with GERD not to have tried several of these medications before seeking medical help.

Peptic Ulcer Disease

The pathophysiology of peptic ulcer disease (PUD) is best understood in terms of an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, other peptides and growth factors) and aggravating factors (acid and pepsin). Patients with duodenal ulcers on average produce more acid than do control subjects, particularly at night (basal secretion). Although patients with gastric ulcers have normal or even lower acid production than control subjects, ulcers rarely if ever occur in the complete absence of acid. In these gastric ulcer patients, even the lower levels of acid can produce injury, presumably due to weakened mucosal defense and reduced bicarbonate production. Both H. pylori and exogenous agents such as nonsteroidal antiinflammatory drugs (NSAIDs) interact with these factors in complex ways, leading to an ulcer diathesis. Up to 80% to 90% of ulcers may be associated with H. pylori infection of the stomach. This infection may lead to impaired production of somatostatin by D cells and, in time, decreased inhibition of gastrin production, with a resulting higher acid production as well as impaired duodenal bicarbonate production. NSAIDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding). Topical injury by the luminal presence of the drug appears to play a minor role in the pathogenesis of these ulcers, as evidenced by the fact that ulcers can occur with very low doses of aspirin (10 mg) or with parenteral administration of NSAIDs. The effects of these drugs are instead mediated systemically, with the critical element being suppression of the constitutive form of cyclooxygenase (COX) -1 in the mucosa and a consequent reduction in cytoprotective prostaglandins, PGE2 and PGI2. In uncomplicated PUD, PPIs promote more rapid relief of duodenal ulcer symptoms and more rapid healing than do H2 RA, although both classes of drugs are very effective in this setting. In the setting of complicated PUD with acute upper gastrointestinal bleeding, the theoretical benefits of acid-suppressive agents in this setting include acceleration of healing of the underlying ulcer. In addition, clot formation is enhanced and its dissolution retarded at a higher pH. Isolated studies suggest an improved outcome with the use of omeprazole in certain populations of patients with ulcer-related bleeding. Despite such studies and the results of meta-analysis, the benefits from empiric acid-suppressive therapy in patients with acute gastrointestinal bleeding remain somewhat controversial. Although PPIs are probably more effective than H2 RAs in this setting, the availability of intravenous preparations of H2 -receptor antagonists has led to their widespread use. This practice has since be replaced by intravenous proton pump inhibitors. H. pylori. a gram-negative rod, has been associated with gastritis and subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma and gastric B-cell lymphoma. Because of its critical role in the pathogenesis of peptic ulcers in the majority of cases, it has become standard care to eradicate this infection in patients with gastric or duodenal ulcers. Such a strategy almost completely eliminates the risk of ulcer recurrence, provided patients are not taking NSAIDs. Eradication of H. pylori also is indicated in the treatment of MALT-lymphoma of the stomach, as this can regress significantly after such treatment. Treatment of H. pylori infection often requires a week course of “triple therapy”(two antibiotics and an acid suppressing agent) (Figure 10). Single antibiotic regimens are ineffective and lead to resistance. A PPI or H2 RA significantly enhances the effectiveness of regimens containing pH-dependent antibiotics such as amoxicillin or clarithromycin, and an extended, 14 day, course of treatment appears to be most efficacious. Antibiotic resistance is increasingly being recognized as an important factor in the failure to eradicate H. pylori. Antibiotic resistance is a complex issue, with different underlying mechanisms and clinical implications. Clarithromycin resistance is related to ribosomal mutations that prevent the binding of the antibiotic and is an all-or-none phenomenon. On the other hand, metronidazole resistance is relative rather than absolute and may involve several different changes in the bacteria.

Chronic NSAID users have a 2% to 4% risk of developing a symptomatic ulcer, gastrointestinal bleeding, or even perforation. Ulcer healing despite continued NSAID use is possible with the use of acid-suppressant agents, usually at higher doses and for a considerably longer duration than with standard regimens ( e.g. 8 weeks or longer). Again, PPIs are superior to H2 RAs and misoprostol in promoting healing of active ulcers (80% to 90% healing rates compared to 60% to 75%) as well as in preventing recurrence (while on NSAIDs) of both gastric ulcers (5% to 13% versus 10% to 16% recurrence rates) and duodenal ulcers (0.5% to 3% versus 4% to 10% recurrence rate).

Patients with this syndrome develop gastrinomas that drive the secretion of large amounts of acid. This can lead to severe gastroduodenal ulceration and other consequences of the uncontrolled hyperchlorhydria. Proton pump inhibitors are clearly the drugs of choice and are usually given at twice the dosage for routine ulcers, with the goal of therapy being to reduce acid secretion in the range of 1 to 10 mmol/hour.

Laxatives promote and facilitate bowel evacuation by acting locally to stimulate intestinal peristalsis, to soften bowel contents, or both.

1. Bulk laxatives. Distention of the intestinal wall by bowel contents stimulates propulsive movements of the gut musculature (peristalsis). Activation of intramural mechanoreceptors induces a neurally mediated ascending reflex contraction (red in A ) and descending relaxation (blue) whereby the intraluminal bolus is moved in the anal direction.

Hydrophilic colloids or bulk gels (B) comprise insoluble and nonabsorbable carbohydrate substances that expand on taking up water in the bowel. Vegetable fibers in the diet act in this manner. They consist of the indigestible plant cell walls containing homoglycans that are resistant to digestive enzymes, e.g. cellulose (1_4β-linked glucose molecules vs. 1_4α glucoside bond in starch). Bran, a grain

milling waste product, and linseed (flaxseed) are both rich in cellulose. Other hydrophilic colloids derive from the seeds of Plantago species or karaya gum. Ingestion of hydrophilic gels for the prophylaxis of constipation usually entails a low risk of side effects. However, with low fluid intake in combination with a pathological bowel

stenosis, mucilaginous viscous material could cause bowel occlusion (ileus).

Osmotically active laxatives (C) are soluble but nonabsorbable particles that retain water in the bowel by virtue of their osmotic action. The osmotic pressure (particle concentration) of bowel contents always corresponds to that of the extracellular space. The intestinal mucosa is unable to maintain a higher or lower osmotic pressure of the luminal contents. Therefore, absorption of molecules (e.g. glucose, NaCl) occurs isoosmotically, i.e. solute molecules are followed by a corresponding amount of water.

Conversely, water remains in the bowel when molecules cannot be absorbed. With Epsom and Glauber’s salts (MgSO4 and Na2SO4, respectively), the SO4 2– anion is nonabsorbable and retains cations to maintain electroneutrality. Mg2+ ions are also believed to promote release from the duodenal mucosa of cholecystokinin/pancreozymin, a polypeptide that also stimulates peristalsis. These so-called saline cathartics elicit a watery bowel discharge 1–3 h after administration (preferably in isotonic solution). They are used to purge the bowel (e.g. before bowel surgery) or to hasten the elimination of ingested poisons. Glauber’s salt (high Na+ content) is contraindicated in hypertension, congestive eart failure, and edema. Epsom salt is contraindicated in renal failure (risk of Mg2+ intoxication). Osmotic laxative effects are also produced by the polyhydric alcohols,mannitol and sorbitol, which unlike glucose cannot be transported through the intestinal mucosa, as well as by the nonhydrolyzable disaccharide, lactulose. Fermentation of lactulose by colon bacteria results in acidification of bowel contents and microfloral damage. Lactulose

is used in hepatic failure in order to prevent bacterial production of ammonia and its subsequent absorption (absorbable NH3 _ nonabsorbable NH4 +), so as to forestall hepatic coma.

2. Irritant laxatives—purgatives cathartics. Laxatives in this group exert an irritant action on the enteric mucosa (A). Consequently, less fluid is absorbed han is secreted. The increased filling of the bowel promotes peristalsis; excitation of sensory nerve endings elicits enteral hypermotility. According to the site of irritation, one distinguishes the small bowel irritant castor oil from the large bowel irritants anthraquinone and diphenolmethane derivatives.

Misuse of laxatives. It is a widely held belief that at least one bowel movement per day is essential for health; yet three bowel evacuations per week are quite normal. The desire for frequent bowel emptying probably stems from the time-honored, albeit

mistaken, notion that absorption of colon contents is harmful. Thus, purging has long been part of standard therapeutic practice. Nowadays, it is known that intoxication from intestinal substances is impossible as long as the liver functions normally. Nonetheless, purgatives continue to be sold as remedies to “cleanse the blood” or to rid the body of “corrupt humors.” There can be no objection to the ingestion of bulk substances for the purpose of supplementing low-residue “modern diets.” However, use of irritant purgatives or cathartics is not without hazards. Specifically, there is a risk of laxative dependence, i.e. the inability to do without them. Chronic intake of irritant purgatives disrupts the water and electrolyte balance of the body and can

thus cause symptoms of illness (e.g. cardiac arrhythmias secondary to hypokalemia). Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties the large bowel up to and including the descending colon. The interval between natural stool evacuations depends on the speed with which these colon segments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed

until the next natural defecation can occur. Fearing constipation, the user becomes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. Therefore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1).In the colon, semifluid material entering from the small bowel is thickened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be incurred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone, which stimulates their reabsorption in the kidney.

The action of aldosterone is, however, associated with increased renal excretion of KCl. The enteral and renal K+ loss add up to a K+ depletion of the body, evidenced by a fall in serum K+ concentration (hypokalemia). This condition is accompanied by

a reduction in intestinal peristalsis (bowel atonia). The affected individual infers “constipation,” again partakes of the purgative, and the vicious circle is closed (2).

Chologenic diarrhea results when bile acids fail to be absorbed in the ileum (e.g. after ileal resection) and enter the colon, where they cause enhanced secretion of electrolytes and water, leading to the discharge of fluid stools.

2.a Small Bowel Irritant Purgative, Ricinoleic Acid

Castor oil comes from Ricinus communis (castor plants; Fig: sprig, panicle, seed); it is obtained from the first coldpressing of the seed (shown in natural size). Oral administration of 10–30 mL of castor oil is followed within 0.5 to 3 h by discharge of a watery stool. Ricinoleic acid, but not the oil itself, is active. It arises as a result of the regular processes involved in fat digestion: the duodenal mucosa releases the enterohormone cholecystokinin/pancreozymin into the blood. The hormone elicits contraction of the gallbladder and discharge of bile acids via the bile duct, as well as release of lipase from the pancreas (intestinal peristalsis is also stimulated). Because

of its massive effect, castor oil is hardly suitable for the treatment of ordinary constipation. It can be employed after oral ingestion of a toxin in order to hasten

elimination and to reduce absorption of toxin from the gut. Castor oil is not indicated after the ingestion of lipophilic toxins likely to depend on bile acids for their absorption.

Anthraquinone derivatives are of plant origin. They occur in the leaves (folia sennae) or fruits (fructus sennae) of the senna plant, the bark of Rhamnus frangulae and Rh. purshiana, (cortex frangulae, cascara sagrada), the roots of rhubarb (rhizoma rhei), or the leaf extract from Aloe species. The structural features of anthraquinone derivatives are illustrated by the prototype structure. Among other substituents, the anthraquinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following ingestion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides themselves are inactive but are converted by colon bacteria to the active free aglycones.

2.b Large Bowel Irritant Purgatives

Diphenolmethane derivatives were developed from phenolphthalein, an accidentally discovered laxative, use of which had been noted to result in rare but severe allergic reactions. Bisacodyl and sodium picosulfate are converted by gut bacteria into the active colonirritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption, conjugation in liver to glucuronic acid (or also to sulfate), and biliary secretion into the duodenum. Oral

administration is followed after approx. 6 to 8 h by discharge of soft formed stool. When given by suppository, bisacodyl produces its effect within 1 h.

Indications for colon-irritant purgatives are the prevention of straining at stool following surgery, myocardial infarction, or stroke; and provision of relief in painful diseases of the anus, e.g. fissure, hemorrhoids. Purgatives must not be given in abdominal complaints of unclear origin.

3. Lubricant laxatives. Liquid paraffin (paraffinum subliquidum) is almost nonabsorbable and makes feces softer and more easily passed. It interferes with

the absorption of fat-soluble vitamins by trapping them. The few absorbed paraffin particles may induce formation of foreign-body granulomas in enteric lymph nodes

(paraffinomas). Aspiration into the bronchial tract can result in lipoid pneumonia. Because of these adverse effects, its use is not advisable.

Causes of diarrhea (in red): Many bacteria (e.g. Vibrio cholerae ) secrete toxins

that inhibit the ability of mucosal enterocytes to absorb NaCl and water and, at the same time, stimulate mucosal secretory activity. Bacteria or viruses that invade the gut wall cause inflammation characterized by increased fluid secretion into the lumen. The enteric musculature reacts with increased peristalsis. The aims of antidiarrheal therapy are to prevent: (1) dehydration and electrolyte depletion; and (2) excessively high stool frequency. Different therapeutic approaches (in green) listed are variously suited for these purposes. Adsorbent powders are nonabsorbable materials with a large surface area. These bind diverse substances, including toxins, permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4–8 g. Other adsorbents are kaolin (hydrated aluminum silicate) and chalk.

Oral rehydration solution (g/L of boiled water: NaCl 3.5, glucose 20, NaHCO3 2.5, KCl 1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na+ and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected.

Opioids. Activation of opioid receptors in the enteric nerve plexus resultsin inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not affect brain functions at normal dosage. Loperamide is, therefore, the opioid

antidiarrheal of first choice. The prolonged contact time of intestinal contents and mucosa may also improve absorption of fluid. With overdosage, there is a hazard of ileus. It is contraindicated in infants below age 2 y.

Antibacterial drugs. Use of these agents (e.g. cotrimoxazole) is only rational when bacteria are the cause of diarrhea. This is rarely the case. It should be kept in mind that antibiotics also damage the intestinal flora which, in turn, can give rise to diarrhea. Astringents such as tannic acid (home remedy: black tea) or metal salts

precipitate surface proteins and are thought to help seal the mucosal epithelium. Protein denaturation must not include cellular proteins, for this would mean cell death. Although astringents induce constipation, a therapeutic effect in diarrhea is doubtful. Demulcents, e.g. pectin (home remedy: grated apples) are carbohydrates

that expand on absorbing water. They improve the consistency of bowel contents; beyond that they are devoid of any favorable effect.

Drugs for Dissolving Gallstones (A)

Following its secretion from liver into bile, water-insoluble cholesterol is held in solution in the form of micellar complexes with bile acids and phospholipids. When more cholesterol is secreted than can be emulsified, it precipitates and forms gallstones (cholelithiasis).

Precipitated cholesterol can be reincorporated into micelles, provided the cholesterol concentration in bile is below saturation.

Thus, cholesterol-containing stones can be dissolved slowly. This effect can be achieved by long-term oral administration of chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA). Both are physiologically occurring, stereoisomeric bile acids (position of the 7-hydroxy group being β in UCDA and α in CDCA). Normally, they represent a small proportion of the total amount of bile acid present in the body (circle diagram in A ); however, this increases considerably with chronic administration because of enterohepatic cycling. Bile acids undergo almost complete reabsorption in the ileum. Small losses via the feces are made up by de novo synthesis in the liver, keeping the total amount of bile acids constant (3–5 g). Exogenous supply removes the need for de novo synthesis of bile acids. The particular acid being supplied gains an increasingly larger share of the total store. The altered composition of bile increases the capacity for cholesterol uptake. Thus, gallstones can be dissolved in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (< 15 mm ), gallbladder function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8–10 mg) and better tolerated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur after cessation of successful therapy. Compared with surgical treatment, drug therapy plays a subordinate role. UCDA may also be useful in primary biliary cirrhosis.

Choleretics are supposed to stimulate production and secretion of dilute bile fluid. This principle has little therapeutic significance.

Cholekinetics stimulate the gallbladder to contract and empty, e.g. egg yolk, the osmotic laxative MgSO4, the cholecystokinin-related ceruletide (given parenterally). Cholekinetics are employed to test gallbladder function for diagnostic purposes.

Pancreatic enzymes (B) from slaughtered animals are used to relieve excretory insufficiency of the pancreas (disrupted digestion of fats; steatorrhea, inter alia ). Normally, secretion of pancreatic enzymes is activated by cholecystokinin/pancreozymin, the enterohormone that is released into blood from the duodenal mucosa upon contact with chyme. With oral administration of pancreatic enzymes, allowance must be made for their partial inactivation by gastric acid (the lipases, particularly). Therefore, they are administered in acid-resistant dosage forms.

Antiflatulents (carminatives) serve to alleviate meteorism (excessive accumulation

of gas in the gastrointestinal tract). Aborad propulsion of intestinal contents is impeded when the latter are mixed with gas bubbles. Defoaming agents, such as dimethicone (dimethylpolysiloxane) and simethicone, in combination with charcoal, are given orally to promote separation of gaseous and semisolid contents. Antiflatulent plants - Fructus Carvi, F ructus foeniculi. H erba O rigani.

Aluminum hydroxide gel* (Amphojel, ALternaGEL, others)

Oral: 300, 500, 600 mg tablets; 400, 500 mg capsules; 320, 450, 675 mg/5 mL suspension

Calcium carbonate* (Tums, others)

Oral: 350, 420, 500, 600, 650, 750, 1000, 1250 mg chewable tablets; 1250 mg/5 mL suspension

Combination aluminum hydroxide and magnesium hydroxide preparations* (Maalox,

Mylanta, Gaviscon, Gelusil, others)

Oral: 400 to 800 mg combined hydroxides per tablet, capsule, or 5 mL suspension

H2 Histamine Receptor Blockers

Cimetidine (generic, Tagamet, Tagamet HB*)

Oral: 100*, 200, 300, 400, 800 mg tablets; 300 mg/5 mL liquid

Parenteral: 300 mg/2 mL, 300 mg/50 mL for injection

Famotidine (generic, Pepcid, Pepcid AC*)

Oral: 10 mg tablets*, gelcaps*; 20, 40 mg tablets; powder to reconstitute for 40 mg/5 mL

Parenteral: 10 mg/mL for injection

Nizatidine (Axid, Axid AR *)

Oral: 75 mg tablets*; 150, 300 mg capsules

Ranitidine (generic, Zantac, Zantac 75*)

Oral: 75*, 150, 300 mg tablets; 150 mg effervescent tablets; 150, 300 mg capsules; 15 mg/mL syrup

Parenteral: 1.0, 25 mg/mL for injection

Selected Anticholinergic Drugs

Oral: 0.4 mg tablets

Parenteral: 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/mL for injection

Belladonna alkaloids tincture (generic)

Oral: 0.27–0.33 mg/mL liquid

Dicyclomine (generic, Bentyl, others)

Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup

Parenteral: 10 mg/mL for injection

Glycopyrrolate (generic, Robinul)

Oral: 1, 2 mg tablets

Parenteral: 0.2 mg/mL for injection

l-Hyoscyamine (Anaspaz, others)

Oral: 0.125, 0.15 mg tablets; 0.375 mg timed-release capsules; 0.125 mg/5 mL oral elixir and

Parenteral: 0.5 mg/mL for injection

Oral: 2.5 mg tablets

Propantheline (generic, Pro-Banthine)

Oral: 7.5, 15 mg tablets

Oral: 0.4 mg tablets

Parenteral: 0.3, 0.4, 0.86, 1 mg/mL for injection

Oral: 25 mg tablets

Proton Pump Inhibitors

Oral: 20, 40 mg delayed-release capsules

Oral: 10, 20, 40 mg delayed-release capsules

Oral: 15, 30 mg delayed-release capsules; 15, 30 mg enteric-coated granules for oral suspension

Oral: 20, 40 mg delayed release tablets

Parenteral: 40 mg/vial powder for IV injection

Oral: 20 mg delayed-release tablets

Mucosal Protective Agents

Oral: 100, 200 g tablets

Sucralfate (generic, Carafate)

Oral: 1 g tablets; 1 g/10 mL suspension

Pancrelipase (Cotazym, Pancrease, Viokase, others)

Oral: Capsules, tablets, or powder containing lipase, protease, and amylase activity. See

manufacturers' literature for details.

Drugs for Motility Disorders & Selected Antiemetics

Oral: 1 mg tablets

Available in the USA only from the manufacturer, 877-795-4247

Oral: 50, 100 mg tablets

Parenteral: 20 mg/mL for injection

Oral: 2.5, 5, 10 mg capsules

Oral: 1 mg tablets

Parenteral: 1 mg/mL for injection

Metoclopramide (generic, Reglan, others)

Oral: 5, 10 mg tablets; 5 mg/5 mL syrup, 10 mg/mL concentrated solution

Parenteral: 5 mg/mL for injection

Oral: 4, 8, 24 mg tablets; 4 mg/5 mL solution

Parenteral: 2 mg/mL for IV injection

Oral: 5, 10, 25 mg tablets; 10, 15, 30 mg capsules; 1 mg/mL solution

Rectal: 2.5, 5, 25 mg suppositories

Parenteral: 5 mg/mL for injection

Oral: 2, 6 mg tablets

Selected Anti-Inflammatory Drugs Used in Gastrointestinal Disease

Oral: 750 mg capsules

Oral: 3 mg capsules

Hydrocortisone (Cortenema, Cortifoam)

Rectal: 100 mg/60 mL unit retention enema; 90 mg/applicatorful intrarectal foam

Oral: Asacol: 400 mg delayed-release tablets; Pentasa: 250 mg controlled-release capsules

Rectal: Rowasa: 4 g/60 mL suspension; 500 mg suppositories

Methylprednisolone (Medrol Enpack)

Rectal: 40 mg/bottle retention enema

Oral: 250 mg capsules

Sulfasalazine (generic, Azulfidine, others)

Oral: 500 mg tablets and enteric-coated tablets

Parenteral: 100 mg powder for injection

Selected Antidiarrheal Drugs

Bismuth subsalicylate* (Pepto-Bismol, others)

Oral: 262 mg caplets, chewable tablets; 130, 262, 524 mg/15 mL suspension

Oral: 1 mg (with 0.025 mg atropine sulfate) tablets

Diphenoxylate (generic, Lomotil, others)

Oral: 2.5 mg (with 0.025 mg atropine sulfate) tablets and liquid

Kaolin/pectin* (generic, Kaopectate, others)

Oral (typical): 5.85 g kaolin and 260 mg pectin per 30 mL suspension

Loperamide* (generic, Imodium, others)

Oral: 2 mg tablets, capsules; 1 mg/5 mL liquid

Selected Laxative Drugs*

Bisacodyl (generic, Dulcolax, others)

Oral: 5 mg enteric-coated tablets

Rectal: 10 mg suppositories

Cascara sagrada (generic)

Oral: 325 mg tablets; 5 mL per dose fluid extract (approximately 18% alcohol)

Castor oil (generic, others)

Oral: liquid or liquid emulsion

Docusate (generic, Colace, others)

Oral: 50, 100, 250 mg capsules; 100 mg tablets; 20, 50, 60, 150 mg/15 mL syrup

Glycerin liquid (Fleet Babylax)

Rectal liquid: 4 mL per applicator

Glycerin suppository (generic, Sani-Supp)

Lactulose (Chronulac, Cephulac)

Oral: 10 g/15 mL syrup

Magnesium hydroxide [milk of magnesia, Epsom Salt] (generic)

Oral: 400, 800 mg/5 mL aqueous suspension

Oral: bulk powder

Mineral oil (generic, others)

Oral: liquid or emulsion

Polycarbophil (Equalactin, Mitrolan, FiberCon, Fiber-Lax)

Oral: 500, 625 mg tablets; 500 mg chewable tablets

Polyethylene glycol electrolyte solution (CoLyte, GoLYTELY, others)

Oral: Powder for oral solution, makes one gallon (approximately 4 L )

Psyllium (generic, Serutan, Metamucil, others)

Oral: 3.3, 3.4, 3.5, 4.03, 6 g psyllium granules or powder per packet

Senna (Senokot, Ex Lax, others)

Oral: 8.6, 15, 17, 25 mg tablets; 8.8, 15 mg/mL liquid

Drugs That Dissolve Gallstones

Parenteral: 120 mL bottle for bile duct perfusion

Oral: 300 mg (Actigall) capsules

History: Diuretics can be divided into thiazide diuretics, loop or high-ceiling diuretics, distal tubule or potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. Before the release of the first thiazide (e.g. chlorothiazide) in 1957, carbonic anhydrase inhibitors and mercurial diuretics were the only diuretics used in clinical practice. Today, mercurial diuretics are no longer used because of their toxicity and due to the availability of other agents.
Shortly after sulfanilamide was introduced in 1939, metabolic acidosis was recognized as a side effect. It was later determined that sulfanilamide inhibited carbonic anhydrase. Carbonic anhydrase inhibitors and thiazide diuretics, both of which possess diuretic activity, are chemical derivatives sulfonamides. Acetazolamide, the most commonly-used carbonic anhydrase inhibitor today, was originally introduced in 1953. While it produces diuresis immediately, its effects are short-lived due to rapid adaptation by the nephron. As a result, carbonic anhydrase inhibitors are impractical diuretics and are used more frequently in ophthalmology because of their effects on intraocular pressure.
Thiazide diuretics were synthesized in an attempt to create more potent carbonic anhydrase inhibitors. While thiazide diuretics do not inhibit carbonic anhydrase, they nevertheless replaced mercurial diuretics since thiazides were much less toxic. Although thiazide diuretics are chemically similar to sulfonamides, thiazides possess no antimicrobial activity. After chlorothiazide was marketed in 1957, no fewer than 7 additional thiazides were released in the next several years. Today, hydrochlorothiazide is the predominant thiazide diuretic used in clinical practice.
During the 1980s, the popularity of thiazides as antihypertensive agents declined somewhat, due in part to the availability of many, new antihypertensive agents, and to the discovery that thiazides could increase serum lipids. It has since been determined that thiazides affect serum lipids only modestly and, because of their extremely low cost, they have reaffirmed their role as important agents in the treatment of hypertension.
Two distal tubule diuretics, spironolactone and triamterene, were made available in the early 1960s, followed, in the late 1960s, by 2 loop diuretics, furosemide and ethacrynic acid. Amiloride, another potassium-sparing distal tubule diuretic, was released in 1981. Additional loop diuretics were released in 1983 (bumetanide) and 1994 (torsemide). Finally, several additional sulfonamide/thiazide derivative diuretics have also been marketed: chlorthalidone, metolazone, and indapamide.
Osmotic diuretics have been available for decades. Hypertonic solutions of dextrose, glycerin, mannitol, sucrose, and urea have all been employed as osmotic diuretics. Today, mannitol is most commonly chosen when there is a need for a systemic osmotic agent. Glycerin is too rapidly metabolized to be an effective diuretic.
Mechanism of Action: With the exception of mannitol and other osmotic agents, all diuretics affect electrolyte transport at the nephron epithelium. Thiazides inhibit sodium reabsorption at the cortex level, specifically, the section of the nephron just distal to the loop of Henle. Thiazides exert their actions from the luminal side of the nephron membrane, thus, they first must be filtered to reach the site of action. Metolazone, a highly-potent, long-acting thiazide, may act in the proximal tubule in addition to the distal tubule. Unlike the rest of the thiazides, metolazone maintains its effectiveness when GFR is poor, and this may be explained by its proximal site of action or, more likely, its superior potency demonstrated by the ability of metolazone to penentrate to the site of action when GFR is impaired.
Carbonic anhydrase inhibitors interfere with the actions of carbonic anhydrase in not only the renal cortex, but also in the eye, resulting in decreased aqueous humor production; and in the CNS, to control seizures and decrease the rate of formation of CSF. In the kidney, drugs such as acetazolamide enhance the clearance of sodium and bicarbonate. In the distal tubule, potassium is lost in an effort to reclaim filtered sodium.
The actions of loop diuretics can be mediated by several mechanisms operating within the thick, medullary segment of the ascending loop. These include (a) interference with Na-K-2Cl ion cotransport at the luminal surface, (b) interference with the Na-K pump, and (c) anion exchange. While furosemide appears to exert actions at all 3 sites, bumetanide and torsemide are specific for the Na-K-2Cl cotransport system. Ethacrynic acid also works at Na-K-2Cl cotransport site but by possibly a mechanism unique from the other 3 loop diuretics.
Various drug combinations can produce a powerful diuretic effect. Perhaps the most well-known diuretic combination is metolazone with a loop diuretic. Simultaneous use of metolazone with a loop-active diuretic produces extensive fluid and electrolyte loss due to the inhibition of two sequential sites within the nephron. This drug combination is often used when the response to a loop diuretic is less than desired. A similar response may be obtained when other thiazides are combined with a loop diuretic if creatinine clearance is not impaired to prevent penetration of the thiazide to the site of action. When renal plasma flow is poor, some clinicians use mannitol, an osmotic diuretic, in combination with loop diuretics in an effort to increase delivery of the loop diuretic to the site of action.

Distinguishing Features: Hydrochlorothiazide is the most commonly used agent of the thiazide group. Its oral bioavailability is much better than chlorothiazide. Many other thiazides are currently marketed but none differs substantially from hydrochlorothiazide. In general, thiazide diuretics are ineffective in patients with creatinine clearance values less than 30 ml/min.
Several agents are often grouped with the thiazides, although they differ somewhat. Chlorthalidone is much longer acting than hydrochlorothiazide butchlorthalidone is significantly more expensive. Metolazone, another thiazide-like agent, is much more potent than hydrochlorothiazide and maintains its effectiveness when GFR is less than 30 ml/min. Metolazone is often used in combination with a loop diuretic in cases of edema refractory to other diuretics. Indapamide, a thiazide-like agent, with calcium channel blocking action, is also effective in patients with creatinine clearance values less tha 30 ml/min.
Despite several differences, the 4 loop diuretics are very similar. Aside from subtle differences in their specific sites of action, furosemide, bumetanide, and torsemide are essentially interchangeable, however, torsemide, due a longer duration of action, can be dosed once daily. Ethacrynic acid is both chemically and pharmacologically distinct from the other 3 loop-acting diuretics and some clinicians feel this drug may be effective in acute renal failure when the other three are inactive. Due to adverse reactions, ethacrynic acid has fallen out of routine use.
Adverse Reactions: Aside from electrolyte imbalances, most diuretics are relatively free from adverse reactions if used appropriately. Although some clinicians believe that modest hypokalemia represents a significant loss of total body potassium, a review of numerous studies indicates that this is not significant with thiazide diuretics; only 5% of total body potassium is lost. Electrolyte loss, however, can be more profound with loop diuretics. The major site of magnesium reabsorption is the loop of Henle. Since thiazide diuretics do not exert effects at this site, hypomagnesemia is less of a problem with thiazides than with loop diuretics. Hypersensitivity reactions are possible if thiazides or carbonic anhydrase inhibitors are administered to sulfonamide-sensitive patients. Furosemide is sometimes considered as having cross-reactivity with sulfonamides, however, in clinical practice, this almost never occurs.
Thiazides are known to cause hyperlipidemia but the magnitude is slight and these changes may revert to baseline after several months of use. In a comprehensive meta-analysis, diuretics were associated with increased total and LDL cholesterol, especially among blacks, and HDL cholesterol were decreased in patients with diabetes. Diuretics also increase serum triglycerides and VLDL cholesterol. Long-term trials indicate that serum cholesterol levels are elevated only for the first 6-12 months of therapy and then decrease to pretreatment levels. Pancreatitis has been associated with thiazide diuretic use, but this may be secondary to hypertriglyceridemia.
It has been suspected that thiazides increase plasma glucose however major studies have refuted this. Further, the consensus of clinical trials indicates that long-term therapy with thiazides does not increase the incidence of diabetes. It is well-known that obesity and hypertension can contribute to insulin resistance.
Ototoxicity is a well-known adverse effect of ethacrynic acid but, while ethacrynic acid is the most ototoxic of the 4, furosemide can also be ototoxic, especially if large IV doses are administered too rapidly. While loop diuretics, because of their potency, are often associated with hypokalemia, it is important to note that these diuretics can also cause hypomagnesemia, hyponatremia, and hypochloremia. Patients with hypokalemia often demonstrate hypomagnesemia concomitantly. Hypochloremic metabolic alkalosis is a common adverse reaction of aggressive diuresis without proper potassium chloride supplementation.

History: Pharmacological induction of labor is considered for a number of maternal or fetal conditions. Oxytocic agents increase the strength, duration, and frequency of uterine contractions, thus assisting with labor. Historically, ergot alkaloids have been used to initiate or accelerate parturition. Ergonovine was approved for use as an oxytocic in 1945, followed by methylergonovine in 1946. Both injectable and oral ergonovine preparations are no longer available from the manufacturer. The role of methylergonovine has been confined to the postpartum period. Oxytocin, approved in 1962, has since become the agent of choice for most labor inductions. In 1977, prostaglandin E2. also known as dinoprostone, was introduced for topical application to aid with labor induction. Larger doses, in vaginal suppositories, have been used for pregnancy termination.
Mechanism of Action: Oxytocics all increase the amplitude and frequency of uterine contractions. Ergonovine selectively stimulates the smooth muscle cells of the uterus and the vascular system, producing strong contractions followed by relaxation. Higher doses of the drug can prolong these contractions and obliterate the periods of relaxation. Oxytocin selectively stimulates the smooth muscle cells of the uterus by enhancing the sodium permeability of the myofibril membranes. Rhythmic contractions of the uterus are produced. The response of the uterus to oxytocin increases as the third trimester progresses. The exact mechanism of action of dinoprostone is unknown, but it is believed to involve the regulation of calcium transport across the cellular membrane as well as the concentration of cyclic 3', 5'-adenosine monophosphate within the cell. As a result of these actions, dinoprostone induces uterine contractions via stimulation of uterine smooth muscle (myometrium).
Unlike oxytocin, ergonovine increases cervical activity, leading to increased cervical contractions. Oxytocin and dinoprostone reduce cervical tone, producing dilation of the cervix. Oxytocic-induced increases in the amplitude and frequency of uterine contractions cause a brief impediment to uterine blood flow. Hemostasis, secondary to ergonovine-induced contractions of the uterine wall around bleeding vessels, also can occur.
Distinguishing Features / Adverse Reactions: The oxytocic agents vary in mechanism of action and adverse reactions. Like other ergot alkaloid derivatives, ergonovine causes vasoconstriction, which affects mainly the capacitance vessels. Administration of ergonovine can increase central venous pressure and elevate blood pressure.
Oxytocin also causes contraction of the myoepithelial cells surrounding the alveolar ducts of the breast, stimulating milk ejection. Milk is forced from the alveolar channels into the large sinuses, from where it is readily available. If oxytocin is absent, the milk-ejection reflex in the breasts fails. Ergonovine can decrease serum levels of prolactin during postpartum.
Dinoprostone stimulates the smooth muscle of the GI tract, which could account for the vomiting and/or diarrhea that is frequently associated with its use. Dinoprostone-induced elevations in body temperature (transient pyrexia) also can occur in patients receiving the drug, but temperatures return to normal following its discontinuance. The exact mechanism by which fever occurs is unknown.

History: Ergot alkaloids are old drugs derived from a fungus that grows on rye and other grains. The effects of ergot ingested during pregnancy have been known for over 2000 years, and ergot was used therapeutically as a uterine stimulant nearly 400 years ago. Preparations available for clinical use include: ergonovine and methylergonovine, used primarily as uterine stimulants; ergotamine and dihydroergotamine, used primarily in the treatment of vascular headache; methysergide and ergoloid mesylates, which are seldom used today but were once popular for treating senile dementia; and bromocriptine, probably the most versatile agent of the group, which is used for postpartum breast engorgement, parkinsonism, and cocaine withdrawal.
Mechanism of Action: The pharmacologic actions of ergot alkaloids are complex. These compounds can simultaneously exhibit stimulation and antagonism of alpha-adrenergic receptors, dopamine receptors, and serotonin receptors. Reuptake of norepinephrine also is inhibited by ergot alkaloids. Because peripheral vasoconstriction can be severe, these drugs should be used cautiously in patients with coronary artery or peripheral vascular disease.
Compared with ergotamine, dihydroergotamine has more alpha-adrenergic blocking activity and thus causes less peripheral vasoconstriction. Its oxytocic activity is less than that of ergotamine and much less than that of ergonovine or methylergonovine. Dihydroergotamine is also a weak serotonin antagonist, although it is less potent than methysergide. Dihydroergotamine vasoconstricts capacitance vessels more than resistance vessels. Therefore, it increases venous return and decreases venous stasis and pooling, and it can help to prevent DVT when given with heparin. Effects on blood pressure are unpredictable. The mechanism of action in the treatment of vascular headaches is probably direct vasoconstriction of the dilated carotid artery bed while decreasing the amplitude of pulsations. Actions on serotonin and catecholamines are also believed to be involved.
Bromocriptine is primarily a dopamine-receptor agonist. Stimulation of dopamine receptors in the CNS make it useful in reducing postpartum breast engorgement and in treating parkinsonism. Because dopamine receptors are believed to mediate some of the symptoms of cocaine withdrawal, bromocriptine has also been used successfully in this setting.
Distinguishing Features: Ergonovine and methylergonovine are used primarily to help contract the uterus after delivery or to reduce postpartum bleeding. In April 1989, parenteral ergonovine was removed from the market; it is still available orally.
Ergotamine and dihydroergotamine have been used in the treatment of migraine, although only recently have quality studies evaluated these agents. Naproxen and other NSAIDs are gradually replacing these agents for mild to moderate migraine attacks, and sumatriptan is a less toxic alternative for more severe cases.
Adverse Reactions: Because of their ability to cause peripheral vasoconstriction, ergot alkaloids (except for bromocriptine) should not be used chronically. Peripheral vasoconstriction can be severe enough to cause Raynaud's phenomenon or angina. Methysergide has been associated with pulmonary fibrosis and, since it is chemically related to LSD, hallucinations.

History: Premature labor (uterine contraction beginning before the 37th week of gestation) occurs in as many as 15% of all pregnancies in the western hemisphere. Conservative treatment with bedrest, hydration, and sedation is not always successful, and pharmacologic agents are sometimes needed. Ethanol was once extensively used as a tocolytic agent. Ethanol infusions were given to provide serum concentrations slightly below legal intoxication, producing adverse reactions commonly associated with ethanol use. Ethanol crosses the placenta, and the fetus can also experience the effects and complications of ethanol. Terbutaline, approved in 1974, was the first beta2 -agonist used for tocolysis, however, it is not currently recommeded for this indication. In 1980, ritodrine, a beta2 -agonist, became the only FDA-approved agent for the treatment of premature labor. Other beta-agonists, such as albuterol, have also been used but have not gained the popular clinical acceptance of ritodrine. Currently, ritodrine is the most widely accepted and used tocolytic.
Other agents have been used and are being studied to prevent uterine contractions and premature labor. Magnesium sulfate, an alternative to the betamimetic agents, is a relatively safe and effective option. Magnesium sulfate is more commonly used in obstetrics to prevent seizures associated with preeclampsia. Hormonal agents, such as progesterone and prostaglandin synthetase inhibitors (e.g. indomethacin, naprorex, aspirin), have been used with limited success and significant adverse reactions. Calcium-channel blockers are being studied with variable results; nifedipine appears to have a potential role for this indication.
Mechanism of Action: Tocolytic agents decrease uterine contraction. This action can be accomplished through different mechanisms of action. The betamimetic agents include the commonly used agents ritodrine and terbutaline. Other betamimetic agents have been studied including isoxsuprine, albuterol, metaproterenol, nylidrin, and fenoterol. Betamimetics preferentially affect beta-receptors, and they have little effect on alpha-adrenergic receptors. The stimulatory effect on beta2 -adrenergic receptors results in the inhibition of smooth muscle contraction including smooth muscle in the uterus. Betamimetics probably stimulate the activation of the enzyme adenyl cyclase, increasing production of cyclic adenosine monophosphate (cAMP). The increase in cAMP produces vasodilation and muscle relaxation in vascular and smooth muscle. Increased cAMP may lower intracellular calcium by enhancing the efflux of calcium from vascular smooth muscle cells and preventing calcium transmembrane influx. Cyclic AMP may inactivate myosin kinase, reducing phosphorylation of myosin, relaxing smooth muscle, and preventing uterine contraction.
The mechanism of the less commonly used tocolytics affect calcium or hormonal balance. Magnesium sulfate's mechanism of action as a tocolytic is unclear. It has been suggested that magnesium antagonizes calcium, interfering with actin-myosin interaction and decreasing uterine contraction. Other proposed mechanisms include magnesium blocking or decreasing nerve transmission, or altering acetylcholine release or sensitivity. Calcium-channel blockers (e.g. verapamil, nifedipine) inhibit calcium influx into uterine smooth muscle. Decreased intracellular calcium relaxes the myometrium.
Prostaglandin synthetase inhibitors, such as indomethacin, inhibit prostaglandins responsible for myometrial and cervical ripening. Fetal prostaglandin inhibition can cause premature closure of the ductus arteriosus and intrauterine pulmonary hypertension. Myometrial and cervical ripening are also dependent on low progesterone concentrations. Administering progesterones could have a tocolytic effect by increasing progesterone serum concentrations.
Distinguishing Features / Adverse Reactions: The betamimetic agents all have similar adverse reactions, although they may be more intense with isoxsuprine than with either ritodrine or terbutaline. All can cause sinus tachycardia, hypotension, and/or angina. These effects are dose-related and can often be controlled by altering the infusion rate of the agents. Hyperglycemia is also a potential adverse reaction of the beta-agonists. The other tocolytic agents described have less efficacy and potentially more serious adverse reactions than do the betamimetics.

Drugs acting on the renal tubules are useful in ancuety of clinical conditions evolving abnormal eleclyte or water metabolism Because the anatomic gments of the nephron are highly specialized in function, the actions of each agent in this group can be bestiderstood in relation to its site of action in the nephron and the normal physiology of that segment. Diuretics (saluretics) elicit increased production of urine (diuresis). In the strict sense, the term is applied to drugs with a direct renal action. The predominant action of such agents is to augment urine excretion by inhibiting the reabsorption of NaCl and water.

The most important indications for diuretics are: Mobilization of edemas (A): In edema there is swelling of tissues due to accumulation of fluid, chiefly in the extracellular (interstitial) space

When a diuretic is given, increased renal excretion of Na+ and H2O causes a reduction in plasma volume with hemoconcentration. As a result, plasma protein concentration rises along with oncotic pressure.

As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease in plasma volume and interstitial volume means a diminution of the extracellular fluid volume (EFV). Depending on the condition, use is made of: thiazides, loop diuretics, aldosterone antagonists, and osmotic diuretics. Antihypertensive therapy. Diuretics have long been used as drugs of first choice for lowering elevated blood pressure. Even at low dosage, they decrease peripheral resistance (without significantly reducing

EFV) and thereby normalize blood pressure. Therapy of congestive heart failure. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload); cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EFV and venous return decrease (reduction in preload). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics. Prophylaxis of renal failure. In circulatory failure (shock), e.g. secondary to massive hemorrhage, renal production of urine may cease (anuria). By means of diuretics an attempt is made to maintain urinary flow. Use of either osmotic or loop diuretics is indicated.

Massive use of diuretics entails a hazard of adverse effects (A): (1) the decrease in blood volume can lead to hypotension and collapse; (2) blood viscosity rises due to the increase in erythro- and thrombocyte concentration, bringing an increased risk of intravascular coagulation or thrombosis. When depletion of NaCl and water (EFV reduction) occurs as a result of diuretic therapy, the body can initiate counter-regulatory responses (B), namely, activation of the renin-angiotensin- aldosterone system. Because of the diminished blood volume, renal blood flow is jeopardized. This leads to release from the kidneys of the hormone, renin, which enzymatically catalyzes the formation of angiotensin I. Angiotensin I is converted to angiotensin II by the action of angiotensin-converting enzyme (ACE). Angiotensin II stimulates release of aldosterone. The mineralocorticoid promotes renal reabsorption of NaCl and water

and thus counteracts the effect of diuretics. ACE inhibitors augment the effectiveness of diuretics by preventing this counter-regulatory response.

NaCl Reabsorption in the Kidney (A)

The smallest functional unit of the kidney is the nephron. In the glomerular capillary loops, ultrafiltration of plasma fluid into Bowman’s capsule (BC) yields primary urine. In the proximal tubules (pT), approx. 70% of the ultrafiltrate is retrieved by isoosmotic reabsorption of NaCl and water.

Thiazides and related diuretics inhibit the reabsorption The nephron is the functional unit of the kidney. Note the various tubules, the site of most diuretic activity. The loop of Henle is the site of action for the loop diuretics. Thiazide diuretics act at the ascending portion of the loop of Henle and the distal tube of the nephron.

In the thick portion of the ascending limb of Henle’s loop (HL), NaCl is absorbed unaccompanied by water. This is the prerequisite for the hairpin countercurrent mechanism that allows build-up of a very high NaCl concentration in the renal medulla. In the distal tubules (dT), NaCl and water are again jointly reabsorbed.

At the end of the nephron, this process involves an aldosterone- controlled exchange of Na+ against K+ or H+. In the collecting tubule (C), vasopressin (antidiuretic hormone, ADH) increases the epithelial permeability for water, which is drawn into the hyperosmolar milieu of the renal medulla and thus retained in the body.

As a result, a concentrated urine enters the renal pelvis. Na+ transport through the tubular cells basically occurs in similar fashion in all segments of the nephron. The intracellular concentration of Na+ is significantly below that in primary urine. This concentration gradient is the driving force for entry of Na+ into the cytosol of tubular cells. A carrier mechanism moves Na+ across the membrane.

Energy liberated during this influx can be utilized for the coupled outward transport of another particle against a gradient. From the cell interior, Na+ is moved with expenditure of energy (ATP hydrolysis) by Na+/K+-ATPase into the extracellular space. The enzyme molecules are confined to the basolateral parts of

the cell membrane, facing the interstitium; Na+ can, therefore, not escape back into tubular fluid. All diuretics inhibit Na+ reabsorption. Basically, either the inward or the outward transport of Na+ can be affected. Osmotic Diuretics (B)Agents: mannitol, sorbitol. Site of action: mainly the proximal tubules. Mode of action: Since NaCl and H2O are reabsorbed together in the proximal tubules, Na+ concentration in the tubular fluid does not change despite the extensive eabsorption of Na+ and H2O. Body cells lack transport mechanisms for polyhydric alcohols such as mannitol and sorbitol, which are thus prevented from penetrating cell membranes. Therefore, they need to be given by intravenous infusion. They also cannot be reabsorbed from the tubular fluid after glomerular filtration. These agents bind water osmotically and retain it in the tubular lumen. When Na ions are taken up into the tubule cell, water cannot follow in the usual amount. The fall in urine Na+ concentration reduces Na+ reabsorption, in part because the reduced concentration gradient towards the interior of tubule cells means a reduced driving force for Na+ influx. The result of osmotic diuresis is a large volume of dilute urine. Indications: prophylaxis of renal hypovolemic failure, mobilization of brain edema, and acute glaucoma.

Diuretics of the Sulfonamide Type

These drugs contain the sulfonamide group -SO2NH2. They are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the luminal membrane of the tubule cells. Loop diuretics have the highest efficacy. Thiazides are most frequently used. Their forerunners, the carbonic anhydrase inhibitors, are now restricted to special indications.

Carbonic anhydrase (CAH) inhibitors, such as acetazolamide and sulthiame,act predominantly in the proximal tubules. CAH catalyzes CO2 hydration/ dehydration reactions: H+ + HCO3 –.H2CO3.H20 + CO2. The enzyme is used in tubule cells

to generate H+, which is secreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3 –, leading to formation of CO2 via the unstable carbonic acid. Membrane-permeable CO2 is taken up into the tubule cell and used to regenerate H+ and HCO3 –. When the enzyme is inhibited, these reactions are slowed, so that less Na+, HCO3 – and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3

– leads to acidosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor. Present

indications for drugs in this class include: acute glaucoma, acute mountain sickness, and epilepsy. Dorzolamide can be applied topically to the eye to lower intraocular pressure in glaucoma.

include furosemide (frusemide), piretanide, and bumetanide. With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis). The site of action of these agents is the thick portion of the ascending limb of Henle’s loop, where they inhibit Na+/K+/2Cl– cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases.

Special toxic effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents. Indications: pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels _ preload reduction); refractoriness to thiazide diuretics, e.g. in renal hypovolemic failure with creatinine clearance reduction (<30 mL/min); prophylaxis of acute renal hypovolemic

failure; hypercalcemia. Ethacrynic acid is classed in this group although it is not a sulfonamide.

Thiazide diuretics (benzothiadiazines) include hydrochlorothiazide, benzthiazide, trichlormethiazide, and cyclothiazide. A long-acting analogue is chlorthalidone. These drugs affect the intermediate segment of the distal tubules, where they inhibit a Na+/Cl– cotransport. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension, cardiac failure, and mobilization of edema. Unwanted effects of sulfonamidetype diuretics: (a) hypokalemia is a consequence of excessive K+ loss in the terminal segments of the distal tubules where increased amounts of Na+ are available for exchange with K+; (b) hyperglycemia and glycosuria; (c)

hyperuricemia —increase in serum urate levels may precipitate gout in predisposed patients. Sulfonamide diuretics compete with urate for the tubular organic anion secretory system.

Pharmacokinetics. All of the thiazides are absorbed when given orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is less lipid- soluble and must be given m relatively large doses Chlorthalidone is slowly absorbed and therefore appears to have a longer duration of action. Indapamide is excreted primarily by the biliary system and is useful in patieiits_with renal insufficiency All of the thiazides are secreted by the organic acid secretory system and compete to some extent with the secretion of unc acid by that system As a result, the uric acid secretory rate may be reduced, with a concomitant elevation in serum uric acid level. In the steady state, unc acid production and therefore renal excretion are not affected by the thiazides.

Pharmacodynamics. Thiazides inhibit NaCI reabsorption in the early segments of the distal tubule Early clearance studies demonstrated an effect on NaCI reabsorption during excretion of diluted urine under water-loaded conditions. This finding suggested that the site of action was at a "cortical diluting segment," since there was no renal excretion can theoretically be achieved by increasing urinary bicaibonate excretion with carbonic anhydrase inhibitors Similarly, renal excretion of weak acids (eg, aspirin) is increased by raising the urine pH. These effects are of relatively short duration and require bicarbonate infusion to maintain continuing bicarbonate diuresis.

C. Reduction of Total Body Bicarbonate Stores: Carbonic anhydrase inhibition will cause acute sodium bicarbonate diuresis as long as the filtered load of bicarbonate exceeds the renal capacity for bicarbonate absorption This approach can be useful m chronic metabolic alkalosis associated with resistance to other diuretic agents Another example is posthyperoapnic metabolic alkalosis. Carbonic anhydrase inhibitors can be used to correct this condition if saline administration is ineffective or contramdicated because of elevated cardiac filling pressures.

D. Acute Mountain Sickness: Weakness, breathlessness, dizziness, and nausea can occur m mountain climbers who rapidly ascend above 3000 m and overexert themselves. The symptoms are usually mild and last for a few days In some climbers, rapidly progressing pulmonary or cerebral edema can be life-threatening Acetazolamide increases performance status and decreases overall symptomatology A recent study (see Greene reference on p 188) proposed taking 500 mg (one sustained-release capsule) by mouth at night for 5 nights before a climb

E. Other Uses: Carbonic anhydrase inhibitors have been used as adjuvants for the treatment of epilepsy, in some forms of hypokaleimc periodic paralysis, and to increase urinary phosphate excretion during severe hyperphosphatemia. Toxicity A. Hyperchloremic Metabolic Acidosis: This is the predictable consequence of chronic reduction of body bicaibonate stores Bicarbonate wasting will ultimately limit the diuretic efficacy of carbonic anhydrase inhibitors m direct proportion to the overall reduction in filtered load of bicarbonate.

B. Renal Stones: Phosphatuna and hypercalcluria occur during the bicarbonaturic response to carbonic anhydrase inhibition. Renal excretion of solubihzmg factors (eg, citrate) may decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that renal stone formation can occur. C. Renal K"^ Wasting: Potassium wasting can be severe, especially during the acute bicarbonate diuresis stage. This complication may limit the useful ness of carbonic anhydrase inhibitors in chronic metabolic alkalosis associated with prior diuretic ad-ministration

D. Other Toxicities: Drowsmess and pares thesias are common following large doses Hypersen- sitivity reactions (fever, rashes, bone marrow suppression, interstitial nephritis) can also occur

Potassium-Sparing Diuretics (A)

These agents act in the distal portion of the distal tubule and the proximal part of the collecting ducts where Na+ is reabsorbed in exchange for K+ or H+.

Their diuretic effectiveness is relatively minor. In contrast to sulfonamide diuretics, there is no increase in K+ secretion; rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration. a) Triamterene and amiloride, in addition to glomerular filtration, undergo secretion in the proximal tubule. They act on the luminal membrane of tubule cells. Both inhibit the entry of

Na+, hence its exchange for K+ and H+. They are mostly used in combination with thiazide diuretics, e.g. hydrochlorothiazide, because the opposing effects on K+ excretion cancel each other, while the effects on secretion of NaCl complement each other. b) Aldosterone antagonists. The mineralocorticoid aldosterone promotes the reabsorption of Na+ (Cl– and H2O follow) in exchange for K+. Its hormonal effect on protein synthesis leads to augmentation of the reabsorptive capacity of tubule cells. Spironolactone, as well as its metabolite canrenone, are antagonists at the aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are: (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosterone-stimulated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be replaced by de novo synthesis. A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast). Clinical uses include conditions of increased aldosterone secretion, e.g. liver cirrhosis with ascites.

Plant that have diuretic properties

Agents influence on miometrium

Drugs which influence on miometrium

І Influence mostly on miometrium contraction

Aleve (Naprorex) Delivery

You can order delivery of a Aleve (Naprorex) to the Germany, Spain, Singapore or any other country in the world. Residents of the USA can order Aleve (Naprorex) to any city, to any address, for example to Omaha, San Diego, Los Angeles or Houston.