Diuretics: Renal Pharmacology Carbonic Anhydrase Inhibitors Thiazides Loop Diuretics Potassium-sparing Diuretics

Renal Pharmacology Kidneys: Represent 0.5% of total body weight, but receive ~25% of the total arterial blood pumped by the heart Each contains from one to two million nephrons: The glomerulus The proximal convoluted tubule The loop of Henle The distal convoluted tubule

Renal Pharmacology Functions Renal processes Clean extracellular fluid and maintain ECF volume and composition Acid-base balance Excretion of wastes and toxic substances Renal processes Filtration - glomerulus Reabsorption Tubular secretion In 24 hours the kidneys reclaim: ~ 1,300 g of NaCl ~ 400 g NaHCO3 ~ 180 g glucose almost all of the 180 L of water that entered the tubules

Renal Pharmacology Blood enters the glomerulus under pressure This causes water, small molecules (but not macromolecules like proteins) and ions to filter through the capillary walls into the Bowman's capsule This fluid is called nephric filtrate Not much different from interstitial fluid Nephric filtrate collects within the Bowman's capsule and flows into the proximal tubule: Here all of the glucose and amino acids, >90% of the uric acid, and ~60% of inorganic salts are reabsorbed by active transport The active transport of Na+ out of the proximal tubule is controlled by angiotensin II. The active transport of phosphate (PO4)3- is regulated (suppressed by) the parathyroid hormone. As these solutes are removed from the nephric filtrate, a large volume of the water follows them by osmosis: 80–85% of the 180 liters deposited in the Bowman's capsules in 24 hours As the fluid flows into the descending segment of the loop of Henle, water continues to leave by osmosis because the interstitial fluid is very hypertonic: This is caused by the active transport of Na+ out of the tubular fluid as it moves up the ascending segment of the loop of Henle In the distal tubules, more sodium is reclaimed by active transport, and still more water follows by osmosis.

Renal Pharmacology Diuretics: Basic mechanism: Increase output of urine Primary indications are hypertension and mobilization of edematous fluid (e.g. kidney problems, heart failure, cirrhosis,…) Basic mechanism: Block reabsorption of sodium and chloride => water will also stay in the nephron Diuretics that work on the earlier nephron have greatest effect, since they are able to block more sodium and chloride reabsorption

Renal Pharmacology Diuretics: Carbonic anhydrase inhibitors: Azetazolamide Can trigger metabolic acidosis Not in use as diuretic anymore Primary indications is glaucoma (prevents production of aequous humor) Dorzolamide CA-inhibitors are sulfonamides => cross-allergenic with antibiotics etc.

Renal Pharmacology Diuretics: Loop diuretics (= high ceiling diuretics): Strong, but brief diuresis (within 1 hr, lasts ~ 4hrs) Used for moderate to severe fluid retention and hypertension Most potent diuretics available Act by inhibiting the Na+/K+/2Cl- symporter in the ascending limb in the loop of Henle Major side effects: loss of K+ (and Ca++ and Mg++) Furosemide Bumetanide Torasemide

Renal Pharmacology Diuretics: Thiazide diuretics: Hydrochlorothiazide Used for mild to moderate hypertension, mild heart failure, Most potent diuretics available Act by inhibiting the Na+/Cl- symporter in the distal convoluted tube Major side effects: loss of K+ (and Mg++, but not Ca++) Hydrochlorothiazide Benzthiazide Cyclothiazide …

Renal Pharmacology Major side effects of these diuretics: Hypokalemia, hyponatremia, hypochloremia Hypotension and dehydration Interaction with Cardiac Glycosides => Potassium can be given orally or IV or Potassium-sparing diuretics: Often used in combination with high-ceiling diuretics or thiazides due to potassium-sparing effects Produce little diuresis on their own

Renal Pharmacology Diuretics: Potassium-sparing diuretics: Act on the distal portion of the distal tube (where Na+ is exchanged for K+) Aldosterone promotes reabsorption of Na+ in exchange for K+ (transcriptionally upregulates the Na+/K+ pump and sodium channels) Spironolactone Aldosterone receptor antagonist Onset of action requires several days Amiloride; Trimterene Block sodium channels Quick onset Aldosterone

Renal Pharmacology Diuretics: Potassium-sparing diuretics: Act on the distal portion of the distal tube (where Na+ is exchanged for K+) Aldosterone promotes reabsorption of Na+ in exchange for K+ (transcriptionally upregulates the Na+/K+ pump and sodium channels) Spironolactone Aldosterone receptor antagonist Onset of action requires several days Amiloride; Trimterene Block sodium channels Quick onset Aldosterone Spironolactone

Renal Pharmacology Diuretics: Osmotic diuretics: Mannitol Small, non-reabsorbable molecules that inhibit passive reabsorption of water Predominantly increase water excretion without significantly increasing Na+ excretion => limited use Used to prevent renal failure, reduction of intracranial pressure (does not cross blood-brain barrier => water is pulled out of the brain into the blood) Mannitol Only given IV – can crystallize (=> given with filter needle or in-line filter)

Renal Pharmacology

Renal Pharmacology Uric acid only slightly soluble in water and easily precipitates out of solution forming needle-like crystals of sodium urate sodium urate crystals contribute to the formation of kidney stones and produce the excruciating pain of gout when deposited in the joints. Curiously, our kidneys reclaim most of the uric acid filtered at the glomeruli. Why, if it can cause problems? Uric acid is a potent antioxidant and thus can protect cells from damage by reactive oxygen species (ROS). The concentration of uric acid is 100-times greater in the cytosol than in the extracellular fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens released at the same time to T cells leading to a stronger immune response. => risk of kidney stones and gout may be the price we pay for these protections. Most mammals have an enzyme — uricase — for breaking down uric acid into a soluble product. However, during the evolution of great apes and humans, the gene encoding uricase became inactive. Uric acid is the chief nitrogenous waste of insects, lizards, snakes and birds (the whitish material that birds leave on statues)

Renal Pharmacology Uricosuric agents: Probenicid Sulfinpyrazone At therapeutic doses promote excretion and inhibit reabsorption of uric acid (normally, only 8-12% of the initially filtered urates are eliminated) At low, subtherapeutic doses, both excretion and reabsorption are inhibited => possibility of an increase in uric acid concentration Probenicid Inhibits reabsorption of urates in the proximal convoluted tubule Strong inhibitory effect on penicillin excretion Sulfinpyrazone

Gastrointestinal Pharmacology Antacids Peptic ulcer therapy Antiemetics Laxatives Antidiarrheal drugs

Gastrointestinal Pharmacology Acid production: 2.5 L per day Isotonic HCl solution pH < 1 Produced by parietal cells Mucus production: Produced by mucus-secreting cells Also produce bicarbonate, which becomes trapped in the mucus layer => pH gradient across the mucus layer (can become destroyed by alcohol)

Gastrointestinal Pharmacology Antacids: Weak bases: Aluminum hydroxide Cause constipation Magnesium hydroxide Cause diarrhea => often combined Usally taken 5-7 times per day

Gastrointestinal Pharmacology Antacids: Histamine stimulates acid production by parietal cells Mast cells produce a steady basal level of histamine, which increases in response to gastrin or acetylcholine Parietal cells express histamine H2 receptors => H2 receptor blockers: Cimetidine (Tagamet®) First H2-blocker available Inhibits P450 => Drug interaction Ranitidine (Zantac®) Does not inhibit P450 => fewer side effects Nizatidine (Axid®) Famotidine (Pepcid®)

Gastrointestinal Pharmacology Antacids: Proton pump inhibitors: Irreversibly inhibit the H+/K+ - ATPase in gastric parietal cells Drugs are inactive at neutral pH, but since they are weak bases, are activated in the acidic stomach milieu => restricted activity Acid production abliterated for 24-48 hours Omeprazole (Prilosec®) Lansoprazole (Prevacid®) Esomeprazole (Nexium®) Rabeprazole

Gastrointestinal Pharmacology Gastroesophageal reflux disease (GERD): Backflow of stomach acid into the esophagus Esophagus is not equipped to handle stomach acid => scaring Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !) More severe symptoms: difficulty swallowing, chest pain Reflux into the throat can cause sore throat Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) In some patients, the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus. Primary treatment option are proton pump inhibitors

Gastrointestinal Pharmacology Mucosal protective agents: Misoprostol Prostaglandin E1 analog (PG stimulate mucus and bicarbonate production) Used when treatment with NSAIDs inhibits endogenous PG synthesis Sucralfate Complex of aluminum hydroxide and sulfated sucrose Forms complex gels with mucus => mucus stabilized => diffusion of H+ impaired Not absorbed => essentially free of side effects Must be taken every 6 hours

Gastrointestinal Pharmacology Peptic Ulcer Disease Imbalance between defenses and aggressive factors Defensive factors: Prevent the stomach and duodenum from self-digestion Mucus: continually secreted, protective effect Bicarbonate: secreted from endothelial cells Blood flow: good blood flow maintains mucosal integrity Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid Aggressive factors: Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, may breakdown mucus layer => inflammatory response to presence of the bacteria also produces urease – forms CO2 and ammonia which are toxic to mucosa Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures mucosa Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion NSAIDS: inhibit the production of prostaglandins Smoking: nicotine stimulates gastric acid production

Gastrointestinal Pharmacology Peptic Ulcer Disease (~25 mill. Americans will have an ulcer in their life) Most common cause (> 85%): Helicobacter pylorii (not stress or hot sauce!) Treatment options: Antibiotics Antisecretory agents Mucosal protectants Antisecretory agents that enhance mucosal defenses Antacids Helicobacter pylori (H. pylori) is a spiral-shaped bacterium that is found in the gastric mucous layer or adherent to the epithelial lining of the stomach. H. pylori causes more than 90% of duodenal ulcers and up to 80% of gastric ulcers. Before 1982, when this bacterium was discovered, spicy food, acid, stress, and lifestyle were considered the major causes of ulcers. The majority of patients were given long-term medications, such as H2 blockers, and more recently, proton pump inhibitors, without a chance for permanent cure. These medications relieve ulcer-related symptoms, heal gastric mucosal inflammation, and may heal the ulcer, but they do NOT treat the infection. When acid suppression is removed, the majority of ulcers, particularly those caused by H. pylori, recur. Since we now know that most ulcers are caused by H. pylori, appropriate antibiotic regimens can successfully eradicate the infection in most patients, with complete resolution of mucosal inflammation and a minimal chance for recurrence of ulcers

Gastrointestinal Pharmacology Antibiotic ulcer therapy: Combinations must be used: Bismuth (PeptoBismol®) – disrupts cell wall of H. pylori Clarithromycin – inhibits protein synthesis Amoxicillin – disrupts cell wall Tetracyclin – inhibits protein synthesis Metronidazole – used often due to bacterial resistance to amoxicillin and tetracyclin, or due to intolerance by the patient Standard treatment regimen for peptic ulcer: Omeprazole + amoxicillin + metronidazole

Gastrointestinal Pharmacology Antiemetic drugs: Vomiting: Infection, pregnancy, motion sickness, adverse drug effects,… Triggered by the “vomiting center” or “chemoreceptor trigger zone (CTZ)” in the medulla (CTZ is on the ‘blood side’ of the blood-brain barrier). Treatment options: H1 antagonists: Meclizine, promethazine, dimenhydramine… Muscarinic receptor antagonists: Scopolamine (motion sickness) Benzodiazepines: Lorazepam (during chemotherapy) D2 antagonists: have also peripheral prokinetic effects => increase motility of the GI tract => increases the rate of gastric emptying. Caution in patients with Parkinson’s disease! Metoclopramide Domperidone Cannabinoids: Marihuana ? Synthetic cannabinoids: during chemotherapy Nabilone Dronabinol

Gastrointestinal Pharmacology Laxatives: Laxative – production of a soft formed stool over a period of 1 or more days Catharsis – prompt, fluid evacuation of the bowel, more intense Indications for laxative use: Pain associated with bowel movements To decrease amount of strain under certain conditions Evacuate bowel prior to procedures or examinations Remove poisons To relieve constipation caused by pregnancy or drugs Contraindications: Inflammatory bowel diseases Acute surgical abdomen Chronic use and abuse

Gastrointestinal Pharmacology Laxatives: Stimulate peristalsis Soften bowel contect Classification: Bulk laxatives Non-absorbable carbohydrates Osmotically active laxatives Irritant laxatives = purgatives Small bowel irritants Large bowel irritants Lubricant laxatives Paraffin Glycerol

Gastrointestinal Pharmacology Laxatives: Bulk laxatives: Increase in bowel content volume triggers stretch receptors in the intestinal wall => causes reflex contraction (peristalsis) that propels the bowel content forward Carbohydrate-based laxatives Insoluble and non-absorbable Non digestable; take several days for effect Expand upon taking up water in the bowel Must be taken with lots of water Vegetable fibers (e.g. Psyllium, lineseed) Bran (husks = milling waste product) Osmotically active laxatives Partially soluble, but not absorbable Saline-based (mostly sulfates) Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning) MgSO4 (= Epsom salt) Na2SO4 (= Glauber’s salt)

Gastrointestinal Pharmacology Laxatives: Irritant laxatives: Cause irriatation of the enteric mucose => more water is secreted than absorbed => softer bowel content and increased peristaltic due to increase volume Small bowel irritants Ricinoleic acid (Castor oil) Active ingredient of Ricinus communis The oil (triglyceride) is inactive Ricinoleic acid released from oil through lipase activity Ricin: Lectin from the beans of R.communis Potent toxin: inhibits protein synthesis Potential bioterrorism agent (LD ~100mg) In 1978, ricin was used to assassinate Georgi Markov, a Bulgarian journalist who spoke out against the Bulgarian government. He was stabbed with the point of an umbrella while waiting at a bus stop near Waterloo Station in London. They found a perforated metallic pellet embedded in his leg that had presumably contained the ricin toxin.

Gastrointestinal Pharmacology Laxatives: Irritant laxatives: Large bowel irritants Anthraquinones Active ingredient of Senna sp. (Folia and fructus sennae), Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei): contain inactive glycosides => active anthraquinones released in colon take 6-10 hours to act

Gastrointestinal Pharmacology Laxatives: Irritant laxatives: Large bowel irritants Diphenolmethanes Derivatives of phenolphtalein Bisacodyl Oral administration: effect in 6-8 hrs Rectal administration: effect in 1 hr Often used to prepare for intestinal surgery Sodium picosulfate

Gastrointestinal Pharmacology Laxative abuse: Most common cause of constipation! Longer interval needed to refill colon is misinterpreted as constipation => repeated use Enteral loss of water and salts causes release of aldosterone => stimulates reabsorption in intestine, but increases renal excretion of K+ => double loss of K+ causes hypokalemia, which in turn reduces peristalsis. This is then often misinterpreted as constipation => repeated use

Gastrointestinal Pharmacology Antidiarrheal drugs: Diarrhea is usually caused by infection, toxins, anxiety, drugs… In healthy adults mostly discomfort and inconvenience In children (particularly mal-nourished) a principal cause of death due to excessive loss of water and minerals. Antimotility agents: Muscarinic receptor antagonsists (not useful due to side effects) and opiates: Morphine Codeine Diphenoxylate All have CNS effects - NOT useful for diarrhea treatment Loperamide Selective action on the GI tract Does not produce CNS effects First choice antidiarrheal opoid Combined with Dimethicone (Silicon-based gas-absorbent)

Gastrointestinal Pharmacology Antidiarrheal drugs: treat only symptoms! Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter, clostridium, E. coli), toxins, anxiety, drugs… In healthy adults mostly discomfort and inconvenience In children (particularly mal-nourished) a principal cause of death due to excessive loss of water and minerals. Antimotility agents: Muscarinic receptor antagonists (not useful due to side effects) and opiates: Morphine Codeine Diphenoxylate All have CNS effects - NOT useful for diarrhea treatment Loperamide Selective action on the GI tract Does not produce CNS effects First choice antidiarrheal opoid Adsorbents: Pectin, charcoal, kaolin…