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

2. 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

3. 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

4. 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.

5. 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

6. 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.

7. 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

8. 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 …

9. 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

10. 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

11. 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

12. 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)

13. Renal Pharmacology

14. 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)

15. 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

16. Gastrointestinal Pharmacology
Antacids
Peptic ulcer therapy
Antiemetics
Laxatives
Antidiarrheal drugs

17. 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)

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

19. 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®)

20. 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 hours
Omeprazole (Prilosec®)
Lansoprazole (Prevacid®)
Esomeprazole (Nexium®)
Rabeprazole

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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)

30. 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.

31. 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

32. 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

33. 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

34. 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)

35. 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…