Cardiovascular Pharmacology

1. Cardiovascular Pharmacology

2. Histamine and Serotonin

3. Learning Objectives • Understand the physiological and pathophysiological effects of histamine and serotonin. • Appreciate how selective antagonists (and in some cases agonists) are used in therapy. • These two objectives were a little vague so I really just followed the syllabus. It may be a little overly detailed, but I doubt I missed anything.

4. Production and Release • How is histamine made? • The amino acid histidine is converted by histidine decarboxylase. • In what cells is histamine found? Where is it within those cells? What chemical is it bound too? • Tissue mast cells and blood basophils (others?) • It is stored in granules bound to heparin • What are the two mechanisms of histamine release? What are the differences between these two? • Exocytotic • Requires energy and calcium and is similar to neurotransmitter release • Non-Exocytotic • This release is mediated either by cellular inury or by “displacement” by any of a wide range of therapeutic drugs • Example: Morphine, d-tubocurarine

5. Pharmacophysiology • How do H1 and H2 receptors function with regard to 2nd messengers? • H1- causes the activation of the phosphotidyl inositol cycle • H2- causes an increase in intracellular cAMP • Are there H3 and H4 receptors? • Yes, but their physiology is unclear and we don’t have to know anything else about them at this time. • Generally, how does histamine affect the peripheral vaculature? The heart? The GI tract? The airway? Sensory nerves? • Decreased blood pressure and leakiness/edema • Increased heart rate (baroreceptor reflex mediated) • Contraction, increased gastric secretion, and diarrhea • Bronchoconstriction (and increased secretion) • Stimulation with pain and itching • T/F: Asthmatics respond to histamine similarly to nonasthmatics? • F, they have a 100-1000 fold sensitivity to histamine

6. More Pharmacophysiology • Explain the allergic “triple response” that occurs after intradermal injection of histamine (or a mosquito bite). • A red spot at injection spot caused by local vasodilation • A wider extending flush or flare caused indirectly by further vasodilation • A wheal at the injection site caused by edema • How many clinical uses are there for histamine and histamine agonists? • Zero • What are the 6 classes of histamine pharmacologic antagonists? Which ones are “second generation” and what’s the difference? • Ehtanolamines, ethylenediamines, alkylamines, piperazines, phenothiazines, piperidines • Piperazines and Piperidines are second generation antihistamines; they don’t cross the blood-brain-barrier and thusly do not have any CNS effects (the most important of which is sedation). They also have longer ½ lives. • What are the piperidine drug names? • Loratadine (Claritin), fexofenadine (Allegra) • What is the piperazine drug name? • cetirizine

7. Use • What is the molecular mechanism of histamine blockage by the major antihistamines? • competitive antagonism at H1 receptors with minimal effects at H2 • Which class has the fewest “non-H1 mediated” effects? • Piperidines • What are some of the other actions (non-H1) antihistamines can be used for? Generally, which classes of drugs are best for these actions? • Sedation, antinausea, anti-adrenergic, antiserotonergic, local anesthesia • Generally, phenothiazines are most active for these uses and ethonalamines (diphenhydramine (tradename benadryl)) are 2nd. • What are the main clinical uses of these drugs? • Allergic rhinitis, urticaria (skin triple-response), and everything mentioned above. Also used for “systemic mastocytosis or basophilic leukemia.” • What kind of toxicities are common? • Excitation and convulsion (especially in children) central excitatory effects constitute the greatest danger and may resemble atropine poisoning

8. H2 blockagizing • What are some of the drugs in this class? • Cimetidine, rantidine, nizatidine, famotidine (If you care, here are the tradenames) • cimetidine (Tagamet) • ranitidine (Zantac) • famotidine (Pepcid) • nizatidine (Axid, Tazac) • What is their molecular mechanism? • Selective (reversible) competitive antagonism at H2 receptors • What are their physiologic effects? • Reduction in in both volume of acid secretion and in pepsin concentration • Other GI secretions, gastric motility, sphinctor tonus, the heart are all minimally effected • What are the uses of these drugs? • Peptic duodenal ulcer and gastric ulcer • High effectiveness and promotes healing • Zollinger-Ellison syndrome • Higher doses control symptoms • Used for hypersecretion with high systemic histamine (systemic mastocytosis and basophilic leukemia) • What are the three major toxic effects? What are the minor side effects? • Blood dyscrasias, liver toxicity, and teratogenicity (not a brick) • 1-2% of pts report diarrhea, dizziness, somnambulence, headache, rash • Are there any drug interactions of note? • Yeah, cimetidine is a P450 inhibitor. Other H2 blockers seem not to do this.

9. Now… Serotonin

10. Serotonin • What are the two steps (listed) in serotonin formation? • Hydroxylation of L-tryptophan to 5-hydroxy-tryptophan (rate-limiting) • Decarboxylation to 5-HT, an endole ethylamine • Where is it stored? • In granules within platelets and enterochromafin cells of the GI tract • Is it found in plants? • Yes, also venoms and stings • What two enzymes break serotonin down? • Monoamine oxidase and aldehyde dehydrogenase • 24 hour excretion of 5-HIAA (a serotonin metabolite) is a diagnostic test for carcinoid tumor

11. Serotonergic effects • What second messaging system do 5-HT1 receptors generally use? 5HT2 receptors? • Gi/Go • Gq • What effects does serotonin have on the cardiovascular system? GI? Respiratory? Nervous? • Contraction of larger arteries, arterioles “may” dilate (NO mediated), direct positive chrono- and inotropic effect on the heart, stimulation of platelet aggregation • GI smooth muscle contraction, increase in tone and peristalsis, can cause severe diarrhea • Airway smooth muscle contraction with asthma attacks in high levels (carcinoid patients) • Stimulation of sensory nerve endings (pain, itch), various roles as a neurotransmitter in the brain include sleep, temperature regulation, pain perception, and blood pressure regulation • 5-HT agonists are used to treat what condition? • Migraines

12. Lastly…acid(Lysergic acid diethylamide)

13. Ergot Alkaloids • What organism causes St. Anthony’s Holy Fire? What is another name for this disease? What were the symptoms? Who was hurt the most by this disease historically? • Claviceps purpura, a grain fungus • Ergotism • Extremity burning sensation, vasospastic ischemia, and severe pain and gangrene of limbs • The women who got burned at the stake (as witches) for accidentally poisoning their husbands with ergot-laiden bread • What are the primary mechanisms of action of these drugs? • They are agonists, partial agonists, and antagonists on alpha adrenergic and serotonergic receptors, and agonists on CNS dopaminergic receptors • Some also have direct effects on smooth muscle (uterus and blood vessels) • What are the clinical uses of ergot alkaloids? • Migraine (ergotamine tartrate with caffeine) • Hyperprolactinemia and galactorrhea and amenorrhea caused by anterior pituitary tumor (bromocriptine) • Postpartum hemorrhage (ergonovine maleate) • Used to diagnose variant angina by producing a coronary vasospasm during coronary angiography (sounds dangerous) • What are some of the toxic effects of these drugs? • Prolonged vasospasm w/ischemia and gangrene, nausea, diarrhea, drowsiness, hallucinations, fibroblastic changes.

14. Polypeptides

15. Learning Objectives • Understand the relationships between the renin-angiotensin system and control of blood pressure and how pharmacology can affect the system. • Learn the clinical uses and differences between the ACE inhibitors and A2 antagonists. • Understand how pharmacology is used to alter the physiology/pathophysiology of the kinin system and antidiuretic hormone.

16. Angiotensin 2 Production • Describe the synthesis and breakdown of Angiotensin 2 (A2). (Three steps) • Renin is released from the kidneys and converts ansiotensinogen to angiotensin 1 (A1). • Angiotensin converting enzyme (ACE) converts A1 to A2. • Angiotensinases break down A2 to A3 and A3 to something else (we don’t have to know) • Half life of A2 in the blood is 15-60 seconds • Name three hormones that increase secretion of angiotensinogen. • Corticosteroids, estrogens, and A2 • Where is most ACE found? • Most ACE is found in the lungs, however A2 formation may also occur in the kidneys and the CNS. • What hormone stimulates AT1 receptors? AT2 receptors? Where are these receptors found? • Angiotensin 2 (A2) • Angiotensin 2 (A2) • AT1 receptors are found in vascular smooth muscle, the adrenal cortex, kidney, uterus, and brain. AT2 receptors are widely distributed in fetal tissue but not so much in the adult. • AT2 receptors are found in the adrenal medulla and brain but are not considered to play a major role in blood pressure regulation. • Fetal AT2 receptors make ACEi and A2 antagonists contraindicated in pregnant women.

17. Effectationizingham • What type of second messenger system does A2 use? • “there is coupling to multiple G proteins” • Also indirect effects of A2 are due to sympathetic activation. (Norepinephrine stimulates Aldosterone release) • What effects does A2 cause? • Cardiovascular • Direct vasoconstriction and indirect sympathetic discharge • Adrenal • A2 and A3 stimulate aldosterone biosynthesis and secretion • Kidney • Renal vasoconstriction, prox. tubule Na reabsorption, inhibition of renin secretion (negative feedback) • CNS • Sympathetic discharge (effect on area postrema) and increased secretion of vasopressin (ADH).

18. Learning Objectives • Understand the relationships between the renin-angiotensin system and control of blood pressure and how pharmacology can affect the system. • Learn the clinical uses and differences between the ACE inhibitors and A2 antagonists. • Understand how pharmacology is used to alter the physiology/pathophysiology of the kinin system and antidiuretic hormone.

19. Converting enzyme inhibitors • How do these drugs lower blood pressure (BP)? • These drugs block the formation of A2, which reduces peripheral vascular resistance • Name some ACEi drugs. • Captopril, enalapril, lisinopril, and fosinopril • Lisinopril is the most potent (and it’s on the $4 Plan ) • What are the important adverse effects of these drugs? • Hypotension after the first dose, cough in 5-20% of patients, proteinuria or acute renal failure, and teratogenicity

20. Angiotensin 2 Antagonists • How do these drugs reduce BP? • They are nonpeptide antagonists of the AT1 receptor, which is found in vascular and myocardial tissue as well as adrenal and glomerular cells. • Inhibition is reversible but is generally considered “insurmountable” • How long do these drugs take to produce full blood pressure reduction effects? • A month or more • What are some drugs in this class? • Candesartan, cilexetil, eprosartan, irbesartan, losartan, telmisartan, valsartan • Candesartan, cilexetil, and losartan are prodrugs, grapefruit juice screws losartans metabolism all up (CYP 3A4, of course) • In what way is the side effect profile of these drugs superior to that of ACEi drugs? • While most adverse effects are similar between the two classes, A2 antagonists typically do not cause cough.

21. Learning Objectives • Understand the relationships between the renin-angiotensin system and control of blood pressure and how pharmacology can affect the system. • Learn the clinical uses and differences between the ACE inhibitors and A2 antagonists. • Understand how pharmacology is used to alter the physiology/pathophysiology of the kinin system and antidiuretic hormone. • We’re also going to talk about endothelins, which were covered but may or may not be on the test. Skip that slide if you want.

22. Kinins • Where do bradykinin and kallidin come from? • Bradykinin (BK, a nonapeptide) and Kallidin (decapeptide) are generated from kininogen precursors cleaved by kallikrein. • Where does kallikrein come from? • Prekallikrein is made by the liver • How are kinins (BK and kallidin) inactivated? Why is this important? • Kininase I and II inactivate them • Kininase II is also known as Angiotensin converting enzyme, so ACEi drugs potentiate BK effects (this is why they cause cough and may also be related to their hypotensive effectiveness) • What is BK’s half life? • Less than 15 seconds

23. Kinin mechanism and effects • What is BK’s mechanism of action (receptor)? • BK works through two classes of membrane receptors BK1 and 2, of which BK2 is more important. Some effects are also mediated by prostaglandins. • What are BK’s effects? • Cardiovascular • Dilation of arterioles (10x potency of histamine), while veins and large arteries tend to contract • Increase in capillary permeabilityedema • Smooth muscle • Contraction of GI, bronchiolar, uterine smooth muscle • Peripheral nervous • Stimulation of sensory nerve endings and pain • Which of these effects cause ACEi drugs to produce a cough? • ACEi = increased BK = bronchoconstriction + stimulation of sensory nerve endings = cough • I promise not to mention that again • Are kinins mediators of acute inflammation and pain? • Yes • What is aprotinin used for? • Aprotinin is a proteinase inhibitor used in cardiopulmonary bypass surgery

24. Antidiuretic hormone (ADH, Vasopressin) • Describe the actions of the two ADH receptors, V1 and V2. • V1 receptors cause vasoconstriction and increased BP • V2 receptors cause water reabsorption in the renal collecting duct • Specific ADH analogues have selective pressor or antidiuretic activity • For what disorder might ADH analogues be beneficial? • They are mainly used in the treatment of Central Diabetes Insipidus (ADH-sensitive DI) • What drugs stimulate ADH secretion? What drugs inhibit ADH secretion? • Nicotine, tricyclic antidepressants, insulin • Ethanol and phenytoin

25. Endothelins • What tissue makes endothelins? • Endothelins are vasoconstrictor proteins synthesized primarily by the vascular endothelium. They have 5 min half lives. • What is the difference between the three forms of endothelins? • ET-1 is the predominant endothelial derived form • ET-2 is the renal and interstitial derived form • ET-3 is the CNS derived form • Contrast the two endothelin receptors, ETa and ETb • ETa receptors are located on smooth muscle cells and cause vasoconstriction and proliferation • ETb receptors are located on both endothelial and smooth muscle cells and they act to clear endothelin and promote the synthesis of vasodilators • What is Bosentan? What is it used for? What are its adverse effects? • Bosentan is a nonselective ET receptor antagonist used for pulmonary artery hypertension. It can be hepatotoxic and is highly teratogenic (Preggers category X)

26. Eicosanoids

27. Objectives • Recognize events that trigger arachidonic acid release and eicosanoid biosynthesis. • Understand the rational for the clinical uses of analogues and inhibitors. • Understand how low dose aspirin affects the interactions between platelets and the vascular wall. • Use table 1 as a study aid to review the effects of autocoids. • I’m just gonna cover all this over 4 slides with emphasis on the various eicosanoids and what each does.

28. Eicosanoid Production • What is the precursor molecule for eicosanoids? • Arachidonic acid • What are the two pathways arachidonic acid can then go through? • Cyclooxygenase generates PGH2, the pivotal substrate which is then converted into: • PGE2, PGF2, PGD2, PGI2, and TXA2 • 5-lipoxygenase generates LTA4, which is then converted to: • LTB4, LTC4, LTD4, and LTE4 • Which of these arachidonic acid derivatives are each of the following cells most associated? • Endothelial cell • PGI2 • Blood Platelet • TXA2 • Inflammatory Cell • LTs (Leukotrienes)

29. Effects • What is the second messenger system associated with PGI2? TXA2? LTs? • PGI2 increases cAMP causing relaxation of smooth muscle • TXA2 increases IP3 increases intracellular Ca2+ •  contraction of smooth muscle • LTs “release” Ca2+.

30. Name the specific effects of each of the following eicosanoids and eico combos. • PGI2- • Vasodilation and inhibition of platelet aggregation • Used for treatment of atherosclerosis and Raynaud’s (experimental) • PGE2- • Maintains patency of ductus arteriosis prenatally, is a potent bronchodilator, acts on the hypothalamus to increase body temperature. • Can be used postnatally to maintain patency, or COX inhibitors can be used to induce closure. • PGI2 and PGE2- • Decrease gastric acid secretion and lower pain threshold • NSAID blockage can cause increased acid secretion and gastric ulcers • TXA2- • Vasoconstriction and stimulation of platelet aggregation • PGE2 and PGF2- • Contract uterus • Analogues can induce labor at any stage, are used clinically to induce labor or as abortifacients. (Given intra-amniotic or intravaginal to avoid systemic effects) • Dinoprostone, Misoprostol, and Alprostadil—PGE analogues and Carboplast—PGF analogue • Inhibiting these with COX inhibitors (NSAIDS) relieves menstrual pain • LTC4 and LTD4- • Increase vascular permeability and constrict bronchioles • Antagonists are being developed for asthma therapy • LTB4- • Chemotactic for inflammatory cells (also decreases pain threshold)

31. More clinical usage • How do corticosteroids affect autocoids? Which ones do they affect? • Corticosteroids inhibit the release of arachidonic acid by inhibiting phospholipase • This inhibits the synthesis of both prostaglandins/thromboxane and leukotrienes • What is the difference between the two cyclooxygenases? How can pharmacologic agents capitalize on this difference? • COX-1 is a constitutive enzyme expressed by most celss, while COX-2 is induced during inflammation. • While traditional NSAIDs inhibit both COX 1 & 2 and thusly have effects on gastric acid secretion and elsewhere, selective COX-2 inhibitors have less GI effect and cause fewer gastric ulcers. • How is aspirin different from other NSAIDs? How is this difference utilized in the prevention and treatment of thrombosis? • Aspirin is an irreversible inhibitor of cyclooxygenase (other NSAIDs are reversible inhibitors) • Endothelial cells can produce new COX, while platelets cannot. Therefore, low dose aspirin can permanently disable platelet COX mediated production of TXA2 without significantly inhibiting PGI2 synthesis by the vasculature (endothelial cells). • Decreased TXA2 means decreased platelet aggregation and decreased thrombus formation, which is particularly helpful considering that diseased and atherosclerotic vessles don’t produce enough NO and PGI2 (which normally antagonize TXA2) • How can drugs in this class be used to treat asthma? • Inhibitors of autocoids can be used in the prophylactic and chronic treatment of asthma: • Zileuton inhibits 5-lipoxygenase • Zafirlukast is an LT receptor antagonist

32. Introduction to Diuretic Therapy and Fluid Balance

33. Learning Objectives • Structure of the Nephron • Mechanism controlling glomerular filtration • Mechanisms of ion transport • Consequences of and therapy for electrolyte imbalance

34. Learning Objectives • Structure of the Nephron • Picture on page 230 • Mechanism controlling glomerular filtration • Next two slides • Mechanisms of ion transport • Pg232, nothing really on this • Consequences of and therapy for electrolyte imbalance

35. Filtration • What size molecules are freely filtered across the glomerular filtration barrier? • Molecules <18 Å are filtered freely • What type of charged molecules are better filtered and why? • Cationic molecules are more readily filtered because of the negative charge of the glomerular basement membrane • What forces effect the GFR? • Basically, you’ve got filtration constant Kf and oncotic and hydrostatic pressure on both sides. • Review the things that effect GFR on pg230-231 (if you need to). • How does sympathetic stimulation effect GFR? • Sympathetic stimulation increases GFR as well as increasing renin release. • How do PGE2 and PGI2 effect renal blood flow? • PGE2 and PGI2 increase renal blood flow by selectively dilating the afferent arteriole

36. Filtration • What other effects does PGE2 have on the kidneys? • PGE2 also (1) antagonizes (physiologically) the effect of ADH on water reabsorption and (2) inhibits choloride reabsorption in the thick ascending limb. • In what way does Angiotensin 2 effect GFR? • A2 increases GFR by selectively constricting efferent arterioles • Name three ways to stimulate renin release? • Increase sympathetic outflow, because β1 receptors on the juxtaglomerular cells stimulate release of renin • Decrease NaCl reabsorption at the macula densa • Decrease the stretch of the afferent arterioles of the glomerulus (intrarenal baroreceptor reflex)

37. How does tubuloglomerular feedback regulate kidney function if the electrolyte concentration at the macula densa is too high? Too low? • If the electrolyte concentration at the macula densa is too high, afferent arterioles constrict • This may be adenosine mediated constriction • If the concentration is too low, renin is released • Increased renin Angiotensin 2 formation efferent arteriole constriction • Are there organic acid and base transporters? If you said yes, how are they useful pharmacomedically? • Yes. They are useful for facilitation of delivery of drugs (like diuretics) to the tubules.

38. Learning Objectives • Structure of the Nephron • Mechanism controlling glomerular filtration • Mechanisms of ion transport • Consequences of and therapy for electrolyte imbalance

39. Limits: I put this in because I wanted to learn it, sorry if it bugs you. (you could easily delete it) • What is the normal range of potassium concentration? • 3.5-5.5 mEQ/L (4-5 in syllabus) • What is the normal range of sodium concentration? • 135-150 mEq/L • What is the normal range of chloride? • 95-112 mEq/L • What is mEq/L? • One “equivalent” is equal to how much of a chemical will react with 1 mole of electrons. So, for monovalent ions like those above, 1mEq/L = 1 millimol per liter. • http://en.wikipedia.org/wiki/MEq

40. Ion Disturbances: Hypokalemia Hypokalemia • What causes hypokalemia? • Vomiting, diarrhea, excessive mineralocorticoid secretion, kidney disease, diuretic drugs and other medications • From pulmonary: transient hypokalemia is caused by what medicine? • β2 agonists • What are some consequences of hypokalemia? • Impaired neuromuscular function: weakness to paralysis • Intestinal dilation and constipation • Prolonged QT interval, broad and flat T wave, development of U-wave (EKG effects probably not on this test, but important) • How might you treat someone with low K? • Acutely, give KCl intravenously • Chronically, fruit juices, bananas, and KCl tablets by mouth

41. Hyperkalemia • What causes someone to have too much potassium? • Kidney disease, ingestion of seawater, hemolysis, tissue necrosis, mineralocorticoid deficiency (as in Addison’s disease) • Getting convicted of capital murder and lethally injected. • What are some consequences of hyperK? • Myocardial dysfunction (increased height of T wave, widenening of the QRS complex, flattening of the P wave, prolongation of the PR interval) • Neuromuscular tingling, (paresthesia) • How might you treat a hyperkalemic patient? • administer Na-polystyrene sulfonate, an ion exchange resin, by mouth. (what could be healthier than polystyrene?) • Ca-gluconate

42. Hyponatremia (<135mEq/L) • What might cause someone to have too little sodium in their blood? • Renal disease (always an option for an electrolyte imbalance!) • Severe cardiac failure, liver disease, addison’s disease, hypopituitarism, hypothyroidism • Drugs: diuretics, vincristine, cyclophosphamide • What are the consequences of hyponatremia? • Hyponatremia causes cell-swelling which causes: • Muscle cramps, lethargy, apathy, anorexia, nausea, and cheyne-stokes respiration • How could you treat hyponatremia? • Water restriction, hypertonic saline IV w/a loop diuretic (to reduce urine concentration) • vasopressin antagonist (like demeclocyline) to treat Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

43. Hypernatremia • What might cause hypernatremia? • Diabetes insipidus (central or nephrogenic) • Renal disease (of course) • Eating a big bowl of salt • What are some consequences of high Na? • CNS dysfunction due to cellular dehydration and shrinkage, restlessness, irritability, and lethargy • How might you treat hypernatremia? • If associated with volume depletion, use isotonic saline then hypotonic saline or 5% glucose. • Water replacement • Diuretics can be used to correct volume expansion

44. Diuretics: Mechanisms of Action

45. Learning Objectives • Sites of action of the various diuretic classes • Mechanisms of aciton • Therapeutic uses • Special considerations rearding toxicity • I will cover these all at once, using the following outline:

46. Outline for the following slides • Na and K in the late distal tubule • Osmotic diuretics • Carboanhydrase inhibitors • Benzothiazide diuretics • Loop diuretics • Potassium sparing diuretics • Diuretic resistance • Renal vasodilators

47. 1. Na and K handling in the late distal tubule • Na channels and Na/K pumps are regulated by what chemical messenger? • Aldosterone • In the late distal convoluted tubule and collecting duct, where are Na/K pumps concentrated? • On the “blood side” opposite the tubule lumen • What happens when you increase Na delivery to the late nephron? • This increases Na exchange for K as well as H+ excretion • This causes the urine to become acidotic and promotes metabolic alkalosis • How does ADH effect this site? • ADH increases permeability to water which increases water reabsorption

48. 2. Osmotic Diuretics • How do osmotic diuretics work? • They work throughout the vascular system and nephron, increasing the osmolality of their environment and pulling water into the lumen. • This causes an increase in urine volume and sodium excretion, but little change in the excretion of other ions and solutes. • Name some osmotic diuretics. • Mannitol, urea, glycerin, isosorbide • What properties must these agents have to be effective? • They must be filterable by the glomerulus but not reabsorbed by the tubule, and they should be inert (not metabolized). • When are these agents useful clinically? • Mannitol is used to treat brain edema and kidney failure • Glycerin, urea, and isosorbide are used in ophthalmology to reduce intraocular pressure • What are some adverse reactions noted with… • All osmotics? • Headache, nausea, vomiting, extravasation causing extracellular edema • Mannitol? • Hypersensitivity reactions • Urea? • Local irritation, pain, thrombosis • Glycerin? • Hyperclycemia, glucosuria

49. 3. Carboanhydrase inhibitors • What component of these drugs is responsible for the inhibition of carboanhydrase (CA)? • The sulfonamide group (-SO2NH2) • What two way reaction does carboanhydrase catalyze? • H2CO3↔ H2O + CO2 • What is carbonic anhydrase used for (2 things)? • Conserving bicarbonate and adjusting body pH • How does inhibiting carboanhydrase cause diuresis? • Inhibiting carboanhydrase reduces bicarbonate formation inside the tubule cell, which reduces the driving force for sodium reabsorption (which uses a luminal Na/H antiporter). • Name some carboanhydrase inhibitors. • Acetazolamide, dichlorphenamide, methazolamide

50. 3. Carboanhydrase inhibitors • What effects do these drugs have on the urine? • Volume increases, sodium and potassium excretion increases, bicarb excretion is very high, and urinary pH becomes alkaline. • What are these drugs used for clinically? • To reduce intraocular pressure in glaucoma and in the treatment of high altitude sickness (remember altitude sickness is caused by low CO2 and respiratory alkalosis). • These drugs are not used in long term diuretic therapy because metabolic acidosis is problematic and because their effects are limited. • What are some adverse reactions of this drug class? • Metabolic acidosis, CNS disturbances