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1997 Clinical pharmacology By Duy Thai

DIURETICS I & II Uses of diuretcis • Reducing oedema associated with the following conditions: 1. Congestive heart failure 2. Hepatic failure 3. Pulmonary oedema 4. Cerebral oedema 5. Glomerulonephritis 6. Premenstrual oedema (???) • Hypertension Normal structure and function of the nephron Collecting tubule • 1-3% of Na+ is reabsorbed here • Na+ is reasbsorbed without Cl-. This results in a net buildup of negative charges in the tubule lumen. To balance out this negative charge, K+ or H+ is secreted. • The amount secreted depends on: • Volume flow • Anion present • Availability of K+ and H+ • Potential difference created by the N+ reabsorption • Aldosterone acts here to increase water reabsorption e.g: SPIRONOLACTONE

Proximal tubule • Reabsorption of: • Na+, Cl-, HCO3-, K+ and H2O • 70% of Na+ and H2O is reabsorbed here • Diuretics which block Na+ reabsorption here will not be very effective because all the sites distal to the proximal tubule will be able to compensate for the excess Na+ they are receiving, and reabsorb it, so that in the end, the amount of Na+ lost is minimal e.g: ACETAZOLAMIDE

Distale tubule • 5% of Na+ is reabsorbed here • Diuretics which act here have a reasonable effect e.g: THIAZIDES

Ascending loop of henle • 22% of the Na+ is absorbed here • The absorptive process + involves co-transport of Na + and K and 2 Cl • The most effective diuretics act here because there is not much opportunity distal to the loop of henle for compensatory reabsorption of the excess Na+ e.g: FRUSEMIDE
+

• Note: Any diuretic which acts before the collecting tubule will result in K loss • In the collecting tubule, the amount of K+ secreted depends on the amount of Na+ arriving. + + Diuretics which block Na reabsorption in the proximal parts of the nephron cause lots of Na to + + arrive at the collecting tubule. The more Na arriving, the more K will be exchanged, and so + there is a loss of K from the body.
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1997 Clinical pharmacology By Duy Thai

• Diuretics which block Na+ reabsorption at the collecting tubule will be preventing this Na+ K+ exchange. Hence, these diuretics will not cause loss of K+. However these diuretics are acting at the last part of Na+ reabsorption, where only 1 - 3% of Na+ is absorbed. Most of the Na+ has already been reabsorbed in the more proximal parts of the nephron and so these diurectics are fairly weak. Classification of diuretics 1. Water • The more fluid you put in to your body, the more you will pee out. Not very useful in the treatment of oedema, because we are trying to minimise the amount of fluid in the body. 2. Acid forming salts 3. Xanthines • Substances such as tea and coffee may have a diuretic effect 4. Mercurials • Not used any more since they needed to be injected intramuscularly • Were a powerful group of diuretcs used extensively for cardiac failure 5. Osmotic 6. Carbonic anhydrase inhibitors These will be discussed in more detail below 7. Thiazides 8. High ceiling (loop diuretcs) 9. K+ sparing Osmotic diuretics • Properties: • Water soluble so that they can be freely filtered by the glomerulus • Need to be poorly reabsorbed by the tubules, because they exert their effect by remaining in the tubular lumen • The drugs are mostly non electrolytes (which are pharmacologically inert) • Mannitol • Urea • Glycerol • Mechanism of action: • These agents act on the parts of the nephron which are freely permeable to water (where there is passive absorption of water) - the proximal tubule, the descending loop of henle and the collecting tubules • By remaining in the tubular lumen, these agents cause an increase in colloid osmotic pressure in the tubular lumen. This results in “suction” of water into the tubular lumen. • There is also reduced water reabsorption due to renal medullary hyperemia (involves prostinoids) • There is impairment of Na+ reabsorption because the diluted solution in the lumen reduces the Na+ concentration gradient, making it harder for Na+ to be reabsorbed. The Na+ loss which occurs is not very marked • Administration and uses • These agents form the major constituents of IV drips. • Given IV to maintain kidney function during trauma or surgery • These situations involve a lot of blood loss, which may cause severe hypotension. This causes the renal arteries to constrict, possibly leading to renal infarction • Osmotic diuretics are not useful in conditions associated with Na+ retention • Glycerol, given orally, is used to reduce intracranial pressure prior to neurosurgery • Urea, given orally or IV, is used to reduce CSF pressure • Also used to increase the excretion of drugs in acute poisoning • Side effects: • Not many. • May cause cardiac failure because these agents are also exerting an osmotic pressure in the blood, which tends to suck fluid out of the cells, increasing blood volume.

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1997 Clinical pharmacology By Duy Thai

Carbonic anhydrase inhibitors • Sulphonamides are used as antibiotics. Their side effects included: • Metabolic acidosis resulting from a loss of HCO3- in the urine (which was associated with a large volume of urine) • Acetazolamide is a derivative of a sulphonamide, but does no possess any antibacterial action. What has happened is that we have exploited the side effects of sulphonamides to make a therapeutically useful substance. • What happens normally in the proximal tubule? • CA is required to convert H2O and CO2 into H2CO3 and vice versa • H2CO3 in the tubular lumen is broken down to H2O and CO2 via CA (Step 1) • The CO2 and H2O is absorbed into the tubular cells (Step 2) • Inside the tubular cell, the CO2 and H2O is recombined to H2CO3 via CA (Step 3) • H2CO3 decomposes to H+ and HCO3- (Step 4) • The H+ which is produced is used to reabsorb the Na+ which is in the lumen (Step 5) • If there no H+ is generated, then Na+ will not be able to be reabsorbed. Lumen NaHCO3 Blood Na HCO3- + H+
+

• CA

H2CO3

„ ƒ

H+ + HCO3-

H2O + CO2

H2CO3 CA CO2 + H2O

• Mechanism of action of the carbonic anhydrase inhibitors: • Prevents the absorption of HCO3- in the lumen by preventing the breakdown of H2CO3 by carbonic anhydrase • Acetazolaminde is a non competitive, irreversible inhibitor of carbonic anhydrase • Since there is no production of H+ by the tubule cell (see step 4), Na+ cannot be reabsorbed. • The mechanism of Na+ reabsorption in the proximal tubule is via counter exchange with H+ • The net result is: • HCO3 retained in the lumen + • Na retained in the lumen + + • K is present in the lumen due to exchange with Na in the collecting tubule • These ions create an osmotic effect, which draws water out into the lumen + • The diuresis is not great because there is compensatory reabsorption of Na is the segments further down the nephron. • Complications: • The urine pH is increased due to lots of HCO3• This makes the NH4+ mechanism to remove acids ineffective, and hence a metabolic acidosis can develop • K+ loss due to lots of Na+ arriving at the collecting tubule • The diuresis is self limiting, i.e. it stops after a while. Why? • There is only a limited amount of HCO3- in the body. When there is none left, there is no use for carbonic anhydrase any more and so acetazolamide will no longer be of any use. • Other side effects: • Drowsiness, numbness and tingling of the face and extremities (due to metabolic acidosis), disturbances of vision. • Administration and uses • Rarely used as a diuretic
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1997 Clinical pharmacology By Duy Thai

• Mainly used in the treatment of glaucoma • Carbonic anhydrase is important in the secretion of aqueous humor • In the context of this usage, diuresis is considered a side effect Thiazides • In the search for more potent carbonic anhydrase inhibitors, other drug classes were discovered. • Thiazides were one of these • Most thiazides are weak inhibitors of CA, but this is not the basis of their action • They became more effective as a diuretic but less effective as a CA inhibitor • Mechanism of action: • Acts at the distal tubule (hence they are medium acting diuretics) • There is a small amount of compensatory reabsorption of Na+ at the collecting duct • However, most of the Na+ is already absorbed in the earlier parts of the nephron. • In the distal tubule, Na+ is reabsorbed via a Na+ Cl- co transport • Thiazides inhibit this cotransport mechanism, thus preventing Na+ from being reabsobed Na+ ClThiazides act here Na+ ClNa+ K+

• Thiazides may also inhibit the Na+ K+ ATPase indirectly • The K+ loss is due to Na+ K+ counter exchange at the collecting tubule • Administration and uses: • Treatment of oedema in cardiac failure • In hepatic cirrhosis, we do not want to have much K+ loss. Thiazides are thus given in conjunction with K+ tablets or with a K+ sparing diuretic. • The drug needs to be present in the tubular lumen to be effective • Side effects: • Increase in blood sugar (hyperglycemia), especially in diabetics, due to impaired release of insulin and reduced glucose utilisation • Reduced insulin also causes increased glycogenolysis and reduced glycogenesis. • All these factors equate to reduced glucose tolerance • Thiazides are secreted in the kidney via the organic acid secretory system. This system is also the mechanism whereby uric acid is secreted. As a result, thiazides may cause a reduced excretion of uric acid, leading to gout. • Hypersensitivity reactions: • The thiazides are sulphonamides, and so share cross reactivity with other drugs of this group. Therefore, if you are allergic to a sulphonamide, chances are you will also be allergic to thiazides. • Photosensitivity, haemolytic anaemia may occur • An example of a thiazide is Chlorothiazide • Also has vasodilator activity Good for use as a hypertensive • Very cheap High ceiling diuretics (loop diuretics) • The most effective diuretics since the later stages of the nephron do not absorb much water and so are provide weak compensatory absorption. A fairly high proportion of Na+ is also reabsorbed here (22%) • Includes the follwing drugs: • Frusemide • Bumetamide • Ethacrynic acid • Mechanism of action: • These drugs act at the ascending limb of the loop of Henle
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1997 Clinical pharmacology By Duy Thai

At this site, Na+ is reabsorbed via co transport with K+ and 2 ClThere is a reduction in active Cl- reabsorption in the ascending limb There is also a reduction in the Na+ K+ ATPase (use is not clear) Reduction in the activity of carbonic anhydrase (minor action) Stimulate the production of prostaglandins • These increase the vascular flow to the kidney, thus promoting more fluid loss • If NSAIDs are given, the effects of the loop diuretics are reduced • Frusemide must be secreted into the tubules to be effective • Drugs like frusemide and thiazides need to be in the tubular lumen to be effective • This means that anything which inhibits their secretion into the tubule (e.g. anything which inhibits the organic acid secretory system -Probenecid) will hinder the action of these diuretics. • Therefore, if probenecid is taken in combination with fresemide, the actions of frusemide (and any other diuretic which use the organic acid transport mechanism) are diminished. • However, if you inject probencid and frusemide directly into the tubular lumen, frusemide will work fine. This indicates that all probencid does to inhibit the action of frusemide is to prevent its access to the lumen where it needs to work. Probenecid does not directly inhibit the action of frusemide. • Administration and uses • Effective orally • Causes marked Na+ excretion • K+ loss (due to exchange with Na+) • Peak effect occurs within 2 hours of taking the drug. The effects last for around 8 hours • The drugs are bound to plasma proteins • The drug is eliminated in the urine or in the bile (in the case of ethacrynic acid) • Ethacryinic acid is not a sulphonamide derivative, and so it is the odd one out in the high ceiling group of diuretics. • Used in renal failure, heart failure and pulmonary and cerebral oedema • Side effects: • Electrolyte imbalance (mainly hypokalemia) • Local irritation of the GI tract • They will compete with other drugs e.g. digitalis (cardiac glycoside) for binding. Also need to be careful if warfarin is given Potassium sparing diuretics • There are 2 groups of drugs in this category. The only thing they have in common are their site of action (they all work in the late distal tubule and collecting duct). Their mechanism of action is quite different. 1. Inhibition of aldosterone • Drug: • Spironolactone • Mechanism of action: • Aldosterone (a steroid hormone) enters tubular cells and binds to a mineralocorticoid receptor in the cytoplasm. • This hormone receptor complex binds to a response element on the DNA. • Binding results in the expression of aldosterone induced proteins: • Activation of silent Na+ channels/pumps • Alters the cycling of the channels and pumps • Increased expression of channels and pumps • Altered permeability of the tight junction (zonula occludens) • All the above effects result in an increase in Na+ conductance (reabsorption) and secretion of K+ (One of the complications of excess aldosterone secretion is hypokalemia) • Spironolactone binds to the mineralocorticoid receptor and prevents aldosterone from binding. • The half life of spironolactone is 10 minutes, but the action of it is much longer. This is explained by the fact that spironolactone acts via an acive metabolite. • Spironolactone is metabolised in the liver to canrenone (half life 12-16 hours)
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1997 Clinical pharmacology By Duy Thai

2. Inhibition of the Na+ K+ exchange in the collecting duct • Drugs: • Triamterine • Amiloride • Mechanism of action • Inhibition of the Na+ and K+ exchange in the aldosterone independent section of the distal tubule • By blocking this, the drug reduces Na+ reabsorption and prevents K+ loss • Uses of K+ sparing diuretics • These diuretics are relatively weak because they are acting in the part of the nephron which reabsorbs the least amount of Na+. Most of the Na+ has already been reabsorbed in the earlier parts of the nephron. • However, they are useful in conditions where K+ loss cannot be tolerated (often used in conjunction with thiazides) • Used in hypertension and congestive heart failure • If a person is being treated with digoxin for their heart failure, loss of K+ can enhance the toxicity of digoxin (cardiac glycoside) • Digoxin (a cardiac glycoside), works by binding to the Na+ K+ ATPase in the myocardium. In particular, it binds to the site where K+ normally enters. This results in Na+ accumulation intracellularly which prevents Ca2+ extrusion via the Ca2+ Na+ counter transport. Increased Ca2+ causes increased force of contraction. • If K+ is reduced, the actions of digoxin are enhanced because normally, digoxin must compete with K+ for the Na+ K+ ATPase. • By using the drugs in combination, there is an enhanced diuretic effect and the added benefit of not losing K+ • Spironolactone is used in primary hyperaldosteronism (tumor of the adrenals) or secondary hyperaldosteronism (cardiac failure, hepatic cirrhosis). • In cardiac failure, there is overactivity of the renin-angiotensin-aldosterone system in an attempt to increase blood pressure • Side effects/toxicity: • Hyperkalemia • Metabolic acidosis • Gynaecomastia, impotence, decreased libido, hirsuitism • Gastric upsets (don’t give these drugs to people prone to gastric ulcers) DRUGS TO ALTER URINARY PH Alkalinising agents • Mechanism of action + + • Sodium or potassium citrate is metabolised to form a stable cation (Na or K ) and a labile anion (citrate) + + • Citrate is taken up for use by the TCA. The Na or K is excreted with the most common anion (HCO3 ) • Hence, you will have an alkaline urine • Administration and use: • Increased action of antibacterials, especially sulphonamides. • Sulphonamides are generally insoluble in acid urine. They may thus precipitate out and crystallise. Therefore, to increase solubility, the urine is made more alkaline. • Increase the excretion of acidic drugs • e.g. Aspirin, salicylates, barbituates Acidifying agents • Mechanism of action: + • Ammonium chloride (NH4Cl) is given and metabolised in the liver to NH4 and Cl + • The Cl is excreted along with Na • The base conserving mechanisms secrete H+ and NH4+ into the urine
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1997 Clinical pharmacology By Duy Thai

• Uses: • Increase action of antibacterials • Increase excretion of basic drugs • e.g. Pethidine, amphetamine GOUT & URICOSURIC AGENTS Uricosuric agents • Diuretics which utilise the organic acid transport mechanism (thiazides and high ceiling) to be secreted into the tubular lumen to become active also have the problem of causing uric acid retention (because uric acid excretion uses the same mechanism) • Hyperuricemia can develop, leading to secondary gout • There are 2 sorts of gout: • Primary gout: • Due to increased uric acid synthesis • Secondary gout: • Result of a disease process where there is excessive protein breakdown (e.g. leukemia, lymphomas) • Drugs which compete for uric acid excretion • Salicylates, alcohol, diuretics • Uric acid is secreted and reabsorbed in the proximal tubule • Uricosuric agents compete for uric acid reabsorption • e.g. Probenecid & sulfinpyrazone • Mechanism of action: • At low doses, these drugs cause increased serum and decreased urinary levels of uric acid • This happens because they block uric acid secretion (just like diuretics do) • At high doses, the drugs cause decreased serum and increased urinary levels of uric acid • This happens because they now block uric acid reabsorption and not secretion. • Uricosuric agents are often used in combination with allopurinol • Allopurinol inhibits uric acid synthesis by inhibiting xanthine oxidase. • It does this by competing with the natural substrate of xanthine oxidase (which is hypxanthine and xanthine ) Xanthine oxidase Xanthine oxidase

Hypoxanthine

Xanthine

Uric acid

• In addition, allopurinol acts as a substrate for xanthine oxidase, and is metabolised to alloxanthine, which itself is an irreversible inhibitor of xanthine oxidase. • Allopurinol also inhbits microsomal drug metabolising enzymes DIURETICS & URICOSURIC DRUGS • Indacrinone • The - isomer is diuretic and uricosuric • The + isomer is uricosuric

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