3. Diuretics Diuretics (natriuretics) are drugs which cause a net loss of Na+ and water in urine.

4. CLASSIFICATION 1. High efficacy diuretics /High Ceiling (Loop Diuretic) Furosemide Bumetanide Torasemide ethacrynic acid (only historical) 2. Medium efficacy diuretics Thiazides  Hydrochlorothiazide  Benzthiazide  Hydroflumethiazide  Bendroflumethiazide Thiazide-like  Chlorthalidone  Indapamide  Clopamide  Xipamide 3. Weak diuretics Carbonic anhydrase inhibitors  Acetazolamide Potassium sparing diuretics  Aldosterone antagonist:  Spironolactone  Eplerenone  Inhibitors of Na reabsortion and K secretion  Triamterene  Amiloride Osmotic diuretics  Mannitol  Isosorbide  Glycerol

6. LOOP DIURETICS Furosemide Its maximal natriuretic effect is much greater than that of other classes. The major site of action is the thick ascending limb of loop of Henle (therefore called loop diuretics) where furosemide inhibits Na+- K+- 2Cl¯ cotransport. Furosemide increases: HCO3¯ excretion, Ca2+ excretion (contrast thiazides which reduce it), Mg2+ It tends to raise blood uric acid level ⇒ hyperuricaemia t½ - 1–2 hour

7. LOOP DIURETICS Bumetanide It is similar to furosemide in all respects, but is 40 times more potent. It induces very rapid diuresis and is highly effective in pulmonary edema. Bumetanide is more lipid-soluble; oral bioavailability is 80–100%. It is preferred for oral use in severe CHF, because its bioavailability is impaired to a lesser extent than that of furosemide. t½ ~60 min Torasemide High ceiling diuretic with properties similar to furosemide, but 3 times more potent. Oral absorption is more rapid and more complete. The elimination t½ (3.5 hours) and duration of action (4–8 hours) are longer.

8. Use of loop diuretics 1. Edema (cardiac, hepatic, renal)  Acute pulmonary edema (acute LVF, following MI)  Cerebral edema 2. Hypertension (in hypertensive emergencies) 3. Hypercalcaemia of malignancy 4. Forced diuresis with saline and furosemide infusion to treat poisonings.

10. THIAZIDE DIURETICS Act on the distal convoluted tubule and inhibit the sodium-chloride symporter. A thiazide-like diuretic is a diuretic that has similar physiological properties to a thiazide diuretic, but does not have the chemical properties of a thiazide.

11. Thiazides /Thiazide-like Inhibit reabsorption of sodium (Na+) and chloride (Cl−) ions ⇒ increase excretion Increase calcium reabsorption (contrast loop diuretics) ⇒ decrease excretion Inhibit reabsorption of HCO3¯ increase excretion Inhibit reabsorption of Mg2+ and K+ ⇒ increase excretion Inhibit excretion of urate/ uric acid ⇒ hyperuricaemia Dilate blood vessels (Indapamide )

12. Thiazides /Thiazide-like  Hydrochlorothiazide  Benzthiazide  Hydroflumethiazide  Bendroflumethiazide  Chlorthalidone  Indapamide (little diuretic action, antihypertensive use only)  Clopamide  Xipamide To treat : Hypertension (systematic management)- first line drugs Edema (caused by heart, liver, or kidney disease) Hypocalcemia Nephrolithiasis (ideopathic hypercalciuria) Bromide intoxication Nephrogenic diabetes insipidus

13. Complications of loop and thiazide type diuretic therapy Hypokalaemia Acute saline depletion Dilutional hyponatraemia GIT and CNS disturbances Hearing loss (loop diuretics) Allergic manifestations Hyperuricaemia Hypocalcaemia Magnesium depletion Aggravated renal insufficiency Risk of miscarriage, foetal death.

15. CARBONIC ANHYDRASE INHIBITORS Carbonic anhydrase is an enzyme which is found in the proximal convoluted tubule and functioned in CO2 and HCO3 ¯ transport and in H+ ion secretion. Inhibit of HCO3¯ and accompanying Na+ reabsorption

17. POTASSIUM SPARING DIURETICS Aldosterone antagonists and renal epithelial Na+ channel inhibitors indirectly conserve K+ while inducing mild natriuresis, and are called ‘potassium sparing diuretics’.

18. Spironolactone is a competitive antagonist of aldosterone. Aldosterone normally adds sodium channels in the collecting duct and late distal tubule of the nephron. Spironolactone prevents aldosterone from entering the principal cells, preventing sodium reabsorption.

19. Spironolactone Spironolactone is a weak saluretic because majority of Na+ has already been reabsorbed proximal to its site of action. However, it antagonises K+ loss induced by other diuretics and slightly adds to their natriuretic effect. Spironolactone increases Ca2+ excretion by a direct action on renal tubules. Spironolactone is used only in combination with other more efficacious diuretics.

21. Medical uses To counteract K+ loss due to thiazide and loop diuretics. Edema( It is more useful in cirrhotic and nephrotic edema in which aldosterone levels are generally high) Hypertension( Used as adjuvant to thiazide to prevent hypokalaemia, it may slightly add to their antihypertensive action ) Antiandrogen Hormone replacement therapy for trans women

22. Spironolactone as Antiandrogen Spironolactone is an antagonist of the androgen receptor as well as an inhibitor of androgen production (hyperandrogenism in polycystic ovary syndrome). It is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone, play a role (androgenic alopecia in men and women, and hirsutism, acne, and seborrhea in women) In males -high risk of feminization

23. Hormone replacement therapy for trans women Spironolactone is frequently used as a component of hormone replacement therapy in trans women in addition to an estrogen. Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels. The clinical response consists of decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.

24. Adverse effects Hyperkalaemia Drowsiness Mental confusion Gynaecomastia Physical feminization in general Erectile dysfunction Loss of libido in men Breast tenderness or menstrual irregularities in women.

25. Eplerenone (Inspra) It is a newer and more selective aldosterone antagonist Low affinity for other steroidal receptors ⇒ much less likely to produce hormonal disturbances like gnaecomastia, impotence, menstrual irregularities, etc. This feature makes it particularly suitable for longterm use in the therapy of hypertension and chronic CHF.

26. Epithelial sodium channel blocker Triamterene and amiloride work by directly blocking the epithelial sodium channel thereby inhibiting Na+ reabsorption in the late distal convoluted tubules and collecting ducts in the kidneys. This promotes the loss of sodium and water from the body, but without depleting K+. The drugs are used:  in conjunction with thiazide or loop diuretics to prevent hypokalaemia.  management of hypertension  congestive heart failure Due to its potassium-sparing capacities, hyperkalemia is occasionally observed in patients

27. OSMOTIC DIURETICS Mannitol is a nonelectrolyte that is pharmacologically inert— can raise osmolarity of plasma and tubular fluid. Mannitol limits tubular water and electrolyte reabsorption. Action : increase urinary volume, excretion of all cations (Na+, K+, Ca2+, Mg2+) and anions (Cl¯, HCO3¯). Uses:  Increased intracranial tension (acute head injury, stroke, etc.)  Before and after brain surgery to prevent acute rise in intracranial pressure

28. ADR Adverse effect DiureticsSymptoms Hypovolemia loop diuretics thiazides lassitude thirst muscle cramps hypotension Hypokalemia acetazolamides loop diuretics thiazides muscle weakness paralysis arrhythmia Hyperkalemia amilorides triamterenes spironolactone arrhythmia muscle cramps Hyponatremia thiazides furosemides CNS symptoms: coma Hypercalcemia thiazidestissue calcification Hyperuricemia thiazides loop diuretics gout

30. Hypolipidemic drugs A group of pharmaceuticals that are used in the treatment of hyperlipidemias.

32. Hypolipidemics differ in both their impact on the cholesterol profile and adverse effects. For example, some may lower the low density lipoprotein (LDL) ("bad cholesterol") more so than others, while others may preferentially increase high density lipoprotein (HDL), "the good cholesterol".

33. Classes of hypolipidemic drugs Statins: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin and Simvastatin Fibrates: Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, Clinofibrate Niacin ( nicotinic acid = vitaminPP= vitamin B3) Bile acid sequestrants: Cholestyramine, Colestipol, Colesevelam