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Pharmacology 3rd stage

Diuretics
These drugs increase renal excretion of sodium (solutes) and water, thus increase the volume of urine and often change its PH as well as the ionic composion of the urine and blood.
Renal mechanism:-
Glomerular filtration in 24 hrs will be 180 liters per day ,while the volume of urine is 1.5 liters , so the rest is reabsorbed by the renal tubules , the major effect of these drugs is to inhibit the reabsorption of sodium by renal tubules ; so that ; to increase sodium excretion which is accompanied with water ,so as to keep the osmotic balance of the body .
Hydrogen ion help in the reabsorption of sodium and bicarbonate (HCO3), and help in the ammonium ion excretion, hydrogen and potassium can exchange with sodium and substitute for each other.
Regarding physiology of nephron:-
1) At proximal convoluted tubule, 70% of filtered sodium, chloride and water are reabsorbed in such rapidity that osmotic balance is kept between intraluminal and interstitial fluid.
2) Ascending loop of Henle; in this part there is active reabsorption of chloride followed by sodium and no water reabsorption in this part, so it is known also as diluting segment; 20-30% of filtered sodium and chloride is reabsorbed here.
3) Distal convoluted tubule: - sodium is reabsorbed in exchange with potassium and hydrogen under aldosterone influence, this part is responsible for 5% of filtered sodium reabsorption.
4) Collecting duct; it is the site of ADH because in the presence of ADH, this part is going to be permeable to water, urine become hypertonic, and vice versa; no ADH, the urine become hypotonic.
Groups of diuretics according to their efficacy in excretion of sodium (Natriuretic effect).
1)High efficacy diuretics or high ceiling diuretic or loop diuretics :- they are Frusemide ; Ethacrying acid ; Bumetanide ; Piretanide and torasemide ; they are called loop diuretics due to their action on the medullary part of ascending loop of Henle ,also slight effect on proximal convoluted tubule.
They can work even if the G.F.R. below 10 ml/min.
Anuria is a contraindication of this group; they are chemically different but although have similar properties and indications, and they are vary in their efficacy.

Mechanism of action :-

Inhibiting chloride and sodium reabsorption lead to excretion of both of them in urine which is usually accompanied by water ;Potassium is also excreted lead to hypokalemia ,because of large amount of sodium is subjected to the distal tubule where it has more chance to be exchanged with potassium ; this loss of potassium may be corrected by either potassium supplement or using of low –efficacy diuretics (Potassium sparing diuretics ) that retain potassium to the body .
Their onset of action is within 2-10 min. if given I.V. and 1 hr. if given orally; duration of action may persist for 4-6 hrs.
Clinical indications:-
1) Acute pulmonary edema due to congestive heart failure, the relief occur before induce the dieresis.
2) Hypertensive crisis.
3) All cases of heart failure particularly refractory heart failure.
4) Chronic renal failure.
5) Refractory edema.
6) Nephrotic syndrome.
7) Oligouric state - (decrease in urine volume) – to protect from acute renal failure .but should not used in Anuria
8) Promote calcium excretion, but not to a state of hypocalcaemia; it is used with saline.
9) In some drugs toxicity by forced alkaline dieresis.
Side effects:-
1) Metabolic alkalosis ,might result as chloride loss is relatively excreted more than HCO3 .
2) Hyperuricemia ,because of that high efficacy diuretics and uric acid have the same secretary mechanism on tubules .
3) Decrease CHO tolerance ,occur with less extent than Thiazide .
4) Hypokalemia which is less serious than that produced by moderate efficacy diuretics ,because of their short duration of action in comparison with moderate efficacy diuretics .
5) might cause renal interstitial nephritis lead to reversible renal failure .
6) Deafness may be transient with Furosemide ; infrequent with Bumetanide ,and permanent with Ethacryinc acid .
7) Gastrointestinal disturbances with or without bleeding ; if it is given to patient with ascitis lead to hepatic coma and probably hepato-renal syndrome ,because of liver cell necrosis .
8) Hypomagnesaemia .
9) Hypotension .
10) Skin rash and parasthesia .
These drugs inhibit 15-20 % of filtered load ,duration of action is about 4-6 hrs .
Moderate efficacy diuretics :-
They are ,Thiazide drugs include : Chlorothiazide (prototype ) , Hydrochlorthiazide , Bendrofluzide , Cyclopenthiazide , …… . and drugs related to Thiazide like Chlorthalidone , Metolazone ….. .
Pharmacokinetic :- These drugs are effective orally , most Thiazide take 1-3 weeks to produce a stable reduction in blood pressure , they exhibit a prolong biological half life
(40 hrs.) . they are represented by Thiazide group ,they inhibit 5-10% of filtered load ,they won't work if G.F.R. is below 20ml/ min. ,their site of action is at cortical diluting segment mainly ,Thiazide are sulfonamide derivative and are related in structure to the carbonic anhydrase inhibitors .

Mechanism of action :-

1)Carbonic anhydrase inhibitory effect ; (because of its structure ) .
2) Direct inhibition of sodium reabsorption ,followed by chloride reabsorption ,so water excreted with potassium .
They have antihypertensive action partly due to volume of urine lost lead to decrease cardiac output ; and partly due to an effect on blood vessels ,because a non diuretic Thiazide which is (Diazoxide ) is act as an antihypertensive agent
Clinical uses :-
1)Chronic renal failure with edema, treated first by loop diuretic , if field ,can give Metolazone with loop diuretic .
2) Edema due to chronic hepatic disease ,but if there is hepatic hypokalemia , may worsen or precipitate encephalopathy .
3) Hypertension ; either used alone or in combination with other anti hypertensive agents .
4) Hypocalceuric effect ,because they decrease excretion of calcium in urine ,so it might used in treatment of idiopathic hypercalceuria .
5) Nephrogenic diabetes insipidus ; Thiazide have a unique ability to decrease volume of urine , they produce hyperosmolar urine . they may reduce the volume of urine from 12l. to 3l.

Side effect :-

1)Hypokalemia , more serious than that with loop diuretic .
2) Hyperuricemia , like H.E.D. with gout attacks .
3) Hyperglycemia , decrease CHO tolerance and increase in glucose level in blood .
4) Hypercalcemia .
5) Hyperlipidemia , Thiazide can cause a 5-15% increase in serum cholesterol .
6) Thrombocytopenic purpura .
Chlorothiazide :- prototype of Thiazide diuretic; active orally, and was capable of affecting the sever edema of liver cirrhosis and congestive heart failure with minimum side effects .
Chlorthalidone :- is a non Thiazide derivative ,often used to treatment hypertension through a single dose per day .
Metolazone :- it is more potent than the Thiazide, and unlike Thiazide cause sodium excretion in advance renal failure .
Low efficacy diuretics :-
They are also called potassium conserving or potassium retaining agents ;they lead to excretion of 5% of filtered sodium ; site of action is distal convoluted tubule mainly .

Spironolactone :-

It is a competitive aldosterone antagonist also called ( true aldosterone antagonist ),it is compete with aldosterone receptors in the distal convoluted tubule .
P/K :- Spironolactone is completely absorbed orally ,strongly bound to plasma proteins and rapidly converted to active to an active metabolite Canrenone which is also antagonize aldosterone ,Spironolactone is induce hepatic cytochrom P-450 ; and only act in presence of exogenous or endogenous aldosterone ; its use lead to decrease potassium excretion .
Clinical uses :-
1)Spironolactone is used in combination with diuretics that lead to potassium excretion in which hypokalemia is a problem .
2) Nephrotic syndrome .
3) Hepatic cirrhosis .
4) Refractory edema which doesn’t respond to other drugs .
Side effects :- Abdominal pain ;slight Hyperuricemia ,gynecomastia in male and menstrual irregularity especially amenorrhea in female .

Triameterene :-

It is not a true aldosterone antagonist ,doesn’t compete for receptors in distal convoluted tubule ,it can act to retain potassium and excrete sodium ,it only acts when diuretics are used with it that lead to sodium excretion ( Natriuretic effect ) or it also act in the presence of excess amount of aldosterone either by pretreatment or spontaneous production .
Side effects :-
Leg cramps ,in some patient cause non-oligouric renal failure when indomethacine is used with it .
Amiloride :- It is related structurally to Triameterene and has uricosuric effect and more potent than the rest ,it is usually combined with Thiazide in order to control potassium level to some extent .
4) Osmotic diuretics :-
They are weak diuretics as mannitol ,urea ,sugar ;site of action is proximal ,distal convoluted and collecting duct ,they are non—electrolyte substances and that’s mean ; they are freely filterable from the glomerulus ,undergo limited reabsorption in the renal tubule ,and pharmacologically they are inert substances ,they cause osmotic balance between the tubular fluid and peritubular fluid ,that limit backward movement of water and in this way they lead to increase volume of urine .

Clinical uses :-

1)In case of oligurea to avoid acute renal failure .
2) Eliminate some drugs that are reabsorbed in renal tubules in acute poisoning of for example ;Salicylate , Barbeturtes and others ,…… .
3) for reduce intracranial and intraocular pressure .
4) rarely used in resistant edema .

5) Carbonic anhydrase inhibitors :-

Chemically they are sulfonamide ,considered as moderate acting diuretics ,site of action is distal convoluted tubule and slightly proximal convoluted tubule also .
C.A.
CO2 + H2O ←→ H+ +HCO3- . ; this reaction is catalyzed by the enzyme carbonic anhydrase ;so by using the inhibitors of this enzyme result is less production of H+ ion which is important for sodium and bicarbonate reabsorption and potassium excretion .
There is increase in sodium ,HCO3 in urine ; and because less H + is available for exchange with sodium ,so there is increase volume of urine and there is metabolic acidosis because of HCO3- loss ; prolong use may lead to acidosis .e. g. Acetazolamide , Ethoxazolamide .
Clinical uses :-
1)Glaucoma when there is excess HCO3 in aqueous humor ,so they decrease production of this fluid .
2) Epilepsy .
3) as diuretics .
Side effects :- renal calculi , parasthesia ,hepatic come in patients with hepatic failure .
6) Minor diuretics :-
as xanthine ,caffeine .theophylline ; they are weak diuretics present in social drinks , site of action is distal convoluted tubule .




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