2 Kidney Functions of the Kidney include: Regulation of the water and electrolyte content of the body.Retention of substances vital to the body such as protein and glucoseMaintenance of acid/base balance.Excretion of waste products, water soluble toxic substances and drugs.Endocrine functions (Secretion of hormones e.g. rennin ,erythropoietin)Regulation of arterial blood pressure.
6 DiureticsOsmotic diuretics: used only in special situations, like neurosurgery. ie, MannitolCarbonic Anhydrase Inhibitors: ie, acetazolamine Used for glaucoma, mountain sicknessLoop diuretics: work on the thick ascending limb. ie, Furosemide (Lasix)Thiazide diuretics: work on distal convoluted tubule. ie, hydrochlorothiazidePotassium sparing diuretics: this category includes aldosterone antagonists (Spironolactone), and inhibitors of Na transport (triampterine)
7 Diuretic Pharmacology The primary therapeutic goal of diuretic use is to reduce edema by reducing the extracellular fluid volumeDiuretics primarily prevent Na+ reabsorbition (mainly the entry of Na into the tubule cell ).All diuretics except spironolactone exert their effects from the luminal side of the nephron ,So it is necessary for diuretics to get into the tubule fluid in order to be effectiveMannitol does this by filtration at the glomerulusAll other diuretics (except spironolactone) are tightly protein bound and undergo little filtration. They reach the urine via secretion across the proximal tubule ( via organic acid or base secretory pathway).
9 Osmotic Diuretics As of now, these include : Glycerol and Mannitol Osmotic diuretics are freely filtered and minimally reabsorbed, not metabolized and are basically are Pharmacologically inert.They are given usually intravenously in amounts large enough to increase plasma osmolarity. In the past Urea and Glycerin have been used but now mannitol is basically the agent.Osmotic Diuretics create an osmotic force within lumen of nephron. So, they prevent H 2 O reabsorption in those segments freely permeable to H 2 O (PCT and descending loop of Henle). There is little effect on loss of K +.It does NOT produce its diuretic effects by blocking reabsorption of Na + or Cl -, it just drags out water.It can only be used intravenously because mannitol cannot diffuse across GI epithelium.(if used orally ,it will produce diarrhea)
10 Clinical Indications1-prophylaxis against acute renal dysfunction2-Glucoma&increased intracranial pressure.Side effectsThe major toxicity is due to increased plasma osmolality, with reduced glomerular filtration rate (as in case CHF or chronic renal failure) potentially worsening heart failure
12 Carbonic Anhydrase Inhibitors Mechanism of Action:(1 )Bicarbonate is primarily reabsorbed in the proximal tubule. H+ ion is secreted into the lumen (by counter transport with Na) where it can combine with filtered bicarbonate (HCO3-) to form H2CO3 that is then converted to CO2 and H2O (catalyzed by carbonic anhydrase).(2)CO2 diffuses into the proximal tubule(3)where it combines with H2O to form H2CO3(catalyzed by carbonic anhydrase).(4) that then forms H+ and HCO3-.(5) HCO3- leave the proximal tubule to the blood , while H+ is again secreted into the tubule lumen (again by counter transport with Na)This results in HCO3- reabsorption. If CA activity is inhibited, HCO3- reabsorption is reduced and exits the proximal tubule in much larger amounts. Because Na+ is the most abundant cation present in proximal tubule fluid, it is the major cation which accompanies HCO3- out of the proximal tubule. In the distal nephron, Na+ is largely reabsorbed (unlike HCO3-) and is exchanged for K+. Therefore acetazolamide primarily causes an increase in urinary HCO3-, K+, and water excretion. Effectiveness is reduced with continued therapy because plasma acidosis
13 Summary : CAI cause Increases urine volume Alkalinization of urine (Increases HCO3-)Increases K+, Na+ in urine (hyookalemia,hyponatremia)Decreases HCO3- in blood: metabolic acidosis(lost effectiveness within days.)Examples of CAI:AcetazolamideDichlorphenamideMethazolamideDorzolamide
14 Indications:1-Generally given for reasons other than diuresis. Because ocular fluid production is dependent on CA enzyme, CA inhibitors can be used to treat glaucoma .2-Acute mountain sickness- one way of dealing with this is by preventing it with CA inhibitors before and during duration of mountain exposure. It prevent the pulmonary and cerebral edema that occurs in these patients.Side effects:1-Metabolic acidosis due to urinary loss of bicarbonate (self-limiting drugs …..Why?)2-Hypokalemia
15 Loop diuretic (high ceiling diuretics) Loop diuretic agents1. Furosemide (Lasix)2. Bumetanide3. Torsemide4. Ethacrynic Acid (Edecrin)Mechanism of actionLoop diuretics have the greatest efficacy, regardless of dose, they cause the excretion of the largest fractional of Na with its water. They work by blocking the Na/K/2Cl co-transporters in the thick ascending limb of the Loop of Henle, preventing passive water reabsorption from the descending limb of the Loop ( counter current mechanism) .
17 THERAPEUTIC EFFECTS Treatment for Severe Edema Increase Na Excretion to 25% of Filtered LoadTreatment forOliguric ARFIncrease Urine VolumeTreatment forHypercalcemiaIncrease Ca ExcretionTreatment forPulmonary Edema
18 Indications:When we require massive fluid mobilization, like in pulmonary edema.Edema (resulting from CHF, nephrotic syndrome, and cirrhosis).Sever Hypertension.Hypercalcaemia (calcium excretion is increased by loop diuretics i.e. it causes hypocalcaemia), although they are NOT used as such nowadays.
19 Adverse effects of loop diuretic DehydrationHypotension (sever fluid loss )Electrolyte Imbalance:-Hyponatremia-Hypochloremia-**Hypokalemia:, losing potassium can cause arrhythmias. Many of the patients who take these drugs are also taking drugs that are sensitive to the action of potassium e.g. digoxin , disaster may occur unless you monitor it carefully.-Hypocalcaemia…….Not taken in pat. with renal stones-Hypomagnesaemia-Hyperglycemia ……. Not taken in diabetic pat.-Hyperuricemia………. Not taken in pat. Suffering from goutOtotoxicity
20 Thiazide diuretic Thiazide diuretic agents: Chlorothiazide HydrochlorothiazideDiazoxide: a non-diuretic thiazide (used in hypertension )IndapamideThe last one is thiazide-like in terms of action, but is not chemically thiazidesMechanism of Action:They inhibit Na+ and Cl- cotransport in the cortical thick ascending limb and early distal tubule. They have a milder diuretic action than do the loop diuretics because this nephron site reabsorbs less Na+ than the thick ascending limb.
22 Nephrogenic Diabetes Insipidus THERAPEUTIC EFFECTSIncrease Na Excretionto 5% of Filtered LoadTreatment forHypertensionTreatment forNephrogenic Diabetes InsipidusTreatment forMild EdemaTreatment forhypocalcemiaDecrease Ca Excretion
23 Indications:Hypertension (this is the primary use of thiazides)CHF (but thiazides are not as effective as loop diuretics for CHF)Hypercalciuria (thiazides combat the formation of Ca stones, since they enhance Ca reabsorption)Nephrogenic Diabetes Insipidus (mechanism unknown)
24 Adverse Effects:The adverse effects are similar to loop diuretics…PLUS:Hypercalcemia(not hypo –as in loop )so can be used for pat. With renal calculi.Hyperlipidemia (they increase LDL cholesterol, which are bad cholesteroles)Note: an important exception is that there is no ototoxity with thiazides
25 Potassium sparing diuretics These cause a moderate increase in urine production, with a decrease in potassium excretion.They are rarely employed to promote diuresis they are usually used as adjunct to another diuretic, in order to preserve potassium.
27 1-Aldosterone antagonists (Spironolactone) Indication:1- It is used primarily in states of edema due to excess aldosterone (e.g. CHF, cirrhosis, nephrotic syndrome) You get aldosterone excess in these states because you have diminished renal perfusion, so you get the rennin angiotensin aldosterone system enhanced , so you get excess aldosterone.2-As adjunct to another diuretic, in order to preserve potassium.Side effects:1-Major side effects are hyperkalmia2-Gynecomastia, and amenorrhea (mild estrogenic activity) .Contraindications:Do not use in setting of hyperkalemia
28 2-Inhibitors of Na transport Amiloride and TriamtereneMechanism of Action:Both agents inhibit the Na+ channel in the apical membrane of the late distal tubule and collecting duct. Because K+ secretion in this nephron segment is driven by the electrochemical gradient generated by Na+ reabsorption, K+ transport into the urine is reduced (hyperkalemia).Side effects:The most sever side effect is hyperkalemia.Nausea and vomiting are the most frequent side effects.Contraindications:Similar to Spironolactone -- Do not use in setting of hyperkalemia.