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overview
Diuretics as a group are the drugs which cause diuresis, which means increased urine outflow. Most of the diuretics act by blocking reabsorption of sodium. Along with loss of sodium, water also follows.
To understand how diuretics act, we need to know structures of the nephron, which are the urine forming units of the body. Each kidney has about 1million nephrons, which decrease with age, and do not regenerate (after 50yrs, there’s 10% decrease).
Nephron is composed of different parts; afferent artery coming into nephron from renal artery which enters hilum of kidney and branches into interlobar branches; these will go around the pyramids becoming arcuate branches, that further divide into interlobular arteries, which give rise to afferent artery; this will form a tuft of capillaries called the glomerulus, ending in the efferent which will divide into different arteries, vasa recta.
There’s the glomerulus, bowman’s capsule (attached to tubules); officially, there are 14 different parts of the tubules (International division). The kidney is divided into 2 parts; outer part is called cortex, and inner part is called medulla.
Remember PCT, thin descending limb, thick descending limb, DCT, distal collecting duct.
overview
Glomerular filtration rate (GFR) is about 180L/day or 125ml/min; this is the amount filtered in the glomerulus; this is considering both kidneys and taking into account 2 million nephrons. The amount of urine formed is about 1.5L/day, or 1ml/min; the remaining 178.5L is reabsorbed in different parts of the kidney; more than 90% of the filtrate is reabsorbed at a staggering cost of energy; Kidneys utilize twice as much oxygen as the brain because there are so many transporter pumps acting actively in the kidney and require energy.
The glomerular filtration membrane has 3 layers; first is the endothelial lining of the capillaries, the second layer is the glomerular basement membrane, and the third layer is the epithelium of the bowman’s capsule which is composed of foot processes with slits b/w them; these are 3 layers that make up the filtering apparatus; the capillaries are usually composed of 2 layers. The endothelium lining is very thin so it can easily filter stuff. These 3 layers have strong negative charges, and they repel negatively charged proteins e.g. albumin, to be filtered; in nephrotic syndrome (minimal change disease)/kidney disease, there is loss of podocytes (foot processes), and u have albuminouria. In hypertension, there is damage to the endothelium and the charges changed, so proteins will be filtered. In DM, there is change in the basement membrane composition causing change in charge and filtering of proteins.
There are 2 pressures operating in opposite directions in the bowman’s capsule: hydrostatic pressure and oncotic pressure (Known). GFR = (PG – PB) – (IIG – IIB). From this formula we can come to a lot of conclusion;
Suppose we have a drug that causes vasodilation, we have increased blood flow, increased hydrostatic pressure, and increased filtration.
Suppose there is a block/obstruction in both urethras, u have increased hydrostatic pressure in bowman’s capsule, causing opposition of GFR, and u get hydronephrosis (dilatation of the renal pelvis).

PCT: there is absorption of 70% of the filtered load here. Hence, whatever sodium, potassium, chloride filtered, more than 70% is reabsorbed here. PCT is permeable to both sodium and water. Since both water and sodium are reabsorbed here, the urine remains isotonic in osmolarity; hence osmolarity of urine in PCT is equal to that of plasma (300m os/L).

Thin descending limb: this is only permeable to water; once water moves out of tubule, urine becomes hypertonic and osmolarity increases and it becomes about 600mOS/L.
Thick ascending limb: this is only permeable to sodium but not water; here, when only sodium moves out, urine becomes hypotonic and osmolarity decreases (200mOS/L). Here reabsorption is 20%
DCT: here, it is only permeable to sodium, but not water; this is where u have urine being most hypotonic and the least osmolarity (100mOS/L). Here, reabsorption is 5%.
Collecting ducts: These can reabsorb water in the presence of ADH, and sodium because of aldosterone; hence collecting duct is for fine tuning. Here urine composition and osmolarity can change based on the condition of body, e.g. need for more water or more sodium.
Note percentages: PCT (70%), thick ascending limb (20%), DCT (5%), and all others (5%). These need to be known because u need to know how much stuff is lost when diuretics are given. Remember that PCT is permeable to sodium and water both, thin descending to water only, and all others to sodium only. Hence, from thick ascending limb on, these are called diluting loops.
overview
Countercurrent mechanism: the main aim of countercurrent mechanism is to conserve sodium.
2 parts: counter current multiplier and counter current exchanger.
2 key words to remember: medulla is always hypertonic because of this countercurrent mechanism; why, because this is where the tubules are located (there 2 types of nephrons: cortical and non-cortical/medullary nephrons). These happen because of different permeabilities in each segment, and these help conserve sodium.
In the thin descending limb, it is only permeable to water and urine becomes hypertonic; now urine goes to thick ascending limb which is permeable to only sodium which will go with concentration gradient and move into medullary interstitium, making it hypertonic (1,200mOS/L), and causing more water to come out at the same time from collecting ducts and medullary tubes. This is called countercurrent multiplier.
Countercurrent exchanger: this is operating in the vasa recta, which is the loop-like arrangement of blood vessels that surround the tubules in a U-shaped fashion. This vasa recta is suspending from cortex to medulla; remember that medulla is always hypertonic; as u go deeper into the medulla it gets more hypertonic because the thick ascending limb lies in the medulla. These vasa recta prevent sodium from exiting through the kidneys. So, from the interstitium, on one side sodium is entering because of increased concentration as u go down; now as the blood starts going up, u realize that the sodium concentration in vasa recta is more than that in medulla/interstitium, so u have sodium going out; and being taken up on the other side. This counter current exchanger is arranged in a form so the kidneys can’t eliminate sodium except when needed. Hence it is helping the counter current multiplier.
Diuretics: Classification
Acting on PCT (Weak diuretics):
Carbonic anhydrase inhibitors: Acetazolamide
Osmotic Diuretics: Mannitol
Acting on the Loop of Henle (Thick Ascending Limb) : Loop Diuretics- Furosemide, Ethacrynic acid- High Efficacy
Acting on DCT: Thiazides- moderate efficacy diuretics
Acting on collecting ducts (weak diuretics):
Potassium sparing diuretics: Amiloride , triamterene, spirinolactone.

Acting on PCT: these are weak diuretics: CA inhibitors  acetazolamide; Osmotic diuretics  Mannitol. Diuretics acting here are called weak diuretics, why? The thick ascending limb, although it normally reabsorb 20%, it has a high capacity to reabsorb up to 90%; hence no matter how much loss is done in the PCT due to the diuretics, the thick ascending limb picks most of them up. Hence, 70 + 20 = 90%. This is why diuretics which are acting on the thick ascending limb are called high efficacy diuretics.
Acting on loop of Henle (thick ascending limb): these are called loop diuretics/high efficacy diuretics; Furosemide, Ethacrynic acid. After thick ascending limb, all other parts can’t reabsorb much.
Acting on DCT: Thiazides
Acting on collecting ducts: K sparing diuretics  amiloride, triamterene, spirinolactone
Carbonic anhydrase inhibitors: acetazolamide (glaucoma), methazolamide
Competitive inhibitors of carbonic anhydrase enzyme present on the renal tubular cells in PCT
Weak diuretics
Major site of action is PCT & collecting duct – a secondary site
Effect on electrolytes
HCO3 loss- 35% (Greatest because u have normally 90% reabsorption of bicarbonate in PCT)
Sodium loss- 5%, potassium loss- 70%
Increase phosphate excretion
Little effect on Calcium and magnesium loss

These are competitive inhibitors of CA enzyme. This CA is present in renal tubular cells in PCT and RBC, lungs, GIT; another site of action, besides PCT, is collecting duct.
Effect of electrolytes:
Bicarbonate loss is 35%; sodium loss is 5% (what is in the urine); hence the sodium is being reabsorbed in thick ascending limb. Potassium loss is about 70% because there is a mechanism; ANY DIURETIC THAT CAUSES LOSS OF SODIUM WILL INCREASE LOSS OF POTASSIUM, EXCEPT POTASSIUM SPARING DIURETICS.
Carbonic anhydrase inhibitors: Proximal Tubule
USE ANIMATION:
Apical side is the luminal side which will be exposed to the urine; the other side is the basolateral side/interstitium. Most of the reabsorption in different parts of the tubules is taking place because of pumps on interstitial side.
On the interstitial side, there is a sodium/potassium ATPase pump, and this is a primary active pump. This is continuously pumping sodium out of cell, and K is moving into cell. Hence inside cell, sodium concentration is low and potassium is high. Here, inside the cell is negative because of more potassium, similar to cardiac cells; hence positively charged ions are reabsorbed, especially sodium to balance the charges; once sodium enters, hydrogen leaves; this is done by a sodium/Hydrogen antiport which is a secondary active pump, functioning as a result of actions of the primary active pump. In some places, it may be sodium/glucose symport, sodium/another amino acid, but the main pump is the sodium/hydrogen antiport (THIS IS THE MAIN PUMP IN PCT; ALL REGIONS HAVE SODIUM/POTASSIUM ATPase). The hydrogen ion combines with bicarbonate ion to form carbonic acid and the enzyme required is Carbonic anhydrase. Bicarbonate ion comes from urine. Carbonic acid is now broken down into CO2 and H2O by CA, and these then diffuse into the cell, and re-converted into carbonic acid by CA in cytoplasm, creating an extra hydrogen ion for the sodium/hydrogen antiport, and causing HCO3 reabsorption into interstitium through a sodium/HCO3- symport. THE PREDOMINANTLY REABSORBED SUBSTANCES IN PCT are SODIUM (65-70%), and BICARBONATE ION (70%).
IF CA IS INHIBITED, NOTE that the sodium/hydrogen antiport becomes non functional. EXPLAIN TO SELF LATER.
Adverse effects of acetazolamide
Sulfonamide related A/E: Hypersensivity, bone marrow depression, hemolysis in G6PD Deficiency
Diversion of ammonia of renal origin- hepatic encephalopathy
Drowsiness & paresthesia – high dose
Renal Calculus formation due to precipitation of calcium in alkaline urine.
Metabolic acidosis due to loss of bicarbonate in the urine

All the Diuretics are related to sulfonamides; these can cause hypersensitivity rxns, particularly if the patient is allergic to sulfur antibiotics (DO NOT USE).
CA inhibitors will cause loss of bicarbonate ions in urine, hence the bicarbonate concentration in blood decreases causing metabolic acidosis: ALL THE DIURETICS CAUSE METABOLIC ALKALOSIS EXCEPT CA INHIBITORS WHICH CAUSE METABOLIC ACIDOSIS. When bicarbonate ions are lost in urine, urine becomes alkaline; in alkaline urine, there is a tendency for calcium and… pptates leading to formation of renal calculus/calcium stones.
In basic pH, there is tendency for ammonia to be reabsorbed (basic pH favors ammonia reabsorption) into blood from urine; hepatic encephalopathy may result; here the cause is due to cirrhosis of liver, hence compounds are not detoxified; ammonia is being produced by coliform organisms in GIT (large intestine); the ammonia enters liver where it gets detoxified; suppose liver is diseased, say cirrhosis, the ammonia is not broken down; it enters blood circulation causing encephalopathy (seizures is a symptom); hence if u have patient with edema related to cirrhosis of liver, DO NOT USE CA INHIBITORS.
CNS side effects are seen; these are unique to CA because CA enzyme is found in brain also, so it may be affected; paresthesia and drowsiness may result; Paresthesia is abnormal sensation which may include tingling of skin, burning sensation of skin, etc.
Therapeutic uses of CAI’s
Glaucoma: Acetazolamide used parentally, Dorzolamide used as eye drop.
Edema due to CHF, but not drug of choice, so u can forget this
Prophylaxis of acute mountain sickness
Familial periodic paralysis
Epilepsy: Rare use

ALL THE DIURETICS ACTING ON PCT ARE WEAK DIURETICS. WHY?
Glaucoma: acetazolamide is used parentally (IV or IM), and dorzolamide which is used topically as eye drop. Because bicarbonate ions are a major components of aqueous humor, and eye has CA that produces bicarbonate ions; if u inhibit this enzyme, u decrease aqueous humor.
It can be use for treating acute mountain illness; at high altitude, oxygen concentration decreases; u’ll have high CO2 leading to respiratory acidosis. Hence, there’ll be hyperventilation to get rid of CO2. CA inhibitors cause metabolic acidosis; this means that bicarbonate is low; this further causes hyperventilation, which is the compensatory mechanism for metabolic acidosis.
Acidosis can be due to alkalosis, hence it can be given
REMEMBER 2 USES: GLAUCOMA and ACUTE MOUNTAIN SICKNESS. THERE ARE NO OTHER DIURETICS USED IN GLAUCOMA OR MOUNTAIN SICKNESS.
Not Used In: High Altitude Pulmonary Edema (HAPE) and High Altitude Coronary Edema (HACE)
Osmotic diuretics
Glycerine, Isosorbide- oral
Mannitol, Urea- Parenteral
Freely filtered, limited reabsorption in renal tubules & increase osmolality of plasma & tubular fluid and extract water from ICF to ECF and into tubular fluid leading to loss of water and other electrolytes.
Sites of action: PCT & loop

Osmotic diuretics: 2 groups  oral and parenteral; REMEMBER ONLY MANNITOL
Orally: Glycerine and Isosorbide: not used because they are hyperosmotic and cause diarrhea (due to the fact that they are taken orally).
Parentally (IV): MANNITOL and Urea (not used b/c of side effects). Mannitol is not metabolized; when given IV, it gets to kidneys and is freely filtered; after being filtered, it enters tubules; Mannitol has hyperosmotic property; hence it causes osmosis of water into lumen of PCT; so mannitol extracts water from interstitium into tubules in PCT. As a result, tubular fluid becomes hypotonic (diluted). Once the tubular fluid becomes hypotonic, the osmolarity of sodium decreases, hence u have less reabsorption, including all the other ions. Hence mannitol will cause loss of water and electrolytes.
THE MAIN SITE OF ACTION OF MANNITOL IS PCT. Secondary site is the loop. How does this happen? Very important: when mannitol IV is given into blood plasma, blood volume increases because mannitol is hyperosmotic; hence water will come from intercellular to extracellular (blood), increasing ECF. Once ECF increases, RAS decreases, decreasing renin, aldosterone, and ADH. Once there is decreased renin, there is decreased angiotensin II, allowing increased blood flow to the kidney. As a result, the hypertonicity of medulla decreases (vasa recta is being talked about here), which means decreased absorption of NaCl, leading to Diuresis.
Filtration fraction (FF) = RBF/GFR. Read up effects of angiotensin II; there are 2 main effects. At first, for a few days, angiotensin II causes vasoconstriction of the efferent arteriole; this causes decreased outflow of blood/RBF, and increases GFR. How? Well let’s see; as a result of slow blood flow, there is enough time for lots of water to be filtered into the bowman’s space; this is due to increased hydrostatic pressure in the glomerulus (increased Pg); when enough water has been filtered, then u have increased concentration of proteins in the glomerulus, causing an increase in glomerular oncotic pressure (IIg), and also an increase in hydrostatic pressure in the bowman’s space (increased Pb). These 2 pressures oppose filtration, and as a result water enters back into the capillaries in the bowman’s space. This is the second effect of angiotensin II, which is preventing water and electrolyte loss.
Osmotic Diuretics: Mannitol
Increased excretion of all electrolytes
A/E: hyponatremia, dehydration
*C.I. – CHF, pulmonary edema
Glycerine causes hyperglycemia
Uses of mannitol
*Cerebral edema, glaucoma
Acute renal failure ?
Dialysis Disequilibrium syndrome

Mannitol is not specific for any electrolyte. Mannitol will cause loss of all electrolytes. CA inhibitors are more specific for bicarbonate (35% loss).
A/E: hyponatremia, hypokalemia, and dehydration.
USES: CEREBRAL EDEMA, this is DOC. Mannitol helps by pulling water out; given IV, and since it is hyperosmotic, it will extract water from the brain cells into the blood.
In GLAUCOMA, same method; when circulating through the eyeball, it extracts water from the cells and reduces intraocular pressure.
Sometimes in Acute Renal failure, we use mannitol because we want to convert oligouria (>400ml/dayor24hrs) to polyuria (CONFIRM). This is used just to increase outflow; also used to see if kidneys work; if u give mannitol, outflow should increase, hence kidneys are fine, and vice versa.
Mannitol is also used in Dialysis Disequilibrium syndrome: in dialysis, the blood is passed in close contact with another type of fluid in a semipermeable membrane; the fluid is called dialysis fluid and can be made based on what u want; if u want to extract sodium, u put a very low concentration of sodium and sodium will move into tube from blood. If too much of sodium, or water, or potassium is removed from the blood by dialysis, u use mannitol IV to get water back into blood.
Contraindications:
CHF: Here u have decreased preload; if u give mannitol, u have increased preload because of increase in ECF and increase in CO. In CHF, u want to decrease preload, decrease CO, so u decrease oxygen demand of heart. If u increase preload, and increase CO by administering mannitol, the heart works harder than it is supposed to and you have an increase in oxygen demand of the heart, and the heart can’t meet up with the demand.
In pulmonary edema: there is congestion of the lungs already. In this situation, u want to decrease preload. By giving mannitol, u increase preload, and increase amount of blood going to lungs, causing further congestion. THEREFORE, MANNITOL IS DOC FOR ONLY CEREBRAL EDEMA, NO OTHER TYPE OF EDEMA.
Glycerine: this is one of the osmotic diuretics; it is a sugar solution and it can cause hyperglycemia. HENCE, DO NOT ADMINISTER TO DIABETIC PATIENTS.
Loop Diurtics
Furosemide, Bumetanide, Torsemide, ethacynic acid.
Mechanism: Competitive inhibitors of Na-K-2CL symport in the thick ascending limb.
AKA high ceiling/ high efficacy diuretics.

Loop diuretics: these include Furosemide, Bumetanide, Torsemide, and ethacynic acid. REMEMBER FUROSEMIDE.
Mechanism: The primary active pump is the same (Na/K ATPase). The secondary active pump in the thick ascending limb of loop of henle is the Na/K/2Cl symport; this is present in the thick ascending limb only; this is blocked by loop diuretics by competitive inhibition. These diuretics are also called high efficacy/high ceiling diuretics because the thick ascending loop has a large surface area, and can reabsorb up to 90% of filtered substance, especially when mild diuretics/osmotic diuretics are used on the PCT.
The thick ascending limb also has potassium channels; this is the only part of the nephron that has this.
thick ascending loop
All areas have the same primary active pump.
Sodium will move from urine/lumen into interstitium via the Na/K/Cl2 symport. The secondary active pump is responsible for reabsorption of sodium, potassium, and chloride.
Na/K/2Cl are all moving from urine into cells; these cells in the thick ascending limb have potassium channels (only part to have this); as a result, potassium is still pumped cycled between the lumen of the tubule and the cytoplasm of the cell. Remember that the secondary active pump works as a result of the action of the primary active pump; the primary active pump causes increase in potassium and decrease in sodium in the cytoplasm. Once potassium comes out through the potassium pump, the urine/luminal side becomes more positive, and this pushes calcium and magnesium through the paracellular pathway for neutrality to be maintained; hence the potassium pump facilitates reabsorption of calcium and magnesium. SODIUM, CHLORIDE, CALCIUM, & MAGNESIUM ARE MAINLY REABSORBED, and these will be lost if loop diuretics are used. Remember potassium is also lost because all diuretics that cause loss of sodium cause loss of potassium, except K-sparing diuretics. HENCE THESE DRUGS CAN BE USED FOR TREATING HYPERCALCEMIA. Once they cause loss of sodium, they’ll also cause loss of water and potassium.
LOOP DIURETICS: Furosemide
Secreted in proximal tubule by acid mechanisms
Cause a greater natriuresis than thiazides
Effective at low glomerular filtration rates (as occur in chronic renal failure), where thiazides are ineffective
Increase potassium, calcium and magnesium excretion
Decrease urate excretion


Furosemide:
These are SECRETED from interstitium (not filtered) into the proximal tubule (PCT) by acid mechanism; then they go to thick ascending limb.
LOOP DIURETICS ARE THE ONLY DIURETICS EFFECTIVE IF THE GFR IS VERY LOW (>30ml/min). This is because they are not filtered. Loop diuretics will cause loss of sodium, potassium, calcium, and magnesium. They are very useful in treatment of hypercalcemia.
BUT they decrease urate excretion, but the mechanism is not known. As a result, plasma uric acid concentration goes up, and this causes gout.
CLINICAL USES OF LOOP DIURETICS
*EDEMA due to CHF, nephrotic syndrome or cirrhosis
*Acute heart failure with PULMONARY EDEMA: Furosemide IV ??
*HYPERCALCEMIA
not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease) immideate action through prostaglandins

All edema except cerebral edema. DOC in EDEMA due to CHF and Nephrotic syndrome or cirrhosis.
Furosemide is DOC for pulmonary edema (not any other) because when furosemide is given IV, it increase prostaglandins which will cause venodilation, decreasing preload. This is immediate action. If preload decreases, u have decreased pulmonary blood flow. Also, it is a highly effective diuretic. All other diuretics can decrease preload, but none works via prostaglandins for an immediate action.
Loop diuretics cause loss of calcium in urine, hence they are useful in hypercalcemia. Hypercalcemia can be caused by primary hyperparathyroidism, and malignancies associated with bone.
These are not used in HTN. USE THIAZIDES IN HTN. Why?
Adverse Effects of Loop Diuretics similar to thiazides in many respects
Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia
Dehydration and postural hypotension
Hypocalcemia (in contrast to thiazides)
Hypersensitivity
OTOTOXICITY (especially if given by rapid IV bolus)
Drug Interactions : With Aminoglycosides: Increased ototoxicity, NSAIDs blunt diuretic effect of loop diuertics.

Side effects: hyponatremia, hypokalemia, hypocalcemia.
They cause HYPERCHOLESTEROLEMIA (adverse lipid profile), but the mechanism is unknown. Beta blockers also cause adverse lipid profile.
They cause hyperuricemia, leading to gout.
They also cause hyperglycemia, hence not used in diabetic patients. HOW?
OTOTOXICITY: here cochlea and vestibular apparatus are affected; this will cause deafness and vertigo.
Drug interactions: DO NOT COMBINE WITH AMINOGLYCOCIDES; these are antibiotics that cause ototoxicity.
NSAIDs: these will blunt diuretic response because the decrease prostaglandins, blocking effects of furosemide.
DO NOT COMBINE NSAIDs with DIURETICS OR ANY DRUGS THAT LOWER BLOOD PRESSURE.
Thiazide Diuertics
Hydrochlorothiazide, Chlorothiazide Metolazone
Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule
Act on the distal tubule (DCT) to inhibit sodium and chloride transport and result in a modest diuresis
Increase renal excretion of , Na, potassium, magnesium
Reduce calcium and urate excretion
Not effective at low glomerular filtration rates
distal convulated tubule
The secondary active pump, only found in DCT, is Na/Cl symport, with the same primary pump, Na/K ATPase.
Thiazides will block this secondary pump. There are no sodium pumps; they’ll cause loss of sodium, chloride, and potassium.
CLINICAL USES Of THIAZIDES
*HYPERTENSION
2) EDEMA (cardiac, liver renal)
3) *IDIOPATHIC HYPERCALCIURIA
condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion
thiazide diuretics used to prevent calcium loss and protect the kidneys
4) DIABETES INSIPIDUS

HTN tx
EDEMA: DOC is loop diuretics, but these can be used.
Idiopathic hypercalciuria: there is unknown cause of more calcium in urine; THIAZIDES CAUSE HYPERCALCEMIA (REMEMBER) & LOOP DIURETICS CAUSE HYPOCALCEMIA. Thiazides favor calcium reabsorption hence, reduce hypercalciuria, hence causing hypercalcemia.
Theory: thiazide diuretics cause volume depletion; as a result there will be compensatory reabsorption of water, ions, including Ca2+.
Typical question: patient has calcium stones in kidneys, and increased calcium in urine, which is DOC? Thiazides.
4. Diabetes insipidus; this is similar to DM; diabetes means polyuria and polydypsia; DM, urine is sweet, due to excess of glucose; diabetes insipidus, the urine is tasteless. When thiazides are given, initially there is polyuria, but then there is compensatory reabsorption of water, decreasing the polyuria; if u give diuretics, since depletion occurs at first, it increases RAS, which then relieves polyuria.
ADVERSE EFFECTS OF THIAZIDES-1
HYPOKALEMIA
DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION
HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia
HYPERURICEMIA because thiazides compete with urate for tubular secretion
HYPERLIPIDEMIA; mechanism unknown but cholesterol increases usually trivial (1% increase)
IMPOTENCE
HYPONATREMIA
ADVERSE EFFECTS OF THIAZIDES
Less common problems
HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare)
METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen
HYPERCALCEMIA
K+ sparing diuretics
Triamterene, amiloride- block sodium channels in CD , AKA Na channel blockers
Spirinolactone : aldosterone antagonist
Sodium channel blockers: Amiloride, Triamterene
Principal cells in the late distal tubule and collecting ducts have sodium channels in luminal membrane.
Higher permeability of luminal membrane for sodium depolarizes luminal membrane
Leads to lumen negative potential
Secretion of K into lumen via K- channel
late distal tubule and collecting duct
The collecting ducts also have the primary active pump Na/K ATPase.
Principal cells: these are sodium/potassium channels, not voltage gated, but pores; these work in opposite directions; The primary pump is the same. Due to decreased sodium and increased potassium resulting from primary pump, sodium in urine enters through the principal cell Na/K pump. Due to this mechanism, potassium is lost because more sodium enters through the principal cells. If diuretics is blocking the sodium channels alone, u have less K+ coming out because of less sodium entering. Hence, u have less loss of potassium.
Ask how K is lost when Na is lost due to other diuretics use.
therapeutic effects
Ask for explanation of combination. The reason is to balance out potassium loss. Also u have 2 diuretics working at 2 different parts, they cause enhanced natriuresis.
They are also used to prevent hypokalemia.
They are used for treatment of Liddle’s syndrome (HTN due to defect in sodium channels which retain too much sodium).
This is for treatment of lithium-induced diabetes insipidus; if u have overdose of lithium, lithium is reabsorbed through the sodium channels; treatment is done by given sodium channel blockers. Lithium is used in bipolar disorder. Lithium causes nephrogenic diabetes insipidus. Lithium is similar to sodium in structure; both are monovalent ions. As a result it can be reabsorbed by sodium channels, and this can cause toxicity; hence we use sodium channel blockers.
They also enhance natriuresis.
adverse effects
amiloride- Hyperkalemia: any potassium sparing diuretic will cause hyperkalemia. ACEIs also cause hyperkalemia, and this can cause cardiac arrhythmias. As a result, DO NOT COMBINE ANY K-SPARING DRUGS WITH ACEIs.
Triamterene: renal stones, interstitial nephritis (both mech unknown), megaloblastosis (known mech).
MINERALOCORTICOID RECEPTOR ANTAGONISTS
Also Called:
K-Sparing Diuretics
Aldosterone Antagonists


Mineralocorticoid receptor antagonists: SPIRINOLACTONE, EPLERONONE
Spirolactone/spirinolactone: aldosterone antagonists (remember) and also eplerenone. These are also known as K-sparing diuretics.
late distal tubule and collecting duct
The mechanism is the same. There are sodium channels in the collecting ducts that are blocked by sodium channel blockers which are synthesized by aldosterone. Aldosterone causes sodium retention and potassium excretion; same mech of sodium moving in and potassium coming out. Aldosterone as a hormone acts on mineralocorticoid receptor (MR-ALDO); and together they go to nucleus; hence aldosterone is among the family of nuclear receptors; now they cause synthesis of proteins called aldosterone induced proteins (AIP) and these proteins synthesize the sodium channels which are inserted into the cell membrane.
K-sparing diuretics mech are the same: if u’re using aldosterone antagonists, u prevent synthesis of sodium channels. If using sodium channels, u’re directly blocking sodium channels.
THERAPEUTIC EFFECTS
Enhances Natriuresis
Caused by Other Diuretics and Prevents Hypokalemia --> Used in Combination with Loop &
Thiazide Diuretics


blocks aldosterone--> Treatment for
Primary Hyper-aldosteronism, *Treatment for Edema of Liver Cirrhosis, Treatment for
Hypertension, Treatment for
Heart Failure


Combination with loop and thiazide diuretics because they are potassium sparing. Loop and thiazide diuretics cause hypokalemia, but by combining with mineralocorticoid receptor antagonists, you have K-sparing to balance out K-loss.
Treatment of heart failure: spirinolactone/spirolactone is one of the drugs associated with increased survival in heart failure. (ACEIs, beta blockers, and spirinolactone, are the group of drugs associated with increased survival in heart failure).
Treatment of primary hyperaldosternonism: Conn’s syndrome (excess of aldosterone); as a result of high aldosterone, u have retention of sodium and water, hypokalemia, and HTN results.
Treatment of edema associated with liver cirrhosis: spirolactone is drug of choice; why? When there is liver cirrhosis, liver is not synthesizing enough plasma proteins (albumin, etc.); plasma osmolarity/oncotic pressure decreases due to this. Once this occurs, there is activation of RAS, leading to increased aldosterone, and this causes sodium and water retention (with potassium loss); this causes edema. This edema of liver cirrhosis is secondary hyperaldosteronism which causes edema.
ADVERSE EFFECTS
hyperkalemia, metabolic acidosis, impotence, cns side effects, gynecomastia, menstrual irregularities, hirsutism, deepening of voice, peptic ulcers, gastritis

Spirolactone is known for its side effects; these are unique; e.g. gynecomastia, menstrual irregularities, hirsutism, hoarsness of voice, etc. this is because spirolactone interfers with synthesis of steroid hormones in the liver by inhibiting their synthesis, therefore, causing these side effects.

CA inhibitors cause metabolic acidosis: this is directly due to loss of bicarbonate in the urine. There are 2 types of metabolic acidosis:
Normal (hyperchlorimic metabolic acidosis) ASK ABOUT THE 2 TYPES.
Thiazides and loop diuretics cause metabolic alkalosis.
K-sparing diuretics cause metabolic acidosis: FIND OUT THE RELATIONSHIP BETWEEN POTASSIUM AND ACIDOSIS.
Vasopressin (A.D.H/ A.V.P)
Vasopressin (arginine vasopressin or antidiuretic hormone)
overview-
Synthesis : SON & PVN
Transport & storage.
Regulation of Vasopressin secretion
Hyperosmolality : threshold 280mOsm/kg
Hypovolemia & hypotension
Hormones : increased Ach, Dopamine, AgII, PG’s


ADH, along with oxytocin are the 2 posterior pituitary hormones.
In relationship to their synthesis, posterior is synthesized in the hypothalamus, then u have neuro fibers taking them to posterior pituitary, while anterior is synthesized in the anterior.
Supraoptic nucleus and periventricular nucleus of the hypothalamus are where ADH are synthesized, and it is transported and stored in the posterior pituitary.
Regulation: the most important stimuli for ADH is hyperosmolarity. Suppose there is dehydration, there is concentration of sodium due to less water in the blood, and osmolarity/osmolality increases. This will trigger the release of ADH, causing water absorption from the collecting ducts, so urine becomes concentrated. The threshold for ADH is 280mOsm/kg. Below this, there is barely any ADH in the circulation; above this, there is ADH being secreted and working.
Hypovolemia and hypotension will also cause ADH release.
Some hormones can cause ADH release: Angiotensin II causes ADH release, so to increase blood volume and blood pressure.
overview-
Hormones that decrease ADH: ANP, GABA

Drugs that increase ADH : TCA, nicotine, high dose morphine, lithium

decreased ADH : ethanol, phenytoin, Glucocorticoids


Hormones that decrease ADH include ANP and GABA.
Drugs that increase ADH: nicotine, morphine. TCA means tricyclic antidepressants, we’ll discuss later.
Drugs that decrease ADH include: ethanol, phenytoin.
Vasopressin Receptors
V1 : V1a- vascular smooth muscle, hepatocytes, platelets
V1b – Ant. Pituitary
V2 : principal cells of collecting duct

G-protein coupled receptors

There are different vasopressin receptors.
V2 is the one in collecting ducts principal cells that cause water receptors. V1 is present in smooth muscles of blood vessels (vasopressin) causing vasoconstriction. V1 also has some effects on hepatocytes, and increases von willibrand factor (vwf), hence used in deficiency of that factor. All of these are G-protein coupled receptors.
preparations available
Preparations Available: Vasopressin: Sc, IM, Intranasal; Lypressin: nasal spray; Desmopressin : SC, IV, Nasal spray
USES
Post operative ileus
Bleeding esophageal varices
Central DI : desmopressin
Type I von Willebrand’s disease
Primary nocturnal enuresis


Available preparations: Vosopressin, desmopressin, and lypressin (add’n of lysine group). Remember vasopressin and desmopressin (both are commonly used).
They are used in post operative ileus: for increased motility. Bethanechol and neostigmine are cheaper.
Bleeding esophageal varices: where ever there is portal-systemic anastomosis, when liver is cirrhosed, there is compression in portal system, and u have varicoses/tortous veins with high pressure leading to rupture; one of the places is lower end of esophagus. Vasopressin is used to stop bleeding.
Central diabetes insipidus: there are 2 types of DI; central or cranial, wherein there is lack of ADH hormone; here u replace ADH, and preparation of choice is DESMOPRESSIN. Central diabetes insipidus can follow head injury or some brain tumors.
DI: symptoms include polyuria, polydypsia, increased plasma osm (>300mOsm/L), and urine osmolarity is decreased (dilute urine).
Desmopressin challenge: this to differentiate CDI due to lack of ADH, or nephrogenic DI where ADH is normal, but the tubules are not responding. In central DI, when desmopressin is given, u have increase in water reabsorption from collecting duct and urine will become concentrated with decrease in plasma osmolarity (C for concentrated and central DI). If urine does not get concentrated, then it is nephrogenic.
Type I von Willebrand’s disease: there is defficiency of this factor and this causes bleeding; ADH increases the production of this factor.
Primary nocturnal enuresis: ADH will cause less frequency of micturition. But why use hormone, when u can use antimuscarinic drugs such as atropine.
Diseases Affecting ADH
Diabetes Insipidus : Central DI & Nephrogenic DI
Central DI : Desmopressin, chlorpropamide, carbamazepine, clofibrate
Nephrogenic DI : thiazide diuretics, amiloride (Li-induced), Indomethacin
SIADH: Demeclocycline, lithium may be used for treatment.



Central DI: DOC is DESMOPRESSIN, also u can use some drugs that increase ADH; these include chlorpropamide, ….these increase ADH production from the brain.
Nephrogenic DI: u can’t do much because ADH is normal, but there is deffect in the second messenger system at the receptor level; THIAZIDE DIURETICS is one treatment of choice (find out how it works); if u have lithium induced DI, we use sodium channel blockers, and the one extensively used in amiloride (AMILORIDE IN LITHIUM-INDUCED DI).
Syndrome of inappropriate anti-diuretic hormone (SIADH): here, ADH level increases; name is misleading; ADH level is very high. SIADH can be remembered as water intoxication; too much water is absorbed from the tubules, and the plasma osmolarity is less. The treatment option is to make kidneys not respond to ADH. All the drugs that cause nephrogenic diabetes insipidus can be used to treat this; e.g. Lithium, which causes DI. Demeclocycline, this is an antibiotic belonging to tetracycline, can be used.
Diuretics: Must Know
Know the site of action of each diuretics on the nephron.
Mannitol: DOC in cerebral edema, acute congestive glaucoma > Containdicated in CHF and acute pulmonary edema.
Carbonic anhydrase inhibitors: Acetazolamide, used in acute mountain sickness, glaucoma, FPHP. Side effects calcium stones, metabolic acidosis, parasthesias. Avoid in liver disease??
Loop diuretics- Furosemide, block Na/K/2cl symporter in TAL. DOC in acute pulmonary edema, hypercalcemia, CHF, nephrotic syndrome. Side effects: Electrolyte imbalance, ototoxicity, adverse lipid profile, hyperglycemia.
Diuretics: Must Know
Thiazide: acts on DCT, block Na/Cl symporter. Uses: HTN, Idopathic hypercalciurea. Side effects: similar to loop diuretics except no ototoxicity and they cause hypercalcemia.
Spirinolactone: blocks aldosterone receptors. Preferred in cirrhotic edema. Side effects: Hyperkalemia, gynecomastia, amenorrhea etc
Triamterene: Na channel blocker in CD. Weak folate antagonist
Amiloride: similar action. Used in Lithium induced DI and Liddles syndrome