Module 3.1: DIURETICS Flashcards by He LP

 Major effect is in the proximal tubule and descending Loop of Henle  Prevents normal absorption of water by interposing a countervailing osmotic force

OSMOTIC DIURETICS

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[Thiazide Diuretic] only drug available in parenteral admin

CHLOROTHIAZIDE

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[CARBONIC ANHYDRASE INHIBITORS] Indications: (what indication is this?) cystinuria – dissolves cysteine crystals by increasing urinary pH, leads to complete reabsorption of cysteine uric acid crystals – same effect ADR: formation of Ca salts

urine alkalinisation

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Newer, more selective aldosterone blockers have fewer of the progestational and anti-androgenic effects than…

Spirinolactone

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reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs

FUROSEMIDE

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[CARBONIC ANHYDRASE INHIBITORS] PROTOTYPE DRUG:

ACETAZOLAMIDE

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ANTIDIURETIC HORMONE ANTAGONISTS in patients with CHF and and SIADH (x’ss ADH)

LITHIUM DEMECLOCYCLINE*

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ADVERSE DRUG REACTIONS: ARF caused by …

combination of triamterene and indomethacin (NSAID)

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[LOOP DIURETICS] ADVERSE DRUG REACTIONS

Hypotension - Dehydration losses excess volume [take note of patient’s fluid volume] - HYPOnatremia - HYPOkalemia o more effect than hyponatremia- monitor level] o if given with digoxin = arrhythmia [should be given simultaneously]

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DIRECT Na CHANNEL BLOCKER

TRIAMTERENE AMILORIDE

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[OSMOTIC DIURETICS] INDICATION

 to increase urine volume  reduce intracranial and intraocular pressure

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[LOOP DIURETICS] ADVERSE DRUG REACTIONS

ototoxicity (ETHACRYNIC ACID) - hyperuricemia (hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule) - HYPOmagnesimia - allergic reactions (may be due to sulfur)

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[ALDOSTERONE BLOCKERS/K-SPARING DIURETICS] ADVERSE DRUG REACTIONS

 HYPERkalemia  Hyperchloremic metabolic acidosis

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[OSMOTIC DIURETICS] ADVERSE DRUG REACTIONS:

 extracellular volume expansion  dehydration, HYPERkalemia, and HYPOnatremia

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[Thiazide Diuretic] slow absorption, longer duration

CHLORTHALIDONE

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Ineffective in reducing BP in vast majority of individuals with HTN

LOOP DIURETICS

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[ALDOSTERONE BLOCKERS/K-SPARING DIURETICS] INDICATIONS

Hyperaldosteronism treatment - due either to primary hypersecretion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume)

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 decrease pH and increase luminal concentrations of Cl2 and Na  sometimes used in combination with high-ceiling diuretics to counteract alkalosis

ACIDIFYING SALTS [AMMONIUM CHLORIDE]

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[CARBONIC ANHYDRASE INHIBITORS] ADVERSE DRUG REACTIONS:

Hyperchloremic Metabolic Acidosis - Renal stone (phosphaturia, hypercalcuria) - Renal K wasting - Drowsiness and paresthesias - CNS toxicities among renal failure patients - Hypersensitivity reactions

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USED ONLY IN ACUTE PHASES not for chronic use; due to reduction of circulating volume

LOOP DIURETICS

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MOA: Early renal (salt/water excretion) effects – act by inhibiting the Na/Cl reabsorption pump in the DCT; by blocking Na-Cl co-transporter (NCC)

THIAZIDE DIURETICS

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[CARBONIC ANHYDRASE INHIBITORS] Indications: By decreasing cerebrospinal fluid formation and by decreasing the pH of the cerebrospinal fluid and brain leading to an increase in ventilation and diminish symptoms of ….

acute mountain sickness

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 increasing cardiac output and promoting a higher glomerular filtration rate  seldom used as diuretics, but diuresis occurs under other clinical applications (e.g., for bronchodilatation)  MOA: antagonism of adenosine receptors

XANTHINE DIURETICS

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[LOOP DIURETICS] INDICATIONS

 Mild HYPERkalemia - enhance urinary excretion of K +  Acute Renal Failure (ARF) – inc rate of urine outflow, inc excretion of K  Anion overdose

ANTIDIURETIC HORMONE AGONISTS in patients with CENTRAL DIABETES INSIPIDUS (low ADH)

VASOPRESSIN\* DESMOPRESSIN

[CARBONIC ANHYDRASE INHIBITORS] Indications:

- treatment of sleep apnea - adjuvant treatment of epilepsy and in some forms of hypokalemic periodic paralysis - treating patient with CSF leak(tumor or head trauma) - increasing urinary phosphate excretion during hyperphosphatemia

- Prevent reabsorption of Cl and Na by blocking NaK2Cl transporter [leading to excretion of Na and Cl]

LOOP DIURETICS

[CARBONIC ANHYDRASE INHIBITORS] Indications: - Glaucoma by reducing aqueous humor production Topically active agents are...

DORZOLAMIDE BRINZOLAMIDE

[ALDOSTERONE BLOCKERS/K-SPARING DIURETICS] INDICATIONS

- chronic liver disease leads to decreased possibility in development of ascites - chronic heart failure [CHF] - usually given with a thiazide diuretic [not as potent if alone]

ADVERSE DRUG REACTIONS: Kidney stone/nephrolithiasis caused by...

triamterene

- Act on membrane ion transport mechanism in the thick ascending limb of the Loop of Henle

LOOP DIURETICS

MOA of Loop Diuretics for patient with.....: - Loop diuretics effectively reduce ECF volume and BP - The renal and antinatriuretic mechanisms are blunted

Patient with renal dysfunction

- These are VENODILATORS and little arteriolar dilator effect

LOOP DIURETICS

mild diuretic

CAFFEINE

Should be given as IV, if given orally can cause osmotic diarrhea rather than diuresis

MANNITOL (non-reabsorbable solute)

ALDOSTERONE ANTAGONISTS – competitive inhibitor of aldosterone

SPIRINOLACTONE EPLENERONE

[OSMOTIC DIURETICS] INDICATION reduce cellular edema in case of hemorrhagic stroke to decrease ICP

MANNITOL (non-reabsorbable solute)

[Thiazide Diuretic] ADVERSE EFFECTS

 HYPOkalemic metabolic alkalosis and hyperuricemia  impaired CHO tolerance  HYPERGLYCEMIA  Hyperlipidemia – inc in total cholesterol and LDL levels  HYPOnatremia  Allergy- photosensitivity, dermatitis; severe could lead to hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis

[CARBONIC ANHYDRASE INHIBITORS] CONTRAINDICATION

Liver cirrhosis, may contribute to development of hyperammonemia and hepatic encephalopathy

MOA:  They provide effective Anti-HTN treatment especially in low-renin and salt sensitive forms of hypertension  Provide additional benefit in the treatment of heart failure (HF) when combined with ACE Inhibitors (ACE-I), digitalis, and loop diuretics

ALDOSTERONE BLOCKERS/K-SPARING DIURETICS

[CARBONIC ANHYDRASE INHIBITORS] Indications: .....due to excessive use of diuretics among HF patients should only be treated with carbonic anhydrase inhibitors

metabolic alkalosis states

ADVERSE DRUG REACTIONS: Gynecomastia, impotence, and benign prostatic hyperplasia caused by....

spironolactone and eplerenone due to steroid like structure

MOA of Loop Diuretics for patient with.....: - Variety of mechanisms blunts the ability to persistently reduce ECF volume or BP - The initial diuresis is typically followed by longer period of Na retention (neutral or positive balance) \*another reason why it’s not for chronic use

Normal GFR patient

 Predominantly found in the luminal membrane of the PCT  Inhibitors that block NaHCO3 reabsorption

CARBONIC ANHYDRASE INHIBITORS {-ZOLAMIDE}

[Thiazide Diuretic] use in combination with loop diuretics

METOLAZONE

- Induces production of COX-2 leading to production of prostaglandins like PGE2 which inhibits salt reabsorption in the TAL

FUROSEMIDE

[OSMOTIC DIURETICS] PROTOTYPE DRUG:

MANNITOL (non-reabsorbable solute)

- If given IV, check BP before and after administration; if hypotensive from the start, given with this would lead to severe hypotension; if normal BP then administered, dramatic decrease in BP

FUROSEMIDE

[Thiazide Diuretic] INDICATIONS

 Hypertension – mild; or as adjunct with other anti-HTN  Heart failure  Nephrolithiasis due to idiopathic hypercalciuria  Nephrogenic diabetes insipidus

Topical for glaucoma

Brinzolamide, dorzolamide

MOA: Inhibition of the enzyme prevents dehydration of H2CO3 and hydration of CO2 in the proximal convoluted tubule EFFECTS: Reduces reabsorption of HCO3−, causing self-limited diuresis • hyperchloremic metabolic acidosis reduces body pH, reduces intraocular pressure CLINICAL APP: Glaucoma, mountain sickness, edema with alkalosis

Acetazolamide

ROA: Oral and topical preparations available • duration of action ∼ 8–12 h TOXICITY: Metabolic acidosis, renal stones, hyperammonemia in cirrhotics

Acetazolamide

Sulfonamide loop agents like furosemide

Bumetanide, torsemide

Not a sulfonamide but has typical loop activity and some uricosuric action

Ethacrynic acid

MOA: Inhibition of the Na/K/2Cl transporter in the ascending limb of Henle’s loop EFFECTS: Marked increase in NaCl excretion, some K wasting, hypokalemic metabolic alkalosis, increased urine Ca and Mg

Furosemide

CLINICAL APP: Pulmonary edema, peripheral edema, hypertension, acute hypercalcemia or hyperkalemia, acute renal failure, anion overdose ROA: Oral and parenteral preparations • duration of action 2–4 h TOXICITY: Ototoxicity, hypovolemia, K wasting, hyperuricemia, hypomagnesemia

Furosemide

Thiazide Popular for use with loop agents for synergistic effects

Metolazone

Only parenteral thiazide available (IV)

Chlorothiazide

Long half-life (50–60 h) due to binding to red blood cells

Chlorthalidone

MOA: Inhibition of the Na/Cl transporter in the distal convoluted tubule

EFFECTS: Modest increase in NaCl excretion • some K wasting • hypokalemic metabolic alkalosis • decreased urine Ca

Hydrochlorothiazide

CLINICAL APP: Hypertension, mild heart failure, nephrolithiasis, nephrogenic diabetes insipidus ROA: Oral • duration 8–12 h TOXICITY: Hypokalemic metabolic alkalosis, hyperuricemia, hyperglycemia, hyponatremia

Hydrochlorothiazide

Mechanism like amiloride, much less potent, more toxic

Triamterene

Like spironolactone, more selective for aldosterone receptor

Eplerenone

MOA: Pharmacologic antagonist of aldosterone • weak antagonism of androgen receptors

Spironolactone

EFFECTS: Reduces Na retention and K wasting in kidney • poorly understood antagonism of aldosterone in heart and vessels

Spironolactone

CLINICAL APP: Aldosteronism from any cause • hypokalemia due to other diuretics • postmyocardial infarction Slow onset and offset of effect • duration 24–48 h TOXICITY: Hyperkalemia, gynecomastia (spironolactone, not eplerenone) • additive interaction with other K-retaining drugs

Spironolactone

MOA: Blocks epithelial sodium channels in collecting tubules EFFECTS: Reduces Na retention and K wasting • increases lithium clearance

Amiloride

CLINICAL APP: Hypokalemia from other diuretics • reduces lithiuminduced polyuria ROA: Orally active • duration 24 h TOXICITY: Hyperkalemic metabolic acidosis

Amiloride

MOA: Physical osmotic effect on tissue water distribution because it is retained in the vascular compartment EFFECTS: Marked increase in urine flow, reduced brain volume, decreased intraocular pressure, initial hyponatremia, then hypernatremia

Mannitol

CLINICAL APP: Renal failure due to increased solute load (rhabdomyolysis, chemotherapy), increased intracranial pressure, glaucoma ROA: IV administration TOXICITY: Nausea, vomiting, headache

Mannitol