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Clinical use of diuretics: Hypertension
Primary modality of treatment Forms base of treatment regimen
Mobilization of edema fluid Heart failure Liver disease (Cirrhosis) Renal disease
Prevention of renal failure (maintains urine flow)
Mechanism of Action Agents best understood in relation
to sites of action in the nephron. Each site of nephron highly specialized in function.
Almost all diuretics exert their effects at luminal surface of renal tubular cells. Ion transport inhibitors.
Mechanism of Action Diuretics compromise normal
operation of the kidney to promote excretion of water.
Diuretic use can result in:
Hypovolemia Acid-base imbalance Loss of electrolytes
Attempt to Minimize Adverse Effects By:
Short-acting diuretics
Time doses to allow drug-free periods between periods of diuresis. Will allow kidney to readjust ECF to
compensate for undesired alterations.
Diuretic-like Agents: Methylxanthines (caffeine,
theophylline), cardiac glycosides (digoxin) and sympathomimetic amines (dopamine) act at the level of the glomerulus to increase volume of blood filtered via increase in cardiac output.
Renal Function: Cleansing of extracellular fluid (ECF),
maintenance of ECF volume and composition.
Maintenance of acid-base balance.
Excretion of metabolic wastes and foreign substances (drugs, toxins, etc.).
Filtration: Glomerular level
1st step in urine formation
All small molecules filtered… Electrolytes, glucose, amino acids, Na+, K+,
Cl-, HCO3- -- most prevalent Large filtration capacity Nonselective…cannot regulate composition
of urine
Reabsorption: > 99% of filtrate Conserves valuable portions while
allowing wastes to be excreted Reabsorption of solutes—active
transport H20 follows passively PRIMARY ACTION OF DIURETICS! Na+, K+ predominant solutes in filtrate
Active Secretion: Transports compounds from
plasma into lumen of nephron.
Located in PCT. Organic Acids (S2) – uric acid,
antibiotics. Organic Bases (S1 and S2) –
creatinine, choline, and procainamide.
Proximal ConvolutedTubule: High resorptive capacity.
65% of filtered Na+, Cl- reabsorbed.
Also HCO3-, K+, glucose, amino acids.
H2O follows passively.
Solutes and H2O reabsorbed to = extent… Urine is isotonic (300 mOsm/L).
Loop of Henle: Descending Limb:
Thin segment. Freely permeable to H20. As tubular urine moves down loop
thru hypertonic medulla, H2O is drawn from loop into interstitial space.
Will decrease volume of urine and increase concentration.
Loop of Henle: Ascending Limb:
Thick segment. NOT permeable to H2O 30% of filtered Na+ & Cl- reabsorbed (actively). H2O remains in loop as Na+ and Cl- reabsorbed -
tonicity returns to original. Regard as diluting segment. Utilizes Na+/K+/2Cl- cotransport system which is selectively blocked by diuretics. The action of the transporter lead to excess K+ accumulation within the cell.
Results in back diffusion of K+ into tubular lumen lumen + electrical potential.
Driving force for reabsorption of Mg+ and Ca+ via paracellular pathway.
Distal ConvolutedTubule: 10% of filtered NaCl reabsorbed.
H20 follows passively.
Na+ and Cl- neutral cotransport.
Ca+ actively reabsorbed via apical Ca+
channel and basolateral Na+/Ca++
exchanger regulated by PTH.
Collecting Tubule: 2-5% of NaCl reabsorption. Responsible for determining final concentration
of Na+ in urine. Na+/K+exchange…
ALDOSTERONE increases activity of apical membrane channels and basolateral Na+/K+ ATPase.
Major site of K+ excretion. Impermeable to H2O in absence of ADH…dilute
urine produced. Only site in nephron where membrane H2O
permeability can be regulated. ADH increases permeability to H2O
Action of Diuretics: Blockade of Na+ (and Cl-) reabsorption Create osmotic pressure within nephron
that prevents passive reabsorption of H2O CAUSE H2O & SOLUTES TO BE RETAINED
WITHIN THE NEPHRON Thereby PROMOTING THEIR EXCRETION
The increase in urine flow that a diuretic produces is directly related to the amount of Na+ and Cl- reabsorption that the drug blocks
Drugs Whose Site of Action Is Early in the Nephron Will Have the Opportunity to Block the Greatest of Solute Reabsorption…Produce Greatest Diuresis.
180 L Filtrate/day…almost all reabsorbed.
For each 1% of solute reabsorption blocked, urine output increases by 1.8 L
3% blockade = 5.4 L urine/day = 12 lb. weight loss.
Small blockade can have profound effects.
Classification
Loop (High-ceiling) diuretics Thiazide diuretics Osmotic diuretics Potassium-sparing diuretics
Aldosterone antagonists Inhibitors of Na+ transport
Carbonic anhydrase inhibitors Mercurial diuretics
Actions of Diuretic Agents: Inhibition of specific membrane
transport proteins at luminal surface of renal tubular epithelial cells.
Osmotic effect to prevent water reabsorption in water – permeable segments.
Enzyme inhibition. Interfere with hormone receptors in
renal epithelial cells.
Loop (High-Ceiling) Diuretics GREATEST EFFICACY – Cause large
increase in fractional excretion of Na+
Furosemide (Lasix®) Bumetanide (Bumex®) Ethacrynic Acid (Edecrin®) Torsemide (Demadex®)
Loop (High-Ceiling) Diuretics Act to inhibit coupled Na+/K+/2Cl- transport
system in luminal membrane of thick ascending limb of loop of Henle
Blocks Cl- and Na+ reabsorption and prevents passive H2O reabsorption
Normally up to 30% of filtered NaCl reabsorbed in ascending limb
Also diminishes normal lumen-positive potential that drives K+ recycling
Causes increase in Mg++ and Ca++ excretion Transport system driven by Na+/K+ ATPase
dependent pump
Pharmacokinetics: Rapidly absorbed. Response correlates with urinary excretion
rate. Eliminated by renal secretion and filtration. Action may be slowed by probenecid. Duration of action -- 2 or more hours. IV use for rapid effect. Hepatic metabolism. t 1/2 dependent on renal function.
Clinical Indications: Rapid or massive fluid mobilization
Pulmonary edema Acts to decrease LVEDP and decrease pulmonary vascular
congestion Edematous states
CHF Cirrhosis Nephrosis
Hypertension Hypercalcemia Acute renal failure
Convert oliguric to non-oliguric renal failure Anion overdose
Inhibits reabsorption of Br- , F-
Adverse Effects: Dehydration Hypotension Electrolyte Imbalance
Hyponatremia Hypochloremia HYPOKALEMIA Hypocalcemia Hypomagnesemia
Hyperglycemia Hyperuricemia Ototoxicity Cross reactivity in patients with SULFA allergy
Ethacrynic acid in phenoxyacetic acid derivative
Thiazide Diuretics(Benzothiadiazides): All have unsubstituted sulfonamide group. Similar effects as loop diuretics…less
efficacy. *Hydrochlorothiazide (HydroDIURIL®) Chlorothiazide (DIURIL®) Diazoxide—non-diuretic thiazide Chlorthalidone (Hygroton®) Indapamide (Lozol®) Metolazone (Zaroxolyn®, Mykrox®)
Thiazide Diuretics: Act to inhibit NaCl reabsorption from
luminal side of epithelial cells in DCT (early segment).
Bind to Cl- site of electroneutral Na+/Cl- cotransport system.
No effect on loop of Henle.
Enhance Ca+2 reabsorption in DCT.
Clinical Indications: Hypertension
Drug of choice for initial therapy of hypertension
CHF Hypercalciuria, nephrolithiasis Nephrogenic Diabetes Insipidus
reduces polyuria and polydipsia where no response to ADH Seemingly paradoxical effect
Adverse Effects: Most Similar To Those Of Loop Diuretics
Hypercalcemia
Hyperlipidemia {5-15% in cholesterol (LDL)}.
No Ototoxicity.
Hyperglycemia
Potassium-Sparing Diuretics:
Cause mild to moderate increase in urine production
Substantial decrease in K+ excretion.
Rarely employed to promote diuresis.
Spironolactone (Aldactone®) Blocks action of aldosterone via direct competitive
antagonism at level of cytoplasmic mineralocorticoid receptors in distal nephron (DCT + CT). Spironolactone-receptor complex does not attach to DNA. Prevents translocation of receptor complex to nucleus. Aldosterone acts to promote Na+ uptake in exchange for K+ secretion… see Na+ loss and K+ sparing…mild diuretic effect…most Na+ already reabsorbed by more proximal nephron.
Slow onset of action Need to exhaust proteins already formed by aldosterone
action…1-2 days. Well absorbed from GI tract. t ½ =10 minutes Active metabolite canrenone has t ½ = 16 hours.
Spironolactone (Aldactone®) Useful primarily in states of aldosterone
excess associated with diminished effective extracellular volume
CHF Cirrhosis Nephrotic syndrome
Adverse Effects HYPERKALEMIA
Increased risk with renal disease, drugs which decrease renin (-blocker, NSAID) or ACE inhibitor
Hyperchloremic metabolic acidosis Inhibits H+ secretion along with K+ secretion
Gynecomastia, impotence
Eplerenone (Inspra®) Blocks binding of aldosterone to
mineralocorticoid receptor Selective binding compared to
glucocorticoid, progesterone and androgen receptors
Produces sustained increases in plasma renin and serum aldosterone Consistent with negative regulatory
feedback of aldosterone on renin secretion Resultant increased renin activity and
circulating aldosterone do not overcome effects of eplerenone on BP
Eplerenone (Inspra®) Peak concentrations in 1.5 hours 50% plasma protein binding Metabolism via CYP3A4
Inhibitors of CYP3A4 will raise blood levels of eplerenone
Ketoconazole Saquinavir Erythromycin fluconazole
t ½ = 4-6 hours
Eplerenone (Inspra®) Hyperkalemia principal risk Increased risk of hyperkalemia with
ACE inhibitors Angiotensin Receptor Blockers
Well tolerated Indication: HYPERTENSION Introduced: Sept. 2002
Triamterene (Dyrenium®): Influences Na+-K+ exchange in distal
nephron.
Direct inhibitory effect.
No effect on aldosterone.
Acts within few hours.
Limited diuretic efficacy.
Metabolized in liver. Short t1/2. Well absorbed.
Clinical Indications: Hypertension Mild edema Usually combined with another diuretic:
+hydrochlorothiazide = Dyazide® Also, AMILORIDE (Midamor®)-
blocks luminal Na+ channels by which aldosterone produces main effect. Poorly absorbed, slower onset of action, peak 6 hours.
+ hydrochlorothiazide = Moduretic®
Carbonic Anhydrase Inhibitors:
Carbonic anhydrase present in luminal and basolateral membranes, epithelial cell cytoplasm, and RBC’s. Luminal membrane of PCT predominant site.
Catalyzes dehydration of H2CO3…critical step in HCO3 reabsorption. CO2 + OH- HCO3-
Inhibition of Carbonic Anhydrase causes diuresis and reduction in total body HCO3 stores.
Depresses HCO3 reabsorption. HCO3 accumulates in luminal fluid.
Carbonic Anhydrase Inhibitors: Forerunners of modern diuretics.
Sulfonamides [-SO2NH2] noted to cause hyperchloremic, metabolic acidosis with large volumes of alkaline urine.
Thiazides developed to separate natriuretic effects from effects of HCO3 handling.
Carbonic Anhydrase Inhibitors: Acetazolamide (Diamox®) Dichlorphenamide (Daranide®) Methazolamide (Neptazane®) Dorzolamide (Trusopt®)
SO2NH2 Group is essential for activity 85% of HCO3 resorptive activity is inhibited
in PCT. 45% of whole kidney HCO3 reabsorption is
inhibited.
Clinical Actions: Increases urine volume Alkaline pH of urine Increases HCO3
-, K+, Na+ in urine Decreases Cl- in urine Decreases HCO3- in blood: metabolic
acidosis Hypokalemia HCO3- depletion; enhanced NaCl
reabsorption by remaining nephron segments; loss of effectiveness within days.
Carbonic Anhydrase Inhibitors: Carbonic anhydrase also present in
ciliary body and choroid plexus. Aqueous humor and CSF formation are HCO3- dependent. Processes are in opposite direction from that in PCT. Both are able to be inhibited and pH and quantity of fluid formed will be affected.
Pharmacokinetics: Well absorbed after oral
administration.
Increase in urine pH within ½ hour; maximal in 2 hours.
Excretion by tubular secretion in S2 segment.
Clinical Indications: Glaucoma-Inhibition of CA decreases
rate of aqueous humor formation and decreases IOP.
Urinary alkalinization-uric acid, cystine relatively insoluble in acid urine. Excretion of weak acids (aspirin) enhanced in alkaline urine.
Reduction of total body HCO3- stores. Acute mountain sickness. Absence seizures.
Toxicity: Hyperchloremic metabolic acidosis. Hypokalemia. Renal stones - Ca++ salts relatively
insoluble in alkaline urine. HCO3- loss in
urine results also in phosphaturia and hypercalciuria.
CONTRAINDICATED in cirrhosis. Urinary alkalinization results in decreased excretion of NH4
+.
Osmotic Diuretics: Mannitol
Freely filtered. Minimal reabsorption. Not metabolized. Pharmacologically inert. Given in amounts large enough to constitute
appreciable fraction of plasma osmolarity.
Also, Urea and Glycerin
Osmotic Diuretics: Creates osmotic force within lumen of
nephron prevents H2O reabsorption in those segments freely permeable to H2O (PCT and descending loop of Henle).
Degree of diuresis related to amount of mannitol in filtrate. Little effect on loss of K+. Does not produce diuretic effects by blocking reabsorption of Na+ or Cl-.
IV use only. Cannot diffuse across GI epithelium.
Osmotic Diuretics: Clinical Indications: Prophylaxis of renal shutdown.
- Increases Urine volume. Reduction of intracranial or intraocular
pressure.
Adverse Effects: Volume expansion. Dehydration, hypernatremia.
Agents that Affect Water Excretion: ADH (VASOPRESSIN): Acts at collecting
tubule to modulate concentration of final urine.
Secretion during hypotonic volume expansion large volumes of dilute urine formed.
Secretion during volume contraction & hypertonic conditions urine concentration by water abstraction.
Thick ascending limb of loop of Henle plays central role during concentration and dilution of urine.
ADH = Antidiuretic + Vasopressor Effects:
Vasopressin-nonapeptide…arginine @ position 8.
Primarily parenteral administration—IV, IM, intranasal. t1/2 = 20 minutes Renal and hepatic catabolism Reduction of disulfide bond + peptide cleavage.
Receptors: V1 mediate vasoconstriction.
V2 (Renal) mediate antidiuresis through H2O permeability and H2O resorption in CT and CD.
V2 (Extrarenal) mediate release of Factor VIIIc and von Willebrand Factor as well as BP and SVR.
ADH Antagonists: Li+ salts, demeclocycline inhibit
effects of ADH at collecting tubule via adenylyl cyclase and at some step following cAMP generation by ADH…effects of cAMP antagonized.
Preparations: Aqueous Vasopressin (Pitressin®)
Short acting IV, IM, or SQ Q 3-6 hours Lysine Vasopressin (Diapid®)
Short-acting nasal spray Q 4-6 hours Desmopressin (DDAVP®)
1-desamino-8-D-arginine vasopressin. Long-acting synthetic analogue of vasopressin…minimal
V1 activity. Antidiuretic: pressor = 4000 x vasopressin. Most expensive. Preferred for chronic therapy. Nasal spray, nasal tube, IV, SQ, or po Q 8-12 hours.
ADH Agonists: USE:
Diabetes Insipidus (Pituitary): Vasopressin Nocturnal Enuresis: DDAVP GI Bleeding: Vasopressin infusion Assess renal concentrating ability after long-
term lithium therapy: DDAVP Coagulopathy (Hemophilia A, von Willebrand’s):
DDAVP TOXICITY:
Headaches, nausea, cramps Caution: Nasal congestion
Potassium Replacement Products
Potassium gluconate Potassium citrate Potassium bicarbonate Potassium acetate Potassium chloride
mEq/g of various Potassium Salts
Potassium Salt mEq/g
Potassium gluconate 4.3
Potassium citrate 9.8
Potassium bicarbonate
10
Potassium acetate 10.2
Potassium chloride
13.4
Potassium Chloride: Oral Forms
Controlled Release tablets 8 mEq (600 mg); 6.7 mEq (500 mg)
Controlled Release capsules 10 mEq (750 mg)
Liquid 20 mEq/15 ml ( 1500 mg) 30 mEq/15 ml (2250 mg) 40 mEq/15 ml ( 3000 mg)
Potassium Chloride: IV Use Generally prepared in
concentrated form 2mEq/ml 10mEq in 5ml,10ml, 50ml and 100ml
vials 20mEq in 10ml and 20 ml vials
Concentrate MUST me diluted before use
Potassium administration:Guidelines
Serum K+Maximum Infusion
Rate
Maximum Concentratio
n
Maximum 24 hour
dose
>2.5mEq/L 10 mEq/hr 40 mEq/L 200 mEq
< 2 mEq/L 40 mEq/hr 80 mEq/L 400 mEq
Intravenous Fluids NaCl (Saline)
0.9% (Normal Saline) 0.3% 0.33% 0.45% (½ normal saline) 3% (Hypertonic saline)
Ringer’s Injection (Solution) 310 mOsm/L Na, K, Ca, Cl
Lactated Ringer’s Injection Na, K, Ca, Cl, lactate 274 mOsm/L
All available with or without
Dextrose (5%)
Dextrose available without
electrolytes:
D5W, D10W
Magnesium Sulfate (MgSO4) Treatment of
hypomagnesemia Seizure prevention in
eclampsia and pre-eclampsia Treatment of cardiac
arrhythmias Hypomagnesemia Torsades de pointes
Constipation Soft-tissue injuries Status asthmaticus
Epsom Salts