10 Pharmacology of Diuretics Flashcards
1
Q
Diuretics
- Nephrons
- Diseases that disrupt this balance
- Diuretics
A
- Nephrons
- Regulate total body fluid & electrolyte balance via the processes of secretion & reabsorption
- Diseases that disrupt this balance
- –> edema
- Ex. heart failure, renal failure, nephrotic syndrome, & cirrhosis
- Diuretics
- Increase the rate of urine flow and sodium excretion
- Used to adjust the volume and/or composition of body fluids in these disorders
2
Q
Kidney
- Nephron
- Kidney functions
- Kidney consumption of total body oxygen intake
A
- Nephron
- Urine forming unit of the kidney
- ~1 million in each kidney
- Consists of a filtering apparatus (glomerulus) attached to a long tubular portion that reabsorbs and conditions the ultrafiltrate
- Kidney functions
- Filter large quantities of plasma
- Reabsorb substances that the body must conserve
- >99% of ultrafiltrate is reabsorbed
- Leave behind &/or secrete substances that must be eliminated
- Kidney consumption of total body oxygen intake
- 7% despite only being 0.5% of body weight
3
Q
Nephron
- PT
- LOH
- TDL
- TnAL
- TkAL
- Macula densa
- DCT
- Early distal tubule
- CD
- % of filtered Na reabsorbed at each site of the nephron
- PT
- LOH
- DT
- CD
A
- Bowman’s capsule –> PT –> straight portion that enters renal medulla
- 65% of filtered Na is reabsorbed in the PT
- Reabsorption is isotonic b/c the PT is permeable to water
-
LOH
- Proximal straight tubule –> TDL at the junction of the outer & inner stripes of the outer medulla
- TDL penetrates inner medulla –> U-turn –> forms TnAL
- TnAL –> TkAL at the border b/n the inner & outer medulla
- Medullary portion
- Cortical portion
- Post macular segment
- 25% of Na is reabsorbed in the LOH (mostly TkAL)
- TkAL –> b/n AffA & EffA –> contacts AffA via macula densa
- Specialized columnar epithelial cells
- Regulates renin secretion from adjacent JG cells in the wall of the AffA
- Macula densa –> DCT
- Actively transports NaCl
- Impermeable to water
- Tubular fluid is always hypotonic compared to plasma
-
Early distal tubule: postmacular TkAL + DCT
- Aka diluting segment of the nephron
-
CD beings where the DCT ends
- Region of fine modulation of ultrafiltrate volume & composition
- FInal adjustments in electrolyte composition are made
- Regulated by aldo (Na) & ADH (water)
- % of filtered Na reabsorbed at each site of the nephron
- PT: 70%
- LOH: 20%
- DT: 5%
- CD: 1-4%
4
Q
Loop diuretics
- Aka
- Drugs
- Pumps/channels
- Efficacy
- Luminal vs. basolateral membrane potentials & net result
- Loop diuretics
- Main syndrome
A
- Aka
- Na/K/2Cl symport inhibitors
- High ceiling diuretics
- Drugs
- Furosemide (contains sulfonamide)
- Bumetanide (contains sulfonamide)
- Torsemide (sulfonylurea)
- Ethacrynic acid (phenoxyacetic acid derivative)
- Pumps/channels
- Inhibit Na/K/2Cl symporter in the luminal membrane of the TkAL
- Symporter uses the energy of the Na electrochemical gradient to transport K & Cl against their gradients into the cell
- ROMK channels in the luminal membrane recycle K into the lumen
- Cl channels in the basolateral membrane move Cl into the interstitium
- Inhibit Na/K/2Cl symporter in the luminal membrane of the TkAL
- High efficacy
- TkAL has a large reabsorptive capacity (25%) & reabsorbs most rejectate from the PT
- Nephron segments distal to the TkAl don’t possess the same reabsorptive capacity
- Luminal vs. basolateral membrane potentials & net result
- Luminal membranes: hyperpolarized (more negative) b/c of K channels
- Basolateral membranes: depolarized (less negative) b/c of Cl channels
- Net result
- Lumen: (+), interstitium: (-)
- Transepithelial potential difference of 10 mV drives Na, Ca, & Mg into the interstitium
- Na/K/2Cl inhibitors
- Bind the Na/K/2Cl symporter in the TkAL –> block its function –> impair salt transport
- Abolish the transepithelial potential difference –> attenuate Ca & Mg reabsorption
- Bartter’s syndrome
- Inherited hypokalemic alkalosis w/ salt wasting & HoTN
- Mutation in genes coding for the Na/K/2Cl symporter, apical K channel, basolateral Cl channel, or Cl channel subunit Barttin
5
Q
Thiazide diuretics
- Aka
- Drugs
- Pumps/channels
- Thiazide diuretics
- Main syndrome
A
- Aka
- Na/Cl symport inhibitors
- Thiazide-like diuretics
- Drugs
- Chlorothiazide
- Hydrochlorothiazide
- Metolazone
- Chlorthalidone
- Pumps/channels
- Tranport is powered by the basolateral Na pump
- Luminal Na/Cl symporter harnesses this energy to move Na & Cl into the cell
- Na moves down conc gradient, Cl moves against conc gradient
- Cl exits the cell passively via a basolateral Cl channel
- Thiazide diuretics
- Inhibit the Na/Cl symporter
- Gitelman’s syndrome
- Mutations in the Na/Cl symporter –> inherited hypokalemic alkalosis
6
Q
Na channel inhibitors
- Aka
- Drugs
- Drug characteristics
- Effects
- Mechanism in principal cells
- Loop & thiazide diuretics
- Mechanism in intercalated cells (type A)
- RAAS activation by diuretics
- [2nd drug] effects
- Main syndrome
A
- Aka
- K sparing diuretics
- Drugs
- Triamterene (pteridine derivative)
- Amiloride (pyrazinoylguanidine derivative)
- Drug characteristics
- Organic bases
- Transported by the organic base secretory mech in the PT
- Effects
- Increase NaCl excretion
- Antikaliuretic actions offset the effects of other diuretisc that increase K secretion
- Mechanism in principal cells
- Principal cells in the CD have epithelial Na channels in the luminal membranes
- Allow Na entry down the gradient created by the basolateral Na/K pump
- Higher Na permeability of the luminal vs. basolateral membrane
- Depolarizes the luminal membrane
- Creates a lumen-negative transepithelial potential difference –> drives K secretion into the lumen via ROMK in the luminal membrane
- Principal cells in the CD have epithelial Na channels in the luminal membranes
- Loop & thiazide diuretics
- Increase Na delivery to the DT & CD
- Increase luminal Na –> depolarizes luminal membrane –> increases lumen-negative potential difference –> increases K & H excretion
- Mechanism in intercalated cells (type A)
- Intercalated cells mediate H secretion into the tubular lumen
- H-ATPase + partial lumianl membrane depolarization –> tubular acidification
- RAAS activation by diuretics
- Contribues to diuretic induced K & H excretion
- Amiloride effects
- Blocks epithelial Na channels (ENACs) in the luminal membrane of principal cells
- ENAC consists of alpha, beta, & gamma subunits
- Liddle’s syndrome
- AD form of low-renin, volume expanded HTN
- Mutations in the alpha or gamma ENAC subunits –> increased basal ENAC activity
7
Q
Mineralocorticoid receptors (MR) antagonists
- Aka
- Drugs
- Effects
- Mechanism
A
- Aka
- K sparing diuretics
- Aldo antagonists
- Drugs
- Spironolactone
- Eplerenone
- Effects
- Retain salt & water
- Increase K & H excretion
- Mechanism
- Epithelial cells in the late distal tubule and CD contain cytosolic MRs w/ a high aldo affinity
- Aldo enters into the epithelial cell from the basolateral membrane & binds to MRs
- MR-aldo complex translocates to the nucleus & binds to specific sequences of DNA (hormone responsive elements)
- Regulates the expression of multiple gene products called aldosterone-induced proteins (AIPs)
- Net effect of AIPs
- Increase Na+ conductance of the luminal membrane and Na pump activity of the basolateral membrane
- Transepithelial NaCl transport is enhanced & the lumen negative transepithelial voltage is increased
- Increases the driving force for secretion of K+ and H+ into the tubular lumen
8
Q
Edema & diuretics
- Edema
- Local edema
- Generalized edema
- Edema pathophysiology
A
- Edema
- Palpable swelling & accumulation of abnormal amts of fluid in extravascular, EC compartment (IT fluid volume)
- Diuretics relieve edema
- Local edema
- Causes: inflammation, lymphatic obstruction, venous obstruction, thrombophlebitis
- Diuretics have no therapeutic role
- Generalized edema
- More widespread
- CHF & renal disease –> peripheral edema, pulmonary edema, & ascites
- Increase venous pressure –> LV dysfunction & liver cirrhosis –> pulmonary edema & ascites
- Anasarca: severe generalized edema
- Diuretics are useful in managing cardiac, hepatic, & renal edema
- Edema pathophysiology
- Altered starling forces –> Na & water movement from the vascular to IT space
- Retain Na & water –> expand EC fluid volume
9
Q
Mechanism of edema formation
- Edema formation
- Starling forces
- Hydrostatic capillary pressure (Pcap) & oncotic interstitial pressure (πIT)
- Hydrostatic interstitial pressure (PIT) & oncotic capillary pressure (πcap)
- Net driving force for fluid filtration across the capillary wall
- Effect of lymphatics
A
- Edema formation
- Most often due to elevatd capillary hydraulic pressure due to blood volume expansion or venous obstruction
- Starling forces
- Imbalance of starling forces in capillary beds &/or alterations in capillary premeability
- Net filtration = (unit permeability/porosity) * (surface area for filtration) * [(Pcap - PIT) - (πcap - πIT)]
- Hydrostatic capillary pressure (Pcap) & oncotic interstitial pressure (πIT)
- Drive fluid into the IT space
- Hydrostatic interstitial pressure (PIT) & oncotic capillary pressure (πcap)
- Drive fluid into the capillaries
- Net driving force for fluid filtration across the capillary wall
- –> net flux of water into the IT space
- Rate depends on the net driving force & capillary permeability
- Effect of lymphatics
- Lymphatic system can drain away the fluid fast enough –> no edema
- Lymphatic drainage is overwhelmed –> edema
10
Q
Edema
- Renal Na retention
- Primary
- Secondary
- Common causes
A
- Renal Na retention
- Primary
- Advanced renal failure
- Acute glomerulonephritis
- Nephrotic syndrome
- Secondary (“appropriate”)
- CHF
- Liver cirrhosis
- Primary
- Common causes
- CHF
- Liver disease
- Cirrhosis
- Portal HTN
- Renal disease
- Nephrotic syndrome
- Glomerulonephritis
- Chronic renal failure
- Pregnancy
- Anemia
- Drugs
- NSAIDs
- Estrogens
- Steroids
- Minoxidil
- CCB
- Venous & lymphatic obstruction
- Idiopathic edema
- Myxedema
11
Q
Cardiac edema
- Due to…
- Signs & symptoms
- LV dysfunction
- RV dysfunction
- Pathophysiology
A
- Due to CHF
- Signs & symptoms
- Hx of heart disease
- Orthopnea
- SOB
- Exertional dyspnea
- Cogestive symptoms
- Hepatic congestion
- Hepatojugular reflux
- Evidence of volume expansion
- Ventricular gallop rhythm
- Hx of heart disease
- LV dysfunction
- Increased pulmonary venous pressure as fluid backs up in the pulm circulation behind the failing LV –> pulmonary edema
- HoTN –> renal Na retention –> systemic edema
- RV dysfunction
- HoTN –> renal Na retention –> systemic edema
-
Pathophysiology
- Cardiac failure –> decreaed CO
- –> arterial underfilling
- –> activation of ventricular & arterial receptors
- –> stimulation of non-osmotic vasopressin, SNS, & RAAS
- –> renal Na/water retention & increased systemic & renal arterial vascular resistance
- -> maintenanc eo farterial circulatory integrity
- –> primary peripheral arterial vasodilation
- –> renal vasoconstriction, decreased renal perfusion pressure, increaed alpha-adrenergic activity, & increased AII
- –> decreased GFR & increased Na/water reabsorption
- –> decreased distal Na & water delivery
- –> impaired aldo escape
12
Q
Hepatic edema
- Due to…
- Risk factors
- Mechanism
- Pathophysiology
A
- Due to liver disease
- Risk factors
- Hx of liver disease
- Decreased CrCl (nromal serum Cr)
- Evidence of chronic liver disease
- Spider angiomata
- Palmar erythema
- Jaundice
- Hypoaluminemia
- Evidence of portal HTN
- Venous pattern on abdmoinal wall
- Esophogeal varices (can rupture)
- Ascites
- Mechanism
- Chronic damage to hepatocytes
- –> fibrotic changes in the liver (cirrhosis)
- –> distorted, constricted, & compressed hepatic sinusoids & veins
- –> sinusoidal & portal HTN
- –> favored filtration into interstitial spaces
- –> rate of fluid into interstitium > rate of lymph drainage
- –> exudate weeps from surfaces of liver, gut, & mesentery into peritoneal cavity
- –> reduced blood volume & kidney perfusion
- –> RAAS activation
- –> aldo reabsorbs Na
- –> systemic edema
- –> ascites
- –> reduced blood volume & kidney perfusion
- Other processes that contribute to systemic edema
- Hypoalbuminemia due to decreased liver production of albumin
- Lymphatic blockade due to lympahtic vessel compression by visceral congestion
- Pathophysiology
- Cirrhosis
- –> sytemic arterial vasodilation
- –> arterial underfilling
- –> activation of arterial baroreceptors
- –> stimulation of non-osmotic vasopressin, SNS & RAAS
- –> increased CO, Na & water retention, & increased peripheral arterial vascular & renal resistance
- –> arterial underfilling
- –> maintenance of arterial circulatory integrity
13
Q
Renal edema
- Due to
- Risk factors
- Mechanism: nephrotic pathway
- Mechanism: nephritic pathway
A
- Due to kidney disease
- Risk factors
- Hx of kidney disease
- Urinalysis
- Proteinuria
- Hematuria
- Cellular casts
- Renal imaging
- Enlarged kidneys due to nephrotic syndrome, glomerulonephritis, diabetes, or multiple myeloma
- Shrunked kidneys due to CKD
- Frequent kidney steons or UTIs
- Mechanism: nephrotic pathway
- Loss of albumin in urine
- Undelrying renal disease alters the glomerular sieving coefficient
- Large molecules are inappropriately filtered rather than retained in the blood
- Hypoalbuminemia lowers πcap
- Drives fluid into the interstitial space
- –> systemic edema
- Mechanism: nephritic pathway
- Loss of filtration in the glomeruli
- Due to inflammation, abnormal proliferation of mesangial cells, increased production of extracellular matrix, etc.
- Decreased GFR
- Increased Na retention
- –> systemic edema
- Loss of filtration in the glomeruli
14
Q
Idiopathic edema
- General
- Pathophysiology
- Treatment
A
- General
- Pts experience episodes of fluid retention (edema) w/ 5-15 lbs of water weight for no aparent reason
- Leads pts to restrict calorie intake –> eating disorders
- Pathophysiology
- Dysregulation of precapillary vessels
- –> higher transmission of ydrostatic pressure to capillaries &/or increased capillayr permeability
- Treatment
- Idiopathic edema will respond to diuretics
- Diuretic abuse –> electrolte disturbances
- Preferred treatment: pt counseling
- Idiopathic edema will respond to diuretics
15
Q
Pharmacological effects of diuretics
- Diuretics
- Natriuretic agents
- Aquaretic agents
- Treatment of edematous states
- Edematous states
- Main effect
- Common mech
A
- Diuretics
- Substances that increase urine production
- Natriuretic agents
- Clinically relevant diuretics
- Increased diuresis is associated w/ increased Na excretion + concomitant loss of water
- Aquaretic agents
- Increased diuresis is associated w/ increased water excretion
- Ex. osmotic agents (manitol) & ADH inhibitors
- ADH receptor antagonists –> selective water diuresis
- Na/K excretion isn’t affected
- Na & K loss are features of chronic SIADH
- Treatment of edematous states
- Edematous states: CHF, liver cirrhosis, nephrotic syndrome, renal failure, etc.
- Main effect: decrease plasma volume by increasing Na & water excretion
- Common mech: inhbiit Na reabsorption in dif sites in the nephron
16
Q
Na/K/2Cl symptort inhibitors
- Type of diuretics
- Effects
- Chronic administration of these drugs –>
- Vascular effects
- Effect on electrolyte transport
A
- Type of diuretics
- Loop diuretics
- Effects
- Increase urinray Na & Cl excretion
- Decrease transepithelial potential differene –> increase Ca & Mg excretion
- Increase urinary K & titratable acid excretion
- Chronic administration of these drugs –>
- Volume depletion
- –> increased uric acid reabsorptoin
- –> competition b/n diuretic & uric acid for organic acid secretory mechs
- –> enhanced uric acid transported in the PT
- –> reduced uric acid excretion
- Volume depletion
- Vascular effects (esp furosemide)
- Increase systemic venous capacitance
- –> decrease LV filling pressure
- Mediated by prostaglandins
- Requires intact kidneys
- Benefits pts w/ pulm edema
- Increase systemic venous capacitance
- Effect on electrolyte transport
- High doses inhibit electrolyte transport
- Important in the inner ear where altered electrolyte composition of endolymph –> drug-induced toxicity
17
Q
Therapeutic effects of loop diuretics (Na/K/2Cl symport inhibitors)
- Na
- Urine volume
- Ca
- Free water reabsorption
- Venous capacitance
- ECFV
A
- Increase Na excretion
- –> treat severe edema & ascites in liver cirrhosis
- Increase urine volume
- –> treat oliguric ARF
- Increase Ca excretion
- –> treat hypercalcemia
- Impair free water reabsorption + dilute urine
- –> treat hyponatremia
- Increase venous capacitance + natriuresis –> decrease LV filling pressures
- –> treat acute pulm edema
- Decrease ECFV
- –> decrease venous & pulm confestion
- –> treat chronic CHF
18
Q
Adverse effects of loop diuretics (Na/K/2Cl symport inhibitors)
- Most due to…
- Overuse
- Na delivery & RAAS
- K
- Mg & Ca
- Menopause & osteopenia
- Rapid IV administration
- Other
A
- Most due to abnormalities of fluid & electrolyte balance
- Overuse –> Na depletion
- –> hyponatremia
- –> ECFV depletion
- –> HoTN
- –> decreased GFR
- –> circulatory collapse
- –> thromboembolic episodes
- –> hepatic encephalopathy (w/ liver disease)
- Increase Na delivery to distal tubule + RAAS activation
- –> increased urinray K & H excretion
- –> hypochloremic alkalosis
- Insufficienct K intake
- –> hypokalemia
- –> cardiac arrhythmias (esp in pts taking cardiac glycosides)
- Increase Mg & Ca excretion
- –> hypomagnesemia
- Risk factor for cardiac arrhythmias
- –> hypocalcemia
- Rarely –> tetany
- –> hypomagnesemia
- Postmenopausal osteopenic women –> increased Ca excretion
- –> deleteroius effects on bone metabolism
- Rapid IV administration (& sometimes oral administration) & ethacrynic acid
- –> ototoxicity
- Tinnitus, hearing impairment, deafness, vertigo, & sense of fullness in ears
- Hearing impairment & deafness are usulaly reversible
- Other
- Hyperuricemia –> gout
- Hyperglycemia –> diabetes mellitus
19
Q
Na/Cl symport inhibitors
- Type of diuretics
- Efficacy
- Acute effects
- Chronic effects
A
- Type of diuretics
- Thiazide diuretics
- Efficacy
- Moderate b/c 90% of filterd Na is reabsorbed before reaching the DCT
- Acute effects
- Increase Na & Cl excretion in teh DCT
- Increase K & titratable acid excretion
- Dilute urine (but don’t interfere w/ ability to concentrate it)
- Chronic effects
- Decrease urica cid excretion
- Decrease Ca excretion
- Indirectly increase PT reabsorption from volume depletion
- Directly increase reabsorption in the DCT
- Magnesuria & Mg deficiency (esp in elderly)
20
Q
Therapeutic effects of thiazide diuretics (Na/Cl symport inhibitors)
- Edema
- BP
- Ca
- Urine volume
- Free water
- Beneficial characteristics
- Effect of GFR
A
- Treat edema
- Due to CHF, hepatic cirrhosis, & renal disease (nephrotic syndrome, chronic renal failure, & acute glomerulonephritis
- Decrease BP in pts w/ HTN
- Increase slope of renal pressure / natriuresis rltnshp
- Used alone or w/ other anti-HTN drugs to treat HTN
- Aditive/synergistic effects when combined w/ anti-HTN agents
- Common dose for HTN: 25 mg/day of hydrochlorothiazide
- Decrease Ca excretion
- Treat Ca nephrolithiasis & osteoporosis
- Decrease urine volume
- Treat nephrogenic diabetes insipidus
- Decrease free water excretion
- By increasing PT water reabsorption & blocking DCT’s ability to form dilute urine
- Increases urine osmolality
- Beneficial characteristics
- Inexpensive & efficacious
- Administered 1x/day & don’t require dose titration
- Well tolerated w/ few contraindications
- Effect of GFR
- Thiazide diuretics are ineffective when GFR < 30-40 ml/min
21
Q
Adverse effects of thiazide diuretics (Na/Cl symport inhibitors)
- Most serious are due to…
- Volume
- BP
- K
- Na
- Cl
- Acid/base
- Mg
- Ca
- Uric acid
- Glucose
- LDL
A
- Most serious are due to abnormal fluid & electrolyte balance
- EC volume depletion
- HoTN –> increased type II diabetes mellitus
- Hypokalemia –> hyperglycemia
- Hyponatremia
- Hypochloremia
- Metabolic alkalosis
- Hypomagnesemia
- Hypercalcemia
- Hyperuricemia
-
Hyperglycemia
- Decrease glucose intolerance –> diabetes mellitus
- Due to decreased insulin secretion & altered glucose metabolism
- Increase plasma LDL
22
Q
Na channel inhibitors
- Type of diuretics
- Effects
A
- Type of diuretics
- K sparing diuretics
- Triamterene, amiloride
- Effects
- Blocks ENAC
- Blocks Na flow from tubular lumen into principal cells
- Mildly increase Na & Cl excretion
- DT & CD have a limited capacity to reabsorb solutes
- Hyperpolarize luminal membrane
- –> decrease lumen-negative transepithelial voltage
- –> decrease K, H, Ca, & Mg excretion
- Volume contraction –> increase uric acid reabsorption in the PT
- Chronic Na channel inhibitors –> decrease uric acid excretion
- Blocks ENAC
23
Q
Therapeutic effects of K sparing diuretics (Na channel inhibitors)
- Co-administration
- Na-channel inhibitors + thiazide & loop diuretics
- Syndrome trated effectively w/ Na channel inhibitors
- Amiloride
A
- Co-administration
- Rarely used alone to treat edema or HTN due to mild natriuresis
- Major utility is in combo w/ other diuretics
- Na-channel inhibitors + thiazide & loop diuretics
- Increases diuretic & anti-HTN response
- Reduces K excretion to offset kaliuretic effects –> normal plasma K
- Syndrome trated effectively w/ Na channel inhibitors
- Liddle’s syndrome
- Amiloride
- Blocks Li transport into CD cells
- Useful for Li-induced nephrogenic diabetes insipidus
24
Q
Adverse effects of K sparing diuretics (Na channel inhibitors)
- Most dangerous
- Contraindications
- Triamterene
A
- Most dangerous
- Hyperkalemia (life-threatening)
- Contraindications
- Pts w/ or at risk for hyperkalemia
- Older, high dose therapy, renal impairment, hypoaldosteronism, & treatment w/ other drugs that impair renal K excretion (NSAIDs & ACE-Is)
- Triamterene
- Weak folic acid –> folic acid deficiency –> megaloblastosis
- Interstitial nephritis
- Renal stones
25
Q
Mineralocorticoid receptor antagonists
- Efficacy
- Effects
A
- Efficacy
- Function of endogenous aldo levels
- Higher endogenous aldo –> greater MR antagonist effects on urinary excretion
- Effects
- Similar to Na channel inhibitors
- Reduces amt of Na coming into the cell –> increases Na in urine
- Blocks excretion –> K sparing
26
Q
Therapeutic effects of mineralocorticoid receptor antagonists
- Spironolactone + thiazide & loop diuretics
- Spironolactone
- Eplerenone
A
- Spironolactone + thiazide & loop diuretics
- Increased mobilization of edema fluid + decreased K perturbations –> treat edema
- Treat HTN
- Reduces morbidity, mortality, & ventricular arrhythmias in pts w/ heart failure
- Spironolactone
- Treats primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia)
- Treats refractory edema w/ secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, & severe ascites)
- Diuretic of choice for hepatic cirrhosis
- Eplerenone
- Less used clinically than spironolactone
- Safe & effective for HTN
- Added to standard therapy for MI w/ LV systolic dysfunction
27
Q
Adverse effects of mineralocorticoid receptor antagonists
- Most serious
- Contradinications
- Due to affinity for other steroid receptors, spironolactone may cause…
- Other adverse effects of spironolactone
- Chronic or high dose adverse effects of spironolactone
- Adverse CNS effects
A
- Most serious
- Hyperkalemia (life-threatening)
- Metabolic acidosis in pts w/ cirrhosis
- Contradinications
- Pts w/ or at risk for hyperkalemia due to disease or other meds
- Due to affinity for other steroid receptors, spironolactone may cause…
- Gynecomastia
- Impotence
- Decreased libido
- Hirsutism
- Deepening of the voice
- Menstrual irregularities
- Other adverse effects of spironolactone
- Diarrhea
- Gastritis
- Gastric bleeding
- Peptic ulcers
- Chronic or high dose adverse effects of spironolactone
- Breast cancer
- Malignant tumors (rats)
- Adverse CNS effects
- Drowsiness
- Lethargy
- Ataxia
- Confusion
- Headache
29
Q
Celing dose
- Diuretic potency
- Dose response curve
- Ceiling dose
- Ceiling dose depends on…
- Factors that determine the ceiling dose
- Converting IV dosing to oral dosing
- Furosemide
- Bumetanide
- Torsemide
A
- Diuretic potency
- Quantity of Na normally reabsorbed at the diuretic target area
- Ability fo the more distal segments to reabsorb the excess Na
- Dose response curve
- Increase in Na excretion is related to rate of diuretic excretion (availability of the diuretic at the luminal site)
- Ceiling dose
- Dose that provides concs of diuretic in the tubular lumen that yield a near max (“ceiling”) effect
- Most diuretics (except MR antagonists) must gain access to the tubular lumen to be effective
- Doses > ceiling dose: increased risk of adverse effects w/o increased therapeutic response
- Dose that provides concs of diuretic in the tubular lumen that yield a near max (“ceiling”) effect
- Ceiling dose depends on…
- Diuretic
- Loop > thiazide > K-sparing
- Disease
- Diminished nephron response in nephrotic syndrome, cirrhosis, & heart failure
- Diuretic
- Factors that determine the ceiling dose
- Potency: increase potency –> decreaes dose
- Tubular transport (ex. ARF/CRF): decrease tubular transport –> increase dose
- Binding urinray proteins (ex. nephrotic syndrome): increaes binding urinary proteins –> increase dose
- Converting IV dosing to oral dosing
- Furosemide: bioavailability = 50% –> conversion factor > 2
- Bumetanide: bioavailability = 100% –> conversion factor = 1
- Torsemide: bioavailability = 100% –> conversion factor = 1
30
Q
Diuretic resistance
- Diuretic resistance
- Mechanisms of diuretic resistance
- Frequent cause
- Most popular sequential blockade
- Frequent dosing or continuous infusion to overcome diuretic resistance
A
- Diuretic resistance
- The response to a diuretic is inadequate to provide the desired level of therapeutic response (edema resolution)
- Mechanisms of diuretic resistance
- Noncompliance –> pt counseling
- NSAIDs –> pt counseling
- Decreased tubular transport (ex. ARF, CRF) –> push to ceiling dose
- Decreased RBF –> bed rest
- Changes in volume hormones (SNS, RAS, ADH, ANF) –> bed rest
- Compensation by distal nephron –> combination therapy (sequential blockade)
- Diminished nephron response (CHF, cirrhosis, nephrotic syndrome) –> more frquent dosing or continuous infusion
- Frequent cause: compensation by distal epithelial cells when proximal transport is inhibited
- Ex. urinary excretion of Na may be adequate initially w/ a loop diuretic
- Eventually the distal epitehlial cells undergo hypertrophy & express more transporters
- Epithelial cells caputre more proximal “rejectate”
- Na excretion becomes inadequate
- Overcome by sequential blockade (combination therapy)
- Use of _>_2 diuretics to inhibit transport in >1 nephron sit
- Ex. urinary excretion of Na may be adequate initially w/ a loop diuretic
- Most popular sequential blockade
- Loop diuretic (blocks LOH) + thiazide diuretic (blocks DT)
- Frequent dosing or continuous infusion to overcome diuretic resistance
- More frequent dosing provides ceiling concs in the tubular lumen for a higher % of the day
- Continuous infusion provides ceiling concs of diuretic throughout the day
31
Q
Postdiuresis Na retention
- Postdiuresis Na retention
- High salt diet
- Low salt diet
- Take home
- Drug interactions
- NSADS, salt decongestants, & probenecid
- ACE-Is, beta-blockers, K supplements, K sparing diuretics, & heparin
- Ototoxic drugs
A
- Postdiuresis Na retention
- Limits diuretic efficacy
- Occurs after a high dose of diuretic during the time that transport is sub-maximally inhibited
- Loss of Na –> kidneys retain Na
- High salt diet
- Increase in Na excretion during first 6 hours after diuretic administration is completely offset by a reduction in Na excretion during the next 18 hours
- Low salt diet
- Postdiuresis Na retention is blocked
- Take home
- Diuretics are more effective in reducing bodoy Na when pts are on a los-salt diet
- Salt restriction attenuates the postdiuretic Na retention phenomenon
- Drug interactions
- NSADS, salt decongestants, & probenecid
- Diminished diuretic response
- ACE-Is, beta-blockers, K supplements, K sparing diuretics, & heparin
- Hyperkalemia
- Ototoxic drugs
- Enhanced ototoxicity of loop diuretics
- NSADS, salt decongestants, & probenecid
