Diuretics Flashcards
Conditions that promote the development of edema
Altered blood circulation (inc arterial or venous pressure)
Altered blood composition (dec osmotic gradient, salt and water retention)
Inadequate lymphatic drainage
Diseases often associated with edema
HF
Hepatic cirrhosis
Nephritis, nephrosis, renal damage due to HTN
Diseases involving increased steroid hormone secretion
Pre-eclampsia, toxemia
Hypersensitivity reactions (anaphylaxis)
_____% of all fluid filtered by the glomerulus is reabsorbed
> 99%
Anything <43kD is filtered
_____% of Na+ is reabsorbed in the proximal tubule
65%
H+ and Na+ via active transport - NaK ATPase
What diuretics work in the proximal tubule?
Acetazolamide (diamox)
Osmotic diuretics
What occurs in the loop of Henle?
Passive H2O reabsorption —> concentration of urine
NOTE - the loop of Henle is thinner b/c this portions need lots of mitochondria to produce energy for ACTIVE transport
What diuretics work on the loop of Henle?
Osmotic diuretics
What exchanges occur in the thick ascending limb of LOH?
Active reabsorption of K+, 2Cl-, Na+
Passive reabsorption of K+, Ca2+, Mg2+, Na+
25% of Na+ is reabsorbed here, but no H2O
What diuretics work on the thick ascending limb of LOH?
LOOP diuretics
What occurs in the early distal tubule?
Reabsorption of NaCl (not H2O) by active transport
4-8% of total Na+ reabsorption occurs here
What diuretics work in the early distal tubule?
Thiazides
What occurs in the late distal tubule?
Ca2+ reabsorption
What occurs in the collecting duct?
K+ and H+ excretion (via Na+/K+ and Na+/H+ exchange)
NaCl reabsorption by aldosterone
H2O reabsorption by ADH
Some K+ and H+ independent of aldosterone
What diuretics work on the collecting duct?
Aldosterone antagonists (by inhibiting NaCl reabsorption)
ADH antagonists (by inhibiting H2O reabsorption)
Osmotic diuretics
Where does potassium reabsorption and secretion occur?
Reabsorption in proximal tubule (CANNOT be influenced by drugs)
Secretion in late distal tubule and collecting duct
• Exchange of Na+ with K+, with or w/o aldosterone
• Can be modified by aldosterone antagonists and K+ sparing diuretics
What affects reabsorption of Calcium and Magnesium occur?
Thiazides diuretics —> increase Ca2+ reabsorption
Loop diuretics —> increased Ca2+ and Mg2+ excretion
The rate of diffusion of organic compounds depends upon…
Lipid solubility, pKa, and pH
Weak acids at low pH will remain mostly unionized (lipid soluble) and are easily diffusible across the epithelium and vice-versa
What do we need to know about uric acid?
It’s secreted and reabsorbed by carrier dependent mechanisms
ACID DRUGS will compete for uric acid excretion —> gouty attack
What drugs are carbonic anhydrase inhibitors?
Acetazolamide (Diamox)
Dorzolamide (Truspot)
Brinzolamide (Azopt)
MOA for carbonic anhydrase inhibitors
Inhibits carbonic anhydrase enzyme
Blocks H2CO3 production
Decreases H+ for exchange with Na+, resulting in increased Na+ and H2O loss
What are the indications for carbonic anhydrase inhibitors?
GLAUCOMA (that’s why two of the drugs are eye drops) —> inhibition of bicarbonate transport in the eye and the chorionic plexus —> decreased aqueous humor and CSF
Alkalinization of the urine
Metabolic ALKALOSIS due to acute mountain sickness
Why are CA inhibitors not used as a regular diuretic?
Their effectiveness decreases after several days b/c metabolism —> build up of H+
Adverse effects of CA inhibitors
HYPERCHLOREMIC METABOLIC ACIDOSIS b/c the Na+ is in the form of NaHCO3 and not NaCl
Hypokalemia (b/c inc Na+ in lumen —> inc Na+/K+ exchange in DCT)
Renal stones (b/c inc PO4 and Ca2+ in urine)
HYPERURICEMIA b/c they are acids and compete for uric acid excretion
Contraindications for CA inhibitors
Hepatic cirrhosis (from dec ammonia excretion)
Sulfa hypersensitivity
What drugs are Loop Diuretics?
Furosemide (Lasix)
Bumetanide
Torsemide
Ethacrynic acid
MOA for Loops
Block the NaK2Cl co-transporter** —> inc Na+ in lumen =—> diuresis
Induce kidney prostaglandins —> reduced salt transport in kidney and VASODILATION
Loops still work for diuresis in patients with _______ when other diuretics will not
Low GFR
Indications for Loops
HF (b/c they move large amounts of water)
PULMONARY EDEMA - relieves pulmonary congestion by increasing systemic venous capacitance
Severe refractory peripheral edema
HYPERCALCEMIA (b/c dec reabsorption of Mg2+ and Ca2+ by reducing K+ gradient)
Pharmacokinetics of loops
Oral or parenteral (for faster action)
Renal excretion
Adverse effects of Loops
High potency —> electrolyte imbalance
HYPOKALEMIC METABOLIC ALKALOSIS (b/c induces K+ and H+ loss at the DCT)
Hypochloremia
HYPOCALCEMIA
HYPOMAGNESESMIA
HYPERURICEMIA
GI upset
IRREVERSIBLE OTOTOXICITY
All looks are ototoxic but ______ is the worst
Ethacrynic acid
Ototoxic effects of loops are worse when given concurrently with…
Aminoglycosides
Contraindications for Loops
SULFA hypersensitivity (EXCEPT ETHACRYNIC ACID)
Drug interactions
• COX inhibitors interfere with its action
• Aminoglycosides (ototoxicity)
• Lithium (loss of Na+ increases Li+ retention —> toxicity)
• Digoxin (loss of K+ —> toxicity)
Overzealous use is dangerous in • Hepatic cirrhosis • Borderline renal failure • HF (We use them still but very carefully)
What makes Ethacrynic acid special?
MOA the same and adverse effects are similar to Lasix BUT
It’s not a sulfonamide so it can be used in pt with sulfa allergy
It has the highest risk of ototoxicity
What drugs are thiazides diuretics?
Hydrochlorothiazide***
Chlorothiazide
Related compounds: Chlorthalidone Metolazone Quinethazone Indapamide
Which diuretics are the most widely used?
Thiazides
MOA for thiazides
Inhibition of sodium resorption at the early distal tubule via inhibition of the Na-Cl cotransporter
Effect is dependent on PG synthesis
Main clinical indications for thiazides
HYPERTENSION
HF (not as effective at reducing edema as loops but can start them on a loop and then switch to HCTZ for maintenance)
Nephrolithiasis
Nephrogenic diabetes insipidus
What are the beneficial and adverse effects of the ATP-dependent K+ channels opened by thiazides —> hyperpolarization of cell membranes
Beneficial: relaxation of smooth muscle cells —> VASODILATION
Adverse: REDUCED INSULIN SECRETION
What are the indications for Thiazides?
Lower systemic BP and enhance the anti-HTN action of other drugs (ACE-I, ARBs, ß-blockers)
Decrease Ca2+ excretion by increasing activity of PTH-dependent Ca2+ channels (not b/c of PTH but b/c inc luminal Na+)
NOT effective in osteoporosis
May be beneficial in renal calculosis
What’s special about thiazide pharmacokinetics?
Oral, well-absorbed
Secreted by the organic acid secreting system —> COMPETES WITH URIC ACID
How is Chlorthalidone different from other thiazides?
Slowly absorbed, therefore appears to have longer duration
Therefore PREFERRED b/c it has the best pharmacokinetics of the class
How is Indapamide different from other thiazides?
Excreted by the biliary system, therefore is useful in patients with RENAL INSUFFICIENCY
Adverse effects of thiazides
Dizziness, weakness, fatigue, leg cramps common
HYPOKALEMIC METABOLIC ALKALOSIS*** b/c of K+ and H+ loss at the DCT
HYPERURICEMIA***
MAGNESIUM LOSS
Iodide and Bromide loss
HYPERGLYCEMIA*** May dec release of insulin and inc glucose intolerance
ELEVATED SERUM LIPID LEVELS
Which thiazide is the exception to the rule of thiazides increasing serum lipid levels?
Indapamide
Contraindications of thiazides
SULFA HYPERSENSITIVY (may be inhibited by NSAIDs)
HYPOKALEMIA can precipitate digitalis toxicity (arrhythmias) and hepatic coma in CIRRHOTIC patients
HYPERGLYCEMIA and carb intolerance may occur in DIABETICS
HYPERURICEMIA so don’t give to someone with GOUT
HYPONATREMIA if too hydrated
HYPERCALCEMIA with latent primary HYPERPARATHYROIDISM
LITHIUM TOXICITY b/c Li clearance reduced
What is unique about Metolazone
Able to produce diuresis in patients with a reduced GFR
Loop diuretics can work at low GFR but most thiazides don’t, except METOLAZONE
What is unique about Indapamide?
3 major differences from other thiazides:
- Causes pronounced vasodilation (Ca2+ channel blocker)
- DOES NOT increase plasma lipids**
- Metabolized in the liver and kidney 50/50**
What are the two classes of potassium sparing diuretics?
Aldosterone antagonists
Direct inhibitors of Na+ flux
How do potassium sparing diuretics work in general?
Interfere with Na+ reabsorption at the distal exchange site —> permits loss of Na+ and H2O and cause conservation of K+
WEAK diuretics compared to thiazides/loops
Reduce K+ loss and alkalosis by other diuretics
Used IN COMBO with other K+ losing drugs
MOA for Aldosterone Antagonists
Competitive inhibition of aldosterone
High doses —> inhibits glucocorticoid and sex hormone receptors
Aldosterone inhibition promotes the excretion of Na+ and retention of K+ at the DCT
• Less Na+ channels, blocked Na+ conductance, reduced K+ excretion
What is the prototype aldosterone antagonist?
Spironolactone
What are the indication for Spironolactone?
Edema associated with HF, cirrhosis, and nephrotic syndrome (in combo)
Most effective drug for treating HYPERALDOSTERONISM
HIRSUTISM (androgen receptor antagonist)
Adverse effects of spironolactone
GYNECOMASTIA (b/c androgen receptor antagonist)
Occasional HYPERKALEMIA (usually only when in combo) • Use with caution with ACE/ARBs
Contraindications for Spironolactone
Hyperkalemia (burn patients)
Chronic renal insufficiency
Liver damage, hyperchloremic acidosis may occur in these patients
How is Eplerenone (Inspra) different from Spironolactone?
Selective aldosterone receptor antagonist
Has the same effects as Spironolactone except…
Decreased endocrine related side effects (NO MAN BOOBS)
Metabolized by CYP3A4 —> drug interactions
What is the MOA for Amiloride and Triamterene?
Inhibit the Na+/K+ ion exchange mechanism INDEPENDENT OF ALDOSTERONE by directly inhibiting the aldosterone-sensitive Na+ channel
Leads to a decreased K+ excretion
Indications for Amiloride/Triamterene
Combo with K+ losing diuretics (weak diuretic effect on their own)
NO HYPERURICEMIA b/c they are not acids*** The only diuretic class that are not
DOC for Li+ induced diabetes insipidus
Amiloride
Adverse effects of potassium sparing diuretics
HYPERKALEMIA in chronic use or combo with other potassium sparing agents
In whom are potassium sparing diuretics contraindicated
Burn patients (b/c prone to hyperkalemia)
Examples of Osmotic diuretics
Mannitol
Isosorbide
Glycerin
Urea
***All are IV only (give diarrhea if given orally)
MOA for osmotic diuretics
Keeps water in the tubules
Produce water diuresis (not dependent upon sodium)
Indications for Osmotic Diuretics
IV ONLY - very specialized use
Prophylaxis for ACUTE RENAL FAILURE
Reduce intraocular pressure prior to eye surgery
Reduce intracranial pressure in pt with brain edema
Protect kidney against nephrotoxic substances
Adverse effects of osmotic diuretics
HA, N/V***, chills, dizziness, polydipsia, lethargy, confusion, chest pain (basically dehydration symptoms)
Excessive administration —> extracellular volume expansion**
PULMONARY EDEMA IN HF (CONTRAINDICATION)
EXCESSIVE CELLULAR DEHYDRATION
Tell me all there is to know about Desmopressin
Synthetic ADH
Activates V2»V1 receptors
Used to treat CENTRAL DIABETES INSIPIDUS
Acts to decrease H2O excretion
Can be given Oral, IV, SC, or intranasal
Side fx:
• GI, HA, Allergy, HYPOnatremia
What drugs are ADH antagonists?
Conivaptan***
Tolvaptan
Demeclocycline (FYI - for SIADH)
Lithium (FY)
What’s special about Conivaptan?
IV ONLY
Adverse effects:
• HYPOKALEMIA
• Injection site rxn
• Orthostatic hypotension, a fib, hypotension
Contraindications:
Hyponatremia associated with HYPOVOLEMIA
How is Tolvaptan different from Conivaptan?
Non-peptide V2 vasopressin receptor antagonist
Administered orally
Initiated and re-initiated in a hospital and then continued on an outpatient basis
What happens when you combine loops and thiazides?
May produce diuresis when none of them is effective alone
What happens when you combine potassium sparing diuretics and loops or thiazides?
May balance out potassium losses
Put the diuretics in order of maximum diuretic effect
Loop»_space; thiazides»_space; [CA inhibitors] > K+ sparing
**CA inhibitors only work for a few days
