Diuretics Flashcards
What are the different functions of the kidneys?
REGULATORY
- fluid balance
- acid-base balance
- electrolytes
EXCRETORY
- waste products
- drug elimination (glomerular filtration and tubular secretion)
ENDOCRINE
- RAAS
- EPO
- prostaglandins
METABOLISM
- vitamin D
- insulin
- PTH
note: angiotensin is made in the liver
Outline the different sites of actions of different diuretics.
Carbonic anhydrase inhibitors (PCT)
- prevents H+ to combine with HCO3- to form water
Osmotic diuretics (PCT & loop of Henle) - cause increased osmolarity of filtrate to cause water loss
Loop diuretics (thick ascending limb of loop of Henle) - inhibits NKCC2
Thiazide-like diuretics (DCT)
- inhibit NaCl transporter
Amiloride inhibits ENaC (DCT and cortical collecting duct)
Spironolactone inhibits aldosterone (usually stimulates ENaC in cortical collecting duct)
ADH antagonists
Describe the mechanism of action of carbonic anhydrase inhibitors. When are they indicated? Give some examples of ADRs associated with their use.
e.g. acetazolamide
Act at PCT
Inhibit HCO3- reabsorption —> accumulation of HCO3- in lumen —–> inhibits NHE (provides H+ to react with HCO3- to form water) —> reduced Na+ reabsorption
Indications:
- glaucoma
- cystinuria
- increased uric acid excretion
- metabolic alkalosis
ADRs (increased [Cl-]blood): - metabolic acidosis - kidney stones - drowsiness - paraesthesia \+ fever, rash, interstitial nephritis
Describe the mechanism of action of osmotic diuretics. When are they indicated? Give some examples of ADRs associated with their use.
e.g. mannitol
Loop of Henle and PCT (most permeable to water)
Increase osmolarity of plasma and tubular fluid —> reduced water reabsorption
Indications:
- increased urine volume in acute renal failure caused by ischaemia, nephrotoxins, haemoglobinuria, and myoglobinuria
- increased intracranial pressure e.g. after head trauma (whilst waiting for other treatment)
- increased intraocular pressure e.g. acute glaucoma
ADRs:
- dehydration
- relative hypernatraemia
- hyponatraemia (due to expansion of ECF) —> N&V, headache
- pulmonary oedema (in congestive heart failure)
Describe the mechanism of action of loop diuretics. When are they indicated? Give some examples of ADRs associated with their use.
e.g. furosemide, bumetanide
Act at thick ascending limb of loop of Henle
Inhibit NKCC2 symporter —> reduced NaCl reabsorption
(+ reduced calcium and magnesium reabsorption; as NKCC2 generates positive lumen potential which drives Ca2+ & Mg2+ reabsorption)
+ increases renal blood flow and systemic venous capacitance (probably via prostaglandins)
Indications:
- acute pulmonary oedema
- chronic congestive heart failure (to reduce venous and pulmonary oedema)
- hypertension
- hypercalcaemia
- hyperkalaemia (+ isotonic NaCl saline)
- acute renal failure (increase urine flow and K+ secretion)
- ascites (IV due to reduced gut absorption)
- peripheral oedema (IV due to reduced gut absorption)
ADRs:
- hypokalaemic metabolic alkalosis
- ototoxicity (furosemide)
- hypomagnesaemia
- allergic
- myalgia (bumetanide)
Describe the mechanism of action of thiazide(like) diuretics. When are they indicated? Give some examples of ADRs associated with their use.
e.g. HCTZ, bendroflumethiazide
Act at DCT
Inhibit NaCl symporter —> reduced NaCl reabsorption
Indications:
- hypertension (inc. isolated systolic hypertension; HCTZ + amiloride treats hypertension with no effect on K+ or glucose)
- oedema in congestive heart failure, cirrhosis, and renal disease
- kidney stones due to hypercalcaemia
- nephrogenic diabetes insipidus
- heart failure
ADRs (water and electrolyte imbalances):
- hypokalaemic metabolic alkalosis
- hyperuricaemia —> gout
- hyponatraemia
- reduced glucose tolerance
- hyperglycaemia
- hyperlipidaemia
- CNS symptoms
- impotence/erectile dysfunction
note: flat dose-BP response curve, therefore can give a low dose to reduce ADRs whilst maintaining efficacy
note: increases Ca2+ reabsorption in DCT (inhibit Na+ entry increases NCE activity - reverses?)
What is the mechanism of action of diuretics which inhibit sodium channels? When are they indicated? Give some examples of ADRs associated with their use.
e.g. amiloride
Act at DCT and cortical collecting duct
Inhibit ENaC
- –> reduced Na+ reabsorption
- –> reduced K+ secretion (POTASSIUM SPARING)
- –> reduced H+ secretion (ENaC establishes negative lumen potential which drives K+ and H+ secretion)
Indications:
- prevent hypokalaemia by combining with other diuretics
- Liddle’s syndrome (hyperaldosteronism)
- lithium-induced nephrogenic diabetes insipidus
- improve mucociliary clearance in cystic fibrosis (inhibits Na+ channel in resp. epithelium)
ADRs:
- hyperkalaemia
- N&V
- headache
What is the mechanism of action of aldosterone antagonists? When are they indicated? Give some examples of ADRs associated with their use.
e.g. spironolactone, eplerenone
Acts at cortical collecting duct
Competitive antagonist of aldosterone —> reduced expression of ENaC channels —> reduced Na+ reabsorption
note: has long duration of action (t1/2 = ~18hrs) as metabolite is also active
Indications:
- oedema (in combination with loop/thiazide diuretics)
- hypertension (in combination with loop/thiazide diuretics)
- primary hyperaldosteronism (e.g. adrenal adenomas)
- oedema of secondary hyperaldosteronism (e.g. heart failure, cirrhosis, nephrotic syndrome)
ADRs:
- hyperkalaemia
- metabolic acidosis in cirrhosis
- painful gynaecomastia
- impotence
- hirsutism
- CNS symptoms
note: spironolactone has androgenic cross-reactivity but eplerenone does not (but only licensed as an alternative to spironolactone in heart failure)
Give some examples of drugs which act as diuretics by antagonising ADH.
Lithium
Demeclocycline
What effect does digoxin have on the nephron? When might digoxin be prescribed?
Inhibits tubular Na+/K+-ATPase (reverses NCE?)
AF, heart failure
Give some examples of important drug-drug interactions with diuretics.
ACE inhibitors + potassium sparing diuretics (e.g. spironolactone, amiloride)
= increased risk of hyperkalaemia —> arrhythmias
Aminoglycosides + loop diuretics
= ototoxicity, nephrotoxicity
Digoxin + loop/thiazide diuretics
= hypokalaemia —> increased digoxin binding and toxicity
Beta-blockers + thiazide diuretics
= hyperglycaemia, hyperlipidaemia, hyperuricaemia
Steroids + loop/thiazide diuretics
= increased risk of hypokalaemia
Carbamazepine + thiazide diuretics
= increased risk of hyponatraemia
Give some examples of causes of diuretic resistance.
Incomplete treatment of primary disorder
Continued high Na+ intake
Non-adherence
Poor absorption e.g. oedematous gut (IV diuretic req.)
Volume depletion
- –> reduced filtration of diuretics
- –> increased serum aldosterone —> increased Na+ reabsorption
NSAIDs —> reduced renal blood flow
Outline the pharmacological management of heart failure.
- loop diuretics
- add on thiazide diuretics
- spironolactone (reduce aldosterone to prevent extracellular matrix deposition and hyperkalaemia)
- ACE inhibitors/angiotensin II receptor antagonists
- beta-blockers (use with caution as the failing myocardium is dependent on heart rate; therefore initiate at low dose and titrate up)
Outline the pharmacological management of hypertension.
- thiazide(like) diuretics
- spironolactone
- loop diuretics
- ACE inhibitors/angiotensin II receptor antagonists
- beta-blockers (reduced sympathetic drive —> reduced risk of arrhythmias and sudden death)
- calcium channel blockers
note: as long as BP is lowered it doesn’t matter what drug is used
What diuretics are indicated in decompensated liver disease? What are they used for?
Spironolactone (high dose)
+ add-on loop diuretics
Reduced albumin —> reduced circulating volume —> increased aldosterone —> water retention —> increased circulating volume —-> ascites and oedema
