Drugs which affect the kidney - diuretic agents Flashcards
List the drugs that can affect the kidney
ACE inhibitors
Anticancer drugs
Antiviral agents
Aminoglycosides
Beta blockers
Lithium
NSAIDs
Radiocontrast media
Vasodilators
What are the 3 types of AKI?
- pre-renal (due to blood loss)
- intrinsic (Nephrotoxic AKI)
- post-renal (due to blockage)
What is a diuretic?
- Any compound that causes the excretion of an increased volume of urine from the body
- More accurate: a drug that increases the excretion of both fluids (water) and solutes (e.g. sodium [Na+])
- Natriuretic:
- Kaliuretic:
- Natriuretic: increases Na+ excretion
- Kaliuretic: increases K+ excretion
What are the 2 ways diuretics can work?
•Most Diuretics increase excretion of Na+ and water by the kidneys
1) They reduce reabsorption of Na+ from the filtrate
2) Increased water loss is secondary to Na+ excretion
Some new diuretics can increase urine excretion without increasing Na+ excretion – these are starting to be called “aquaretic ” agents
What are the 2 modes of action of diuretics?
1) Direct action on the cells of the nephron (more common)
2) Modification of content of the filtrate
What are the 2 major applications of diuretics?
1) Reduce circulating fluid volume
2) Removal of excess body fluid (oedema)
What conditions are diuretics used for?
- hypertension
- chronic heart failure
- liver cirrhosis
- renal disease
- premenstrual oedema
- toxic oedema
- increase elimination of drugs
- rapid weight loss (abuse)
Other actions
- glaucoma
(reduces intra-ocular pressure)
- epilepsy
(reduces pressure of CSF?)
What is the relationship between water and sodium?
“Water generally follows sodium out of the kidney”
Complete the table
What are the most effective diuretics available?
Loop diuretics
What are loop diuretics also known as?
Often called ‘high-ceiling diuretics’: lead to ‘torrential urine flow’
How do loop diuretics work?
- Inhibit the Na+/K+/2Cl- transporters (NKCC2) in the thick ascending limb of the loop of Henle: this reduces reabsorption of Na+, K+ and Cl-
- Reduced Na+ reabsorption leads to rapid and profound diuresis
Loop diuretics cause increased Na+ delivery to the distal tubule - more Na+ in urine from reduced reabsorption means more exchange for K+
Na+ is exchanged for K+ in the DT which is excreted in the urine - more Na+ excreted -> more K+ excreted
This K+ loss contributes to the hypokalaemia associated with loop diuretics
•Single dose dose of loop diuretics can increase urine volume from ____ to _____ ml over 3 h…
•Single dose: can increase urine volume from 200 to 1,200 ml over 3 h…
What are the clinical uses of loop diuretics?
What are the unwanted effects of loop diuretics?
- Dehydration
- K+ loss leading to low plasma K+ (hypokalaemia)
- Metabolic alkalosis (due to H+ loss in urine)
- Hypokalaemia can potentiate effects of cardiac glycosides
- Deafness (when used with aminoglycoside antibiotics)
How do thiazide diuretics work?
•Act in the distal tubule to inhibit the apical Na+/Cl- co-transporter
How effective are thiazide diuretics?
- Cause moderate but sustained Na+ excretion with increased water excretion
- Moderately powerful diuresis: but maximum diuresis produced is considerably lower than that produced by loop diuretics
- Well absorbed from GI tract and long duration of action: up to 24 h
What are the main thiazides used?
- Prototype is hydrochlorothiazide (HydroSaluric®)
- Main thiazide is bendroflumethiazide (bendrofluazide)(Neo-NaClex®, Aprinox®) – useful for mild/moderate heart failure
List some other thiazides
What are thiazide-like diuretics?
HT - hypertension
What are the clinical uses of thiazide diuretics?
What are the unwanted effects of thiazide diuretics?
- Plasma K+ depletion (due to urinary K+ loss)
- Metabolic alkalosis (due to urinary H+ loss)
- Increased plasma uric acid – gout
- Hyperglycaemia (increased blood glucose)
- Increased plasma cholesterol (with long-term use)
- Male impotence (reversible)
What is indapamide?
•INDAPAMIDE: currently preferred diuretic for resistant hypertension due to lower incidence of unwanted effects, e.g. hyperglycaemia
How does thiazide diuretics cause hyperkalaemia?
•Due to increased loss of K+ in the urine, loop diuretics and thiazides can cause hypokalaemia (decreased plasma K+)
- this is an unwanted effect:
What are the symptoms of mild and severe hypokalaemia?
Mild hypokalaemia
- fatigue, drowsiness, dizziness, muscle weakness
Severe hypokalaemia
- abnormal heart rhythm, muscle paralysis, death
What are pottasium sparing diuretics?
•Potassium-sparing diuretics can avoid hyperkalaemia
- Act on distal tubules to inhibit Na+ reabsorption
- However, K+ is not secreted into the distal tubule
What are the 2 subcatagories of pottasium sparing diuretics?
–Aldosterone antagonists (e.g. eplerenone, spironolactone)
–Non-Aldosterone antagonists (e.g. amiloride, triamterene)
How do pottasium sparing diuretics work?
- Spironolactone metabolised to canrenone (its active metabolite)
- A competitive antagonist of aldosterone (mineralocorticoid) receptor
- Reduces Na+ channel formation and its absorption from distal tubule
How effective are pottasium sparing diuretics?
- Limited diuretic action (not as potent as loop diuretics or thiazides)
- As mechanism depends on reduction of protein expression in distal tubular cells, effects normally take several days to develop
Name the 2 types of pottasium sparing diuretics
Spironolactone and Eplerenone
Triamterene and Amiloride
What are the clinical uses of Spironolactone and Eplerenone?
Can also be used for resistant hypertension but some concerns over long-term use due to possible incidence of cancer (note: reported in rat studies only)
What are the unwanted effects of Spironolactone and Eplerenone?
- Hyperkalaemia (increased plasma K+ levels) – needs to be monitored regularly
- Metabolic acidosis (due to increased plasma H+)
- GI upsets (peptic ulceration reported)
- Gynaecomastia, menstrual disorders, testicular atrophy
- Eplerenone produces less unwanted effects than spironolactone
How do Triamterene and Amiloride work?
•Blocks luminal Na+ channel by which aldosterone produces its main effects
How effective are Triamterene and Amiloride?
- Weak diuretics - act on distal tubule to inhibit Na+ reabsorption and decrease K+ excretion
- Of little therapeutic use alone but are useful in combination with potassium-depleting diuretics as they limit hypokalaemia
What are the unwanted effects of Triamterene and Amiloride?
•Main unwanted effect: hyperkalaemia, but also metabolic acidosis, GI disturbances, skin rashes
Why use diuretics in combination?
(1) To increase diuretic effect
Some patients do not respond well to just one type of diuretic
(e.g. loop diuretics) – reasons unknown, probably genetic
Combinations of diuretics with different sites of action can sometimes provide a synergistic action…this can become complicated…
(2) To avoid the unwanted effects of hypokalaemia
To avoid hypokalaemia (reduced plasma K+ levels) the following can be used:
- Combinations of loop diuretics or thiazides with potassium-sparing diuretics
- Diuretic preparations containing K+…….
Which diuretic combinations can be used to limit hypokalaemia?
Loop diuretics with spironolactone - Lasilactone®: furosemide + spironolactone
Loop diuretics with amiloride or triamterene - Co-amilofruse: furosemide + amiloride
Thiazides with spironolactone - Co-flumactone: hydroflumethiazide + spironolactone
Thiazides with amiloride or triamterene - Co-amilozide: hydrochlorothiazide + amiloride
Which diuretics contain K+?
How do carbonic anhydrase inhibitors work?
Main example is azetozolamide (Diamox®)
- Blocks sodium bicarbonate (NaHCO3) reabsorption in the PT
- These were the earliest diuretic agents developed
- Causes only weak diuresis so not now commonly used as diuretic agent
What are carbonic anhydrase inhibitors used for?
•Used for treatment of
- glaucoma (reduces intraoccular pressure)
- epilepsy (reduces volume and pressure of CSF)
What are the unwanted effects of carbonic anhydrase inhibitors?
•Unwanted effects
- metabolic acidosis (due to excretion of HCO3-)
- enhances renal stone formation (due to alkaline urine)
How do osmostic diuretics work?
Main example is mannitol
- Non-reabsorbable solute which undergoes glomerular filtration
- Excreted within 30-60 min
- Diuresis begins in 30-60 min and persists for 6-8 h
What are the clinical uses of osmotic diuretics?
- Treatment of raised intercranial pressure (cerebral oedema)
- Treatment of intraoccular pressure (glaucoma)
- If given orally, can cause ‘osmotic diarrhoea’ – eliminates toxins
- May be useful for treatment of acute renal failure
What are the unwanted effects of osmotic diuretics?
Unwanted effects
•Presence in blood also exerts osmotic pressure leading to increased plasma volume…
…so they can’t be used in patients with hypertension
How does ADH and water work as a diuretic?
- Under normal conditions, increased water intake leads to increase in volume of urine excreted
- Process is controlled by a hormone: antidiuretic hormone (ADH)
- Most important hormone regulating water balance
- Normally some ADH is present in the circulation, maintaining urine volume at approximately 1.5 L/day
- However, this can be adjusted in various ways…e.g. effects of alcohol, nicotine
How does increased fluid intake cause diuresis?
Increased fluid intake leads to reduced secretion of ADH from the posterior pituitary due to reduced in plasma osmolality
Reduced levels of ADH
Reduced expression of AQP2 channels
Reduced expression of AQP2 receptors on apical surface of DT and collecting duct cells means more water excretion
Note – there is no increased excretion of Na+ - the AQP2 channel moves water only
What are ADH antagonists?
- Investigational drugs which inhibit the effects of ADH at the collecting tubule
- Two nonselective agents (orally active)
- Lithium (Li+) and demeclocycline. Also Amphotericin B
How can ADH antagonists cause toxicity?
1) Can cause diabetes insipidus
2) Renal failure reported for both Li+ and demeclocycline
3) Li+ can cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction and leukocytosis
4) Demeclocycline shouldn’t be used in patients with liver disease
What ADH antagonist is in clinical trials for polycystic kidney disease?
Tolvaptan (OPC-41061) – V2 receptor antagonist, approved in US (as “Samsca” or “Jinarc”) for treatment of hyponatriuraemia – ¯ECV leads to plasma [Na+]
In fast track clinical trials for polycystic kidney disease. Not a potent diuretic
Agents which inhibit ADH release and therefore,
increase urine excretion:
–Alcohol
(although tolerance develops rapidly so diuresis not sustained)
Agents which increase ADH release and therefore,
reduce urine excretion:
–Nicotine (anecdotal evidence)
–Ether
–Morphine
–Barbiturates
What are xanthines?
§Examples: caffeine, theophylline, theobromine
§Commonly found in tea and coffee
How do xanthines work?
§Produce their weak diuretic effect by increasing cardiac output
§Possibly also some vasodilatation of the glomerular afferent arteriole
§Results in increased renal and glomerular blood flow which increases glomerular filtration rate and urine output
§Rarely used clinically due to gastric irritant effects
(but theophylline used clinically as a bronchodilator for asthma)
