T3 L6 Drugs which affect the kidney Flashcards
What type of drugs affect the kidneys?
ACE inhibitors Anticancer drugs Antiviral agents Aminoglycosides Beta blockers Lithium NSAIDs Radiocontrast media Vasodilators
What are the 3 types of acute kidney injury?
Pre-renal due to blood loss
Intrinsic
Post-renal due to bloackage
What is a diuretic?
Drug that increases the excretion of both fluids and solutes
What does a natriuretic do?
Increases sodium excretion
What does a kaliuretic do?
Increases potassium excretion
What are aquatic agents?
Increase urine excretion without increasing sodium excretion
What are the 2 main applications to use diuretics?
Reduce circulating fluid volume
Remove excess body fluid (oedema)
What are the reasons to use diuretics for their actions on the kidneys?
Hypertension Chronic heart failure Liver cirrhosis Renal diseases Premenstrual oedema Toxic oedema Increase elimination of drugs Rapid weight loss
What other conditions are diuretics used in?
Glaucoma to reduce intra-occular pressure
Epilepsy to reduce the pressure of CSF
What are the classes of diuretic agents?
Carbonic anhydrase inhibitors Osmotic diuretics Loop diuretics Thiazide & thiazide-like diuretics Potassium-sparing diuretics
Where do carbonic anhydrase inhibitors act?
On the proximal tubule
Old diuretics & aren’t used for hypertension anymore
Where do osmotic diuretics act?
Proximal tubule
Descending loop of Henle
Where do loop diuretics act?
Ascending loop of Henle
Where do thiazide & thiazide-like diuretics act?
Early distal tubule to inhibit apical Na+/Cl- cotransporter
Where do potassium sparing diuretics act?
Late distal tubule
Early collecting tubule
What diuretics can cause hypokalaemia?
Loop
Thiazide
Thiazide-like
Cause you to excrete more potassium
What is the mechanism of loop diuretics?
Inhibit Na+/K+/2Cl- transporters (NKCC2) in thick ascending limb of loop of henle
Reduces reabsorption of Na+, K+ & Cl-
Reduced Na+ reabsorption leads to rapid & profound diuresis
How do loop diuretics cause hypokalaemia?
Increased delivery of sodium to distal tubule
Na+ exchanged for K+ in the distal tubule
Excreted in urine
How much increase in urine volume can a single dose of loop diuretics cause?
Increase urine volume from 200ml to 1200ml over 3 hours
Give an example of a loop diuretic
Furosemide
Bumetanide
Torasemide
Ethacrynic acid - not on market due to hepatic toxicity
What type of diuretic is furosemide?
Loop diuretic
Describe the dosing of furosemide
Oral absorption - diuresis in 60 min. Last for 4-6 hours
IV administration - diuresis in 5 min. Lasts for 2 hours
IM administration - diuresis in 30 min
What are some clinical uses of loop diuretics?
Acute pulmonary oedema Chronic heart failure Cirrhosis of the liver Resistant hypertension Nephrotic syndrome Acute renal failure
What are the unwanted effects of loop diuretics?
Dehydration
Hypokalaemia - can potentiate effects of cardiac glycosides
Metabolic alkalosis - due to H+ loss in urine
Deafness if used with aminoglycoside antibiotic
What do thiazide diuretics do?
Cause moderated by sustained Na+ excretion with increased water excretion
Moderately powerful diuresis - lower than what is produced by loop diuretics
Well absorbed from GI tract
Long duration of action - up to 24h
What is the main thiazide diuretic?
Bendoflumethiazide - used for mild/moderate heart failure
What are some examples of thiazide diuretics?
Bendroflumethiazide Chlortalidone Cyclopenthiazide Benthiazide Cyclopenthiazide Hydroflumethiazide
What are some examples of thiazide-like diuretics?
Indapamide
Metolazone - good combined with loop
Xipamide - lowers BP with less side effects
Clopamide
What are the clinical uses of thiazide & thiazide-like diuretics?
Hypertension
Oedema
Mild heart failure
Generally used for less acute conditions
What are the unwanted effects of thiazide diuretics?
Hypokalaemia Metabolic alkalosis due to H+ loss Increased plasma uric acid - gout Hyperglycaemia Increased plasma cholesterol with long-term use Male impotence - reversible
Why does hypokalaemia occur?
Due to a loss of K+ in the urine
What are the symptoms of mild hypokalaemia?
Fatigue
Drowsiness
Dizziness
Muscle weakness
What are the symptoms of severe hypokalaemia?
Abnormal heart rhythm
Muscle paralysis
Death
How do potassium sparing diuretics avoid hypokalaemia?
Act on distal tubule to inhibit Na+ reabsorption
K+ is not secreted into distal tubule
Aldosterone antagonists & non-aldosterone antagonists
What are aldosterone antagonists?
Potassium sparing diuretics
Competitive antagonists of aldosterone - reduce Na+ channel formation –> reduced Na+ absorption from distal tubule
Limited diuretic action - not as potent as loop or thiazide diuretics
Mechanism depends on reduction of protein expression in distal tubular cells
What are some examples of aldosterone antagonists?
Spironolactone
Eplerenone
What are some clinical reasons to use aldosterone antagonists?
Heart failure
Oedema
Short term use
Resistant hypertension in the short term - concerns for long term due to possible incidence of cancer in rat studies
What are some unwanted effects of aldosterone antagonists?
Hyperkalaemia
Metabolic acidosis
GI upsets
Gynaecomastia, menstrual disorders, testicular atrophy
Eplerenone produces less unwanted effects than spironolactone
What are triamterene & amiloride?
Weak diuretics
Non-aldosterone potassium sparing inhibitors
Act on distal tubule to inhibit Na+ reabsorption & decrease K+ excretion
Blocks luminal Na+ channel which aldosterone uses to produce its main effects
Of little therapeutic use on their own but are useful in combination with potassium-depleting diuretics as they limit hypokalaemia
What are the unwanted effects of triamterene & amiloride?
Hyperkalaemia
Metabolic acidosis
GI disturbances
Skin rashes
What is the purpose of using diuretics in combination?
Increase diuretic effect
Avoid unwanted effects of hypokalaemia
Give some examples of diuretics that are used in combination
Combinations of loop diuretics or thiazides with potassium-sparing diuretics
Diuretic preparations containing K+
Loop diuretics with spironolactone
Loop diuretics with amiloride or triamterene
Thiazides with spironolactone
Thiaxides with amiloride or triamterene
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
What do carbonic anhydrase inhibitors do?
Blocks sodium bicarbonate in the proximal tubule
Weak diuresis so is not commonly used
What are the clinical uses of carbonic anhydrase inhibitors?
Glaucoma
Epilepsy
What are some unwanted effects of carbonic anhydrase inhibitors?
Metabolic acidosis - due to excretion of HCO3-
Enhances renal stone formation - due to alkaline urine
What is mannitol?
Osmotic diuretic
Non-reabsorbable solute which undergoes glomerular filtration
Excreted with 30-60min
What is mannitol used for?
Raised inter cranial pressure
Intraoccular pressure - glaucoma
Can cause osmotic diarrhoea which eliminates toxins
Acute renal failure
What are the unwanted effects of osmotic diuretics?
Presence in blood exerts an osmotic pressure –> increase in plasma volume
How is water as a diuretic controlled?
By ADH
Increased fluid intake –> reduced plasma osmolality –> reduced secretion of ADH from posterior pituitary –> reduced expression of AQP2 on apical surface of distal tubule & collecting duct –> more water excreted
What are some examples of possible ADH antagonists
2 non-selective agents:
Lithium & demeclocycline
Tolvaptan
What are the issues with ADH antagonists?
Can cause diabetes insipidus
Renal failure
Lithium can cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction & leucocytosis
What is tolvaptan?
ADH antagonist
V2 receptor antagonist used for treatment of hyponatraemia –> decreased extracellular fluid –> increased plasma sodium concentration
What inhibits ADH release
Alcohol - tolerance develops rapidly so the diuresis is not sustained
Increases urine excretion
What increases ADH release?
Nicotine Ether Morphine Barbiturates Reduce urine excretion
What are some examples of xanthines?
Caffeine
Theophylline
Theobromine
What do xanthines do?
Produce a weak diuretic effect by increasing cardiac output
May cause some vasodilation of glomerular afferent arteriole
Increase renal & glomerular blood flow –> increases GFR & urine output
Why aren’t xanthines used clinically?
Cause gastric irritant effects
What is theophylline used for?
Bronchodilator for asthma
