Diuretics Flashcards
Resorption ion transporter regions in the nephron
Most resorption happens in the proximal convoluted tubule, too active to be affected by drugs
Ascending limb, early/late distal convoluted tubule, connecting tubule and collecting duct can be affected with drugs
Thick ascending limb
Primary point of resorption
Sodium/ potassium/ chloride transporters are significantly affected by drugs
Ions balance each other (passive)
What are diuretics? Give some (non-medical) examples
Drugs that increase urine flow and salts
Water and alcohol are diuretic as they dilute body fluids and inhibit ADH release
Water eliminated = amount ingested
Main clinical uses of diuretics
Cardiac failure
Oedema
Hypertension
Liver disease and some types of kidney disease
Overdose or poisoning to help excretion
Abuse- eating disorders patients to lose weight
Diuretic classification
- Chemical
- Pharmacological mechanism
- Site of action
- Potency
Inhibitors of carbonic anhydrase
H+ is actively secreted from the tubule and exchanges for sodium (i.e. resorbed)
If CA inhibited, less H+ for exchange with sodium (i.e. diuresis)
Less sodium and bicarbonate is resorbed (urine = alkaline)
Clinical use of inhibitors of carbonic anhydrase
They are of little value in long term value
Self limiting effect: As bicarbonate is lost from the body, plasma becomes acidified- the buffers start to release H+ (exchanges with sodium) without requiring CA
Effective in the eye
Thiazides (Benzothiadiazides)
Moderately potent diuretics
Structure contains a sulfonamide
Thiazides mechanisms of action
Main effect: inhibit sodium chloride co-transporter (i.e. resorption) in the early distal tubule»_space;> water follows passively
Also inhibits potassium and bicarbonate resorption
Weak inhibitors of carbonic anhydrase
Thiazides advantages and disadvantages
Advantage: moderately potent and orally active
Disadvantage: potassium loss (hypokalaemia)
Mechanism of thiazide hypokaleamia in distal tubule
Potassium loss is dangerous in severe coronary artery disease and sensitizes the heart to cardiac glycosides
Use potassium supplements or combination with potassium sparing diuretic
Common side effects of thiazides
Hypokolaemia Gout Hypercalcaemia Hypomagnesaemia Hyponatraemia (sodium)
Thiazide related heterocyclics
Commonly used as less adverse effects e.g. indapamide
Use in hypertension and congestive heart failure 1.25-5mg daily
NB cost effective especially in combination with perindopril e.g. in type 2 diabetes
Loop diuretics
Very effective (high ceiling) e.g. furosemide Rapid acting (peaks 30 mins), short duration (3-4 hours) Use of sulphamoyl benzoates- mainly pulmonary oedema and oedema due to renal failure Produce hypokolaemia, depending on duration of action rather than frequency >> thiazides are more likely to produce hypokalaemia as they are longer acting but cause potassium loss
Loop diuretics mechanisms
Main mechanism: inhibition of sodium potassium chloride cotransporter in thick ascending limb
Minor mechanism: transiently (5 mins) stimulates prostaglandin synthesis, increases renal blood flow
Torasemide
Used for oedema and hypertension
Dose: oedema- 5mg od
Hypertension 2.5-5mg od
Potassium sparing diuretics
Two types: Alodsterone antagonists and sodium channel inhibitors
Aldosterone is a mineralocorticoid secreted from adrenal cortex response to the renin angiotensin cascade
Encourages sodium retention in the late distal tubule and collecting duct
Effect of aldosterone in the distal convoluted tubule and collecting duct
Aldosterone binds to a mineralocorticoid receptor, causing nuclear protein synthesis
Inserts apical sodium channels
Stimulates basolateral sodium potassium ATPase
Stimulates apical potassium channel
Aldosterone antagonists
Mechanism- reverses action of aldosterone at late distal tubule, cause loss of sodium, prevent loss of potassium and H+
Therefore potassium supplements are not necessary
Can be used to potentiate thiazide or loop diuretics
Spironolactone
Antagonises renal effects of other corticosteroids e.g. hydrocortisone (i.e. aldosterone-like effects)
Use is limited because action depends on presence of aldosterone (not useful for oedema of pregnancy- low aldosteron levels)
Side effect = gynecomastia
Dose: 100-400mg od
Clinical uses of aldosterone antagonists
Main use- hepatic oedema- metabolic capacity of the liver for aldosterone is impaired
Also used for primary hyperaldosteronism (Conn’s syndrome)- output capacity of adrenal cortex is increased, hypertension due to tumour/ hyperplasia
Eplerone (spironolactone analogue) 50-100mg od, no gynecomastia, with optimal medical therapy reduces morbidity/ mortality in patients with left ventricular dysfunction after MI
Sodium channel inhibitors
Occupy sodium channels in late distal tubule/ collecting duct epithelial cell membranes
Don’t inhibit sodium pumps
Triamterene
Weak diuretic
Dose 150-200mg daily
May conserve potassium- used with thiazides/ loop diuretics
Amiloride
Weak diuretic
Dose 5-20mg daily
May conserve potassium- used with thiazides/ loop diuretics
Hyperkalaemia through potassium sparing diuretics
Potassium supplements must not be given with potassium sparing diuretics as this may cause hyperkaleamia- malaise, palpitations, muscle weakness, arrythmia, sudden death
Osmotic diuretics
Any substance filtered but not resorbed at the glomerlus may act as an osmotic diuretic e.g. glucose is normaly totally resorbed but in diabetes mellitus found in urine (polyuria)
Once osmotic diuretic is filtered it increases lumen OP thus water passes in by osmosis
Osmotic diuretic characteristics
Ideal osmotic diuretic has low molecular weight, easily filtered but not resorbed, high osmotic activity
Examples of osmotic diuretics
Mannitol must be given in large volumes e.g. 50-200g (10-20% soln) slow IV over 24 hours
Used for osmotic relief of cerebral oedema (raised intercranial pressure)
Urea does not cross BBB, also draws water out of cranial tissue
Drugs acting on renal circulation
Glomerular filtration rate is raised by agents which increase renal blood flow, cardiac output or blood volume
Cardiac glycosides
Increase cardiac output during heart failure, cause secondary rise in RBF and filtration, digoxin often combined with conventional diuretics
Colloidal substances (plasma expanders)
If blood volume falls e.g. blood or protein loss (RBF/GFR falls= renin-angiotensin cascade= oedema) colloidal substances may be given IV to restore RBF/GFR
Dextran
Repeating glucose units joined by glucoside linkages
Plasma expander (10% soln)
Not normally given as primary diuretic
Molecular mass = 70-80kD
Xanthines
e.g. caffeine, theophylline, theobromine
Inhibit sodium and chloride resorption
Raise filtration pressure (dilate afferent > efferent arterioles to glomeruli)
Stimulate cardiac output
Potency/ efficacy of diuretics
High efficacy diuretics: >15% filtered sodium loss: loop diuretics- sulphamoyl benzoates e.g. furosemide
Medium efficacy diuretics: 5-10% filtered sodium loss: thiazides e.g. bendroflumethiazide; thiazide reelated heterocyclics e.g. indapamide
Weak/ adjunctive diuretics: <5% filtered sodium loss: potassium sparing agents e.g. spironolactone, amiloride, mannitol, urea, dextran, caffeine
Give examples of carbonic anhydrase inhibitors. What structure binds the active site?
Acetazolamide, dorzolamide
Sulphonamide binds the active site
Give examples of thiazides and their doses
Bendroflumethiazide 2.5-10mg Cyclopenthiazide 250-500 mg Hydrochlorothiazide 25-50 mg Polythiazide 0.5-4.0 mg All should be taken in the morning
How do thiazides cause hypokalaemia?
Mechanism: diuretic inhibits sodium resorption> high sodium concentration arrives at distal tubule> sodium potassium exchange occurs
What are the four groups of thiazide related heterocyclics? Give examples of each
Pthalimidines e.g. Chlorthalidone 50-200mg
Quinazolines e.g. Metolazone 5-20mg
Benzene sulphonamides e.g. mefruside 12.5-50mg
Chlorbenzamides e.g. indapamide 25mg
