Diuretics

Question 1

Resorption ion transporter regions in the nephron

Answer 1

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

Question 2

Thick ascending limb

Answer 2

Primary point of resorption
Sodium/ potassium/ chloride transporters are significantly affected by drugs
Ions balance each other (passive)

Question 3

What are diuretics? Give some (non-medical) examples

Answer 3

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

Question 4

Main clinical uses of diuretics

Answer 4

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

Question 5

Diuretic classification

Answer 5

1. Chemical
2. Pharmacological mechanism
3. Site of action
4. Potency

Question 6

Inhibitors of carbonic anhydrase

Answer 6

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)

Question 7

Clinical use of inhibitors of carbonic anhydrase

Answer 7

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

Question 8

Thiazides (Benzothiadiazides)

Answer 8

Moderately potent diuretics

Structure contains a sulfonamide

Question 9

Thiazides mechanisms of action

Answer 9

Main effect: inhibit sodium chloride co-transporter (i.e. resorption) in the early distal tubule&raquo_space;> water follows passively
Also inhibits potassium and bicarbonate resorption
Weak inhibitors of carbonic anhydrase

Question 10

Thiazides advantages and disadvantages

Answer 10

Advantage: moderately potent and orally active
Disadvantage: potassium loss (hypokalaemia)

Question 11

Mechanism of thiazide hypokaleamia in distal tubule

Answer 11

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

Question 12

Common side effects of thiazides

Answer 12

Hypokolaemia
Gout
Hypercalcaemia
Hypomagnesaemia
Hyponatraemia (sodium)

Question 13

Thiazide related heterocyclics

Answer 13

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

Question 14

Loop diuretics

Answer 14

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

Question 15

Loop diuretics mechanisms

Answer 15

Main mechanism: inhibition of sodium potassium chloride cotransporter in thick ascending limb
Minor mechanism: transiently (5 mins) stimulates prostaglandin synthesis, increases renal blood flow

Question 16

Torasemide

Answer 16

Used for oedema and hypertension
Dose: oedema- 5mg od
Hypertension 2.5-5mg od

Question 17

Potassium sparing diuretics

Answer 17

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

Question 18

Effect of aldosterone in the distal convoluted tubule and collecting duct

Answer 18

Aldosterone binds to a mineralocorticoid receptor, causing nuclear protein synthesis
Inserts apical sodium channels
Stimulates basolateral sodium potassium ATPase
Stimulates apical potassium channel

Question 19

Aldosterone antagonists

Answer 19

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

Question 20

Spironolactone

Answer 20

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

Question 21

Clinical uses of aldosterone antagonists

Answer 21

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

Question 22

Sodium channel inhibitors

Answer 22

Occupy sodium channels in late distal tubule/ collecting duct epithelial cell membranes
Don’t inhibit sodium pumps

Question 23

Triamterene

Answer 23

Weak diuretic
Dose 150-200mg daily
May conserve potassium- used with thiazides/ loop diuretics

Question 24

Amiloride

Answer 24

Weak diuretic
Dose 5-20mg daily
May conserve potassium- used with thiazides/ loop diuretics

Question 25

Hyperkalaemia through potassium sparing diuretics

Answer 25

Potassium supplements must not be given with potassium sparing diuretics as this may cause hyperkaleamia- malaise, palpitations, muscle weakness, arrythmia, sudden death

Question 26

Osmotic diuretics

Answer 26

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

Question 27

Osmotic diuretic characteristics

Answer 27

Ideal osmotic diuretic has low molecular weight, easily filtered but not resorbed, high osmotic activity

Question 28

Examples of osmotic diuretics

Answer 28

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

Question 29

Drugs acting on renal circulation

Answer 29

Glomerular filtration rate is raised by agents which increase renal blood flow, cardiac output or blood volume

Question 30

Cardiac glycosides

Answer 30

Increase cardiac output during heart failure, cause secondary rise in RBF and filtration, digoxin often combined with conventional diuretics

Question 31

Colloidal substances (plasma expanders)

Answer 31

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

Question 32

Dextran

Answer 32

Repeating glucose units joined by glucoside linkages Plasma expander (10% soln) Not normally given as primary diuretic Molecular mass = 70-80kD

Question 33

Xanthines

Answer 33

e.g. caffeine, theophylline, theobromine Inhibit sodium and chloride resorption Raise filtration pressure (dilate afferent > efferent arterioles to glomeruli) Stimulate cardiac output

Question 34

Potency/ efficacy of diuretics

Answer 34

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

Question 35

Give examples of carbonic anhydrase inhibitors. What structure binds the active site?

Answer 35

Acetazolamide, dorzolamide | Sulphonamide binds the active site

Question 36

Give examples of thiazides and their doses

Answer 36

``` 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 ```

Question 37

How do thiazides cause hypokalaemia?

Answer 37

Mechanism: diuretic inhibits sodium resorption> high sodium concentration arrives at distal tubule> sodium potassium exchange occurs

Question 38

What are the four groups of thiazide related heterocyclics? Give examples of each

Answer 38

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