Diuretics

Question 1

Indications for diuretic use

Answer 1

1. Hypertension
2. Heart failure
3. Chronic kidney disease ! Oedema
   
   • Hepatic cirrhosis
   • Nephrotic syndrome
   • Acute glomerulonephritis ! Corticosteroid and oestrogen therapy

Question 2

ALLHAT trial

Answer 2

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic (JAMA, December 18, 2002, 288(23) 2981-2997)

• *Question**: What is the optimal first-step therapy?
• *Answer: **thiazide-type diuretics are superior in preventing 1 or more major formsof CVD and are less expensive

Question 3

ANBP2 trial

Answer 3

A comparison of outcomes with angiotensin-converting enzyme inhibitors and

diuretics for hypertension in the elderly (NEJM February 13, 2003, 348(7) 583-592)

Question: What are the outcome benefits in older patients with ACEI verses diuretics?

**Answer: **Initiation of antihypertensive treatment with ACEI, particularly in older men yielded better outcomes than diuretics, despite similar blood pressure reductions

Question 4

What are the different classes of diuretics?

Answer 4

1. **Loop ** or ‘high ceiling’ diuretics
2. Thiazide diuretics
3. Potassisum sparing diuretics

Question 5

Examples of loop diuretics

Answer 5

1. Frusemide
2. Bumetanide,
3. Ethacrynic acid,
4. Piretanide

Question 6

Examples of thiazide diuretics

Answer 6

1. Chlorthalidone (used in ALLHAT)
2. Hydrochlorothiazide (used in ANBP2)
3. Indapamide

Question 7

Examples of potassium sparing diuretic

Answer 7

1. Spironolactone
2. Amiloride

Question 8

Examples of osmotic diuretics

Answer 8

Mannitol, urea

Question 9

How to osmotic diuretics work?

Answer 9

These are inert substances filtered in the glomerulus, with minimal reabsorption (if any). They increase amount of water excreted by decreasing passive water reabsorption in the proximal tubule, descending loop and collecting tubules

Question 10

Uses of osmotic diuretics

Answer 10

Prevention of acute renal failure

• In acute renal failure, the reabsorption of salt and water in the proximal tubule is almost complete,
• With very little urine flow, the distal tubules virtually dry up.
• The osmotic diuretics inhibit water reabsorption by retaining fluid in the proximal tubule.

acutely raised intracranial or intraocular pressure

• Do not enter the brain or eye,
• Causes fluid movement out from tissue once filtered at the kidney, the effect is lost.

Question 11

Describe what occurs in the proximal tubule of the nephron

Answer 11

Leaky epithelium, permeable to passive movement of ions and water in both directions

• zonula occludens is also permeable to ions and water and permits passive flows in either direction.
• No build-up of significant ionic or osmotic gradients, as exist in the distal tubule

60-70% of Na is reabsorbed

• Passive diffusion
• Active transport via the Na+/K+ ATPase pump
• Na+, H+ ion exchange
• Glucose and amino acid symports
• The osmotic force generated by solute re-absorption results in water re-absorption

Question 12

Atrial natiuretic peptide

Answer 12

Released in response to increased arterial pressure causes decreased Na+ and water reabsorption

Question 13

Carbonic anhydrase inhibitors examples

Answer 13

1. Acetazolamide
2. Dichlorphenamide

Question 14

Cellular mechanisms of carbonic anhydrase inhibitors

Answer 14

These act in the proximal tubule

• Carbonic Anhydrase inhibitors increase excretion of HCO3-, causing Na+, K+ and water to follow
• Very weak diuretic effect and ineffective in long term use.

Limited therapeutic uses include:

1. glaucoma
2. Reduce the formation of aqueous humour
3. adjunct treatment with anticonvulsants to manage absence seizures.
4. Acetazolamide may be used at altitude to prevent periodic breathing and improve sleeping
5. metabolic acidosis yields compensatory enhanced ventilatory oxygenation
6. Potassium sparing diuretic, Amiloride also can inhibit the Na+/H+exchanger

Question 15

Loop diuretics examples

Answer 15

1. Frusemide
2. Bumetanide
3. Ethacrynic acid
4. Piretanide

Question 16

Functions of loop diuretics

Answer 16

Loop diuretics inhibit the co-transporter in the thick ascending loop of Henle

• Up to 20-30% of filtered Na+ is normally reabsorbed by the co-transporter
• Effective even in advanced renal failure

Indicated in: oedema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome, severe resistant/ refractory hypertension

Additional venodilation effect

• pooling can be useful in treating acute left ventricular failure
• not completely understood.
• Observed after IV administration and before the onset of the diuretic effect.
• Particularly Piretanide,
• thought to be due to prostaglandin release or the release of “a renal factor”

Question 17

Loop diuretics side effects

Answer 17

1. K+ depletion –> hypokalaemia
2. Excessive Na+ depletion –> hyonatraemia
3. H+ depletion –> metabolic alkalosis
4. Mg2+ and Ca2+ depletion is common
5. Hyperuricemia, gout, hypotension and hypovolaemia often result, particularly in the elderly
6. Dilutional hyponatraemia when salt loss exceeds water loss
7. Vertigo and deafness
8. Drug interactions

Question 18

Action of thiazide diuretics

Answer 18

Thiazides act to reduce reabsorption in the distal tubules.

• Thiazide diuretics promote Na+, Cl-, K+, Mg++ and H2O excretion.
• Maximum proportion of Na+ re- absorption at the distal tubule is less than 10%
• Diuretics can cause an increase in plasma renin activity.
• administer thiazides in combination with ACE inhibitors
• Multiple side effects
• Chlorthalidone - unwanted side effect is male impotency

Question 19

Describe the distal tubules of the nephron

Answer 19

• In the distal tubule, The Zona occludens is almost a tight junction, virtually impermeable to water.
  
  • Tubular fluid is further diluted due to active Na+ and Cl- reabsorption and low permeability to water
  • Continues the dilution, started in the ascending LOH.
  • Osmolarity is well below that of plasma
  • K+ and H+ are secreted into the tubule
  • When there is an increased Na+ load presented to the distal tubule, there is a corresponding increase in K+ secretion.
• Parathyroid hormone and calcitrol increase Ca++ re-absorption
  
  • Bind specific receptors on the kidney epithelium.

Question 20

Describe the collecting duct

Answer 20

Two cell types:

1. Principal cells: reabsorb Na+ and secrete K + via channels in the luminal membrane
2. Intercalated cells: H + secretion

Aldosterone enhances Na+ reabsorption and K+ excretion

• The K+ secreted here represents most of the K+ seen in the urine, since most of the filtered K+ is reabsorbed in the proximal and loop.
• Water undergoes passive reabsorption due to the increased osmolarity of the interstial fluid.

Controlled by anti-diuretic hormone (ADH, also known as vasopressin).

Question 21

Action of potassium sparing diuretics

Answer 21

Regulate reabsorption in the collecting tubule principle cells

1. Amiloride and tramterene inhibit the specific Na+ channels.
2. Spironolactone is an aldosterone inhibitor

Question 22

Action of spirinolactone

Answer 22

Specific aldosterone inhibitor by competing for intracellular aldosterone receptors.

• Inhibits aldosterone induced Na+ retention
• Concomitant decrease in aldosterone induced K+ secretion

Major Use:

1. K+ sparing diuretic, used in conjunction with K+ losing diuretics
2. Primary hyperaldosteronism (Conn’s syndrome)
3. Secondary hyperaldosteronism
4. Hepatic cirrhosis
5. Restricted salt intake

Question 23

Amiloride and triamterene actions

Answer 23

• Limited diuretic efficacy
• blocks luminal Na+ channels, decreasing Na+ available for reabsorption

Major Use:

1. K+ sparing diuretic
2. Some patients tolerate better than spironolactone

Question 24

What are the types of HTN in pregnancy?

Answer 24

1. Chronic HTN: diagnosed when hypertension is confirmed before pregnancy or before 20 weeks gestation
2. Pre-eclampsia:

Question 25

What is the risk of chronic HTN in pregnancy?

Answer 25

Increased risk of adverse events, including superimposed pre-eclampsia, placental abruption, fetal growth restriction, premature delivery and stillbirth.

Question 26

Antihypertensives to avoid in pregnancy

Answer 26

Question 27

Pre-eclampsia

Answer 27

The most common presenting features of pre-eclampsia are new onset hypertension after 20 weeks gestation and proteinuria .

The aetiology of pre-eclampsia is unclear

• a combination of maternal and placental factors are likely to contribute.
• Abnormal placental formation, resulting in aberrant angiogenic factor production and systemic endothelial dysfunction, as well as genetic and immunological factors, are thought to play a role.

Risk factors include

• nulliparity, age less than 18 or more than 40 years,
• past history of pre-eclampsia and maternal medical comorbidities
• hypertension, diabetes mellitus, renal disease, obesity, antiphospholipid antibodies or other thrombophilia and connective tissue disease

Pre-eclampsia is associated with fetal growth restriction, preterm delivery, placental abruption and perinatal death.

Severe pre-eclampsia has the potential for progression to eclampsia

• multi-organ failure, severe haemorrhage and rarely maternal mortality.
• The only cure is delivery of the baby

Question 28

Safe antihypertensives to use in preganncy

Answer 28