Diuretics Flashcards
Indications for diuretic use
- Hypertension
- Heart failure
- Chronic kidney disease ! Oedema
- Hepatic cirrhosis
- Nephrotic syndrome
- Acute glomerulonephritis ! Corticosteroid and oestrogen therapy
ALLHAT trial
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
ANBP2 trial
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
What are the different classes of diuretics?
- **Loop ** or ‘high ceiling’ diuretics
- Thiazide diuretics
- Potassisum sparing diuretics
Examples of loop diuretics
- Frusemide
- Bumetanide,
- Ethacrynic acid,
- Piretanide
Examples of thiazide diuretics
- Chlorthalidone (used in ALLHAT)
- Hydrochlorothiazide (used in ANBP2)
- Indapamide
Examples of potassium sparing diuretic
- Spironolactone
- Amiloride
Examples of osmotic diuretics
Mannitol, urea
How to osmotic diuretics work?
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
Uses of osmotic diuretics
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.
Describe what occurs in the proximal tubule of the nephron
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
Atrial natiuretic peptide
Released in response to increased arterial pressure causes decreased Na+ and water reabsorption
Carbonic anhydrase inhibitors examples
- Acetazolamide
- Dichlorphenamide
Cellular mechanisms of carbonic anhydrase inhibitors
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:
- glaucoma
- Reduce the formation of aqueous humour
- adjunct treatment with anticonvulsants to manage absence seizures.
- Acetazolamide may be used at altitude to prevent periodic breathing and improve sleeping
- metabolic acidosis yields compensatory enhanced ventilatory oxygenation
- Potassium sparing diuretic, Amiloride also can inhibit the Na+/H+exchanger
Loop diuretics examples
- Frusemide
- Bumetanide
- Ethacrynic acid
- Piretanide
Functions of loop diuretics
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”
Loop diuretics side effects
- K+ depletion –> hypokalaemia
- Excessive Na+ depletion –> hyonatraemia
- H+ depletion –> metabolic alkalosis
- Mg2+ and Ca2+ depletion is common
- Hyperuricemia, gout, hypotension and hypovolaemia often result, particularly in the elderly
- Dilutional hyponatraemia when salt loss exceeds water loss
- Vertigo and deafness
- Drug interactions
Action of thiazide diuretics
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
Describe the distal tubules of the nephron
- 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.
Describe the collecting duct
Two cell types:
- Principal cells: reabsorb Na+ and secrete K + via channels in the luminal membrane
- 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).
Action of potassium sparing diuretics
Regulate reabsorption in the collecting tubule principle cells
- Amiloride and tramterene inhibit the specific Na+ channels.
- Spironolactone is an aldosterone inhibitor
Action of spirinolactone
Specific aldosterone inhibitor by competing for intracellular aldosterone receptors.
- Inhibits aldosterone induced Na+ retention
- Concomitant decrease in aldosterone induced K+ secretion
Major Use:
- K+ sparing diuretic, used in conjunction with K+ losing diuretics
- Primary hyperaldosteronism (Conn’s syndrome)
- Secondary hyperaldosteronism
- Hepatic cirrhosis
- Restricted salt intake
Amiloride and triamterene actions
- Limited diuretic efficacy
- blocks luminal Na+ channels, decreasing Na+ available for reabsorption
Major Use:
- K+ sparing diuretic
- Some patients tolerate better than spironolactone
What are the types of HTN in pregnancy?
- Chronic HTN: diagnosed when hypertension is confirmed before pregnancy or before 20 weeks gestation
- Pre-eclampsia:
What is the risk of chronic HTN in pregnancy?
Increased risk of adverse events, including superimposed pre-eclampsia, placental abruption, fetal growth restriction, premature delivery and stillbirth.
Antihypertensives to avoid in pregnancy
Pre-eclampsia
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
Safe antihypertensives to use in preganncy
