Lecture 6- Diuretics Flashcards
renal physiology
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Regulatory
- Fluid balance
- Acid-base balance
- Electrolyte balance
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Excretory
- Wate products
- Drug elimination
- Glomerular filtration
- Tubular secretion
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Endocrine
- Renin
- EPO
- Prostaglandins
- 1-apha calciol
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Metabolism
- Vitamin D
- Polypeptides- insulin
- Drugs
- Morphine
- Paracetamol
Drugs acting on the renal tube
- Carbonic anhydrase inhibitors
- Osmotic Diuretics
- SGLT2 inhibitors
- Loop Diuretics
- Thiazides
- Potassium sparing diuretics
- Aldosterone antagonists
- ADH Antagonists
- Diuretic
- increased production of urine
Natriuretic
- loss of sodium in urine
Aquaretic
- loss of water without electrolytes
Other substances with diuretic action
Alcohol
Caffeine
alcohol causes diueresis by
inhibiting ADH release (PP)
caffeine causes diuresis by
increasing GFR and therefore decreases tubular reabsorption of sodium
mode of action of carbonic anhydrase inhibitors drug class
- Inhibits carbonic anhydrase in PCT
- Reduced amount of H2O and CO2 reabsorbed
- Reduces the amount of carbonic acid in the cell converted to H+ and HCO3-
- Less H+ to power the Na/H exchanger
- Less HCO3- to power the HCO3-Na cotransporter
- Therefore less sodium reabsorbed
- Higher osmotic potential in lumen
name a drug under the drug class CA inhibitors
Acetazolamide
when are carbonic anhydrase inhibitors used
- First drug used as diuretics- not used so much as a diuretic now
- Glaucoma
- Altitude sickness
Adverse drug response: Carbonic anhydrase inhibitors
- Hypokalaemia metabolic acidosis
- Less sodium reabsorbed in PCT- enhanced delivery of Na+ to collecting duct causes K+ loss (Na/K+ ATPase)
- Tolerance develops after 2-3 days
mode of action of osmotic agents
- Mannitol- administered IV
- Travels around the body and freely filtered at the glomerulus
- Once it has been filtered there are no transporters in the tubule, so it stays there
- Osmotic effect- draws water into tubule (works along the whole nephron
- Increased water excretion
- Less effect on Na+ (water diuresis)
Adverse drug response: Osmotic agents
- Exerts osmotic effect on blood supply- reducing intracellular volume
- Initially expanding extracellular fluid volume
- Inhibiting renin release
- Increasing renal blood flow
- Decrease blood viscosity
- hypernatremia (due to loss of water)
- Initially expanding extracellular fluid volume
mode of action of SGLT2 inhibitors
- Sodium and glucose co-transporter inhibitors
- Less sodium and glucose being reabsorbed
- Reduces:
- Plasma glucose
- Body weight
- Blood pressure
- Plasma uric acid
- Glomerular hyperfiltration
Name a drug under the drug class SGLT2 inhibitors
flozins
- canagliflozin (Invokana)
- dapagliflozin (Farxiga)
uses for SGLT2 inhibitors
- diabetes mellitus
- diuretic
mode of action of loop diuretics
The most potent diuretic- termed high ceiling diuretic
- Block the Na/2Cl/K channel
- Reduction in Na/2Cl/K reabsorption
- More Na/2Cl/K in lumen
- Reduced reabsorption of water
name a drug under the drug class loop diuretic
Furosemide and bumetanide
uses of loop diuretics
- Very fast onset
- Increase urine volume
- Suitable for emergency situations such as
- Severe oedema associated
- congestive heart failure
- nephrotic syndrome
- decomensated liver disease
- CKD
- Treatment of hypercalcemia
- Acute Pulmonary oedema
- Acute hyperkalaemia
- Acute hypercalcaemia
*
- Severe oedema associated
Adverse drug response: loop diuretic
-
Hypokalaemia metabolic alkalosis
- Enhanced na+ delivery to collecting duct results in excess loss of potassium
- Removal of hydrogen
- Hypocalcemia
- Under drug-free conditions, K+ back diffusion creates a positive luminal membrane Vm that is a driving force for divalent cation reabsorption
- If loop diuretics are being used this is lost and less Ca2+ and Mg2+ are reabsorbed (divalent loss)
- Ototoxicity
- Increased LDL and triglyceride
- Gout
mode of action of thiazide diuretics
- Distal tubule
- Collecting duct
- Block sodium chloride cotransporters
- Increased NaCl excretion
- Increased K excretion
- Increased urinary magnesium excretion
- Increased calcium re-absorption (hypercalcemia) (opposite to loop diuretics)
- Decrease urinary calcium excretion
- Decreased uric acid excretion
name a drug under the drug class thiazide diuretic
Chlorothiazide and metolazone
Uses: thiazides
- essential hypertension
- Nephrotic syndrome
Adverse drug response: thiazides
- Hypokalaemic metabolic alkalosis
- Hypercalcemia
- Gout
- Hyperglycaemia
- Erectile dysfunction
- Increased LDL and triglyceride
mode of action of Potassium sparing and aldosterone antagonists
- Late DCT and Collecting duct
- Both reduce absorption of sodium, but also excretion of potassium
-
Aldosterone antagonist (spironolactone)
- Blocks aldosterone
- Don’t get upregulation of eNAC and ROMK channels
- Blocks aldosterone
-
Potassium sparing (amiloride)
- Block eNac channels
- Less active Na/K ATPase
- Less potassium pumped out into tubule
name a drug under the drug class Potassium sparing and aldosterone antagonists
Spironolactone (aldosterone antagonist) and eplerone (potassium sparing)
uses of potassium sparing and aldosterone antagonists
- Often couple these with other diuretics e.g. furosemide to reduce change of hypokalaemia
- With other diuretics there is going to be a very high conc of sodium in the DCT and CD due to reduced sodium reabsorption along the nephron
- Therefore the eNac channel will absorb lots of sodium, which will be used to fuel the Na/K ATPase which will draw K+ from the blood and into the lumen
- Causing hypokalaemia
- Secondary hyperaldosteronism
- Hypertension (combine with thiazide or loop diuretics to correct hypokalaemia)
- Heart failure
- Nephrotic syndrome
- Decompensated liver disease
Adverse drug response: Potassium sparing and aldosterone antagonists
- Hyperkalaemia
- Impotence
- Painful gynaecomastia (male breast tissue)
Contraindications: Potassium sparing and aldosterone antagonists
- Hyperkalaemia
- As in chronic renal failure, K+ supplementation, B blockers or ACE inhibitors
- Liver disease (dose adjustment needed)
name drugs which come under the class ADH antagonists ‘Aquaretics’
Tolvaptan and Lithium
Mode of action of Tolvaptan
- ADH antagonists
- Less Aquaporin-2 added to collecting duct
- Decreases reabsorption of water but not electrolytes
- Diuretic but not natriuretic
- Used to treat hyponatraemia (prevent cyst enlargement in APCKD)
mode of action of Lithium
- Also inhibits action of ADH- unwanted side effect
- Diuretic but not natriuretic
AVP= vaspressin = ADH
Generic adverse diuretic reaction
- Hypovolaemia and hypotension
- Activates RAAS
- Can lead to acute kidney injury
- Electrolyte disturbance (Na, K, Mg, Ca)
- Metabolic abnormalities
- Acid base
- Anaphylaxis/photosensitivity rash (rare)
DDI of K-sparing diuretics
ACEi
- increased hyperkalaemia (think of how aldosterone works) –> cardiac problem
DDI of loop diuretics
aminglycosides
- ototoxicity
- nephrotoxicity
DDI of thiazide and loop
1) digoxin
- hypokalaemia –> increased digoxin binding and toxicity
2) steroids
- increased risk of hypokalaemia
DDI of thiazide
-
B blockers
- hyperglycaemia, hyperlipidemia, hyperuricaemia
-
carbamazepine
- increased risk of hyponatremia
which diuretics are used to treat hypertension
- Thiazide diuretics
- Vasodilation as well as diuresis
- Spironolactone
- Secondary hypertension (little syndrome)
- Loop diuretics
Which diuretics are used to treat Heart failure
- Loop diuretics
- Spironolactone
- To tackle hypokalaemia
- SGLT2
- diabetes
- ?Tolvaptan
which diuretics are used to treat Decompensated liver disease
- Spironolactone
- Loop diuretics
- Tolvaptan
which diuretics are used to treat nephrotic syndrome
- Loop diuretics
- +/- Thiazides
- +/- potassium sparing diuretics
which diuretics are used to treat Chronic kidney disease
- Decreased GFR leads to salt and water retention
- Loop diuretics
- Alkalosis and kaliuretic (getting rid of potassium) effect potentially beneficial
- Generally avoid K+ sparing diuretics
- Loop diuretics
Diuretic resistance
Implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, oedema, or congestion, despite escalating doses of a loop diuretic to a ceiling level
patients will need more diuretic
Diuretic delivery to renal tubule and disease: liver disease
- Gut oedema- reduces absorption or oral diuretic
- Reduced albumin- furosemide needs to be bound to albumin to be delivered to the kidneys
- Bound to albumin so not filtered
- Actively transported into PCT lumen via Organic Anion Transporter with albumin
Diuretic delivery to renal tubule and disease: kidney disease
- OAT also transports other toxins into the renal lumen – furosemide will need to compete with these other toxins
- Reduced number of nephrons
- Reduced delivery of furosemide
Diuretic delivery to renal tubule and disease: Heart failure
- Pump isn’t working
- Furosemide not pumped effectively around the body
The importance of salt
- Diuretics only work well if pt reduces salt intake
- However if you give diuretic pt may feel thirsty or feel like salty food
Refractory oedema
- Diuretics work well on day 1, getting rid of salt and water.
- Then the body tries to hold onto salt and water (upregulated channels somewhere else in the nephron e.g. eNac and ROMK due to increased aldosterone due to decreased BP detected by macula densa cells)
how do we avoid refractory oedema
Therefore we use combination of diuretics- prevent upregulation of other channels- prevent resistance
Bartter’s syndrome
- Genetic defects which cause cotransporter not to work
- 100% blockage of the Na+/K+/2Cl- channel
- Like giving someone extreme furosemide
Common symptoms include:
- muscle weakness, cramping and spasms
- fatigue
- excessive thirst (polydipsia)
- excessive urination (polyuria)
- nocturia
Gitelman’s syndrome
- Genetic defects which cause cotransporter not to work
- 100% blockage of Sodium chloride channel
- Like giving extreme thiazide
Symptoms
- painful muscle spasms (tetany), muscle weakness or cramping,
- dizziness, and
- salt craving
Liddle’s syndrome
- eNac channels permanently turned on (dont need aldosterone) therefore excessive excretion of potassium and excessive reabsorption of sodium
- hypernatremia
- hypertension
symptoms
- weakness
- fatigue
- palpitations
- muscular weakness
- shortness of breath
- constipation/abdominal distention
- exercise intolerance
- long-standing hypertension could become symptomatic.
diuretics summary
