3. Drug Class 3,4,5,6: Thiazides, K+ sparing diuretics, Loop diuretics, Aldosterone-Antagonists

Thiazides/Benzothiadiazides (Not to be confused with benzodiazepines and benzothiazides)

3.1 Mode of action

-Moderately potent diuretics, they inhibit absorption of sodium and chloride in the proximal segment of the DCT and produce a corresponding increase in potassium excretion.

-Essentially blocks Na+/Cl- symporter

-They also promote vasodilation directly at low doses (e.g. open Ca2+/activated K+ channels, leading to hyperpolarisation of vascular smooth muscle cells–>Relaxation–>Vasodilation)

-When used in recommended low doses for hypertension, they lower BP mostly by vasodilator effect.

3.2 Clinical Indications

1. Mild to moderate hypertension

2. Edema associated with heart failure or hepatic cirrhosis

3. Nephrogenic diabetes insipidus (a form of diabetes insidipus but not due to lack of ADH but due to a lack of sensitivity of kidneys or nephrons to ADH)

*Diabetes insipidus (DI) is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. Insufficient ADH produced.

3.3 Precautions

1) Gout. Diuretic induced rise in serum uric acid concentration may precipitate gout (more likely with higher doses)

  • Urate reabsorption from the tubular fluid into the cell is mediated by urate transporter 1 (URAT1), OAT4, and OAT10, located on the luminal membrane, and from the cell back to the peritubular capillary blood through glucose transporter 9 (GLUT9) located on the basolateral membrane.
  • Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion
  • A direct effect of diuretics on promoting urate reabsorption by the proximal tubule.
  • An indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule.

2) Heart Failure (with significant edema). Hyponatremia may occur, particularly if higher doses are used with a salt-restricted diet and/or potassium sparing diuretics and excess water intake.

3) K+ excreting drugs. Amphotericin (Anti-fungal)-Increases risk of hypokalemia

*Monitoring blood K+ levels is neccesary.

4) Renal patients

Contraindicated in severe renal impairment or anuria (less than 45 ml urine per day)

-Thiazides are relatively less effective as diuretics in significant impairment (Creatinine Clearance <24ml/min), however they are still effective (at low doses where they reduce BP by direct vasodilation)

Normal Creatinine Clearance

    1. Men
      1. Average: 120 ml/min/1.73 m2 (+/-25) or 175 Liters/day
      2. Range: 97-137 ml/min/1.73 m2 (0.93-1.32 ml/sec/m2 IU)
    2. Women
      1. Average: 95 ml/min/1.73 m2 (+/-20) or 135 Liters/day
      2. Range: 88-128 ml/min/1.73 m2 (0.85-1.23 ml/sec/m2 IU)

-When used with loop diuretics in heart failure, thiazides may reduce renal perfusion and precipitate uremia (urea accumulated in urine).

5) Hepatic impaired

Contraindicated in hepatic precoma and coma (refers to alterations in behaviour in parenchymatous hepatic disorder).

-In cirrhosis, diuretic-induced volume depletion and/or electrolyte disturbance may precipitate hepatic coma or hepatic enchephalopathy (accumulation of toxic substances in the brain which leads to confusion)

6) Elderly

-More susceptible to electrolyte imbalance (e.g. hypokalemia) and orthostatic/postural hypotension.

7) Pregnant women

-AVOID USE. May cause electrolyte disturbances or neo-natal thrombocytopenia (lack of platelets in newborn), reduction in maternal blood volume may diminish uteroplacental perfusion.

*They are not allowed or not permitted in treatment of pregnancy associated hypertension/Gestational hypertension (CAT C-Aus).

-Placental Hypoperfusion and transient volume depletion.

8) Breastfeeding 

-Unlikely to suppress lactation. Thiazides appear in breast milk, should be avoided by nursing mothers.

3.3 Adverse Effects/Side Effects

1. Glucose tolerance, plasma lipid levels and male sexual function impaired/Erectile dysfunction (minimal with low doses)

2. Dizziness and Weakness

3. Muscle Cramps

4. Polyuria

5. Orthostatic hypotension

6. Hyponatremia (low sodium)

7. Hypokalemia (low potassium)

8. Hyperuricemia (High uric acid)–>Leading to Gout

9. Hypochloremic alkalosis (Low chloride)

10. Hypomagnesaemia (Low magnesium)

11. Hypercalcemia (Ca2+ excretion inhibited)

Way to remember: 2 Highs (Ca2+, Uric acid), 4 Lows (Na+, K+, Cl-, Mg2+), Hypertension related effects, Glucose+lipid metabolism, Erection

*Other infrequent side effects: Rash, hyperglycaemia, hypercalcemia, blurred vision, impotence, dyslipidemia (increase in total lipid cholesterol), LDL and triglyceride concentrations increase and reduced LDL concentration.

*Rare side effects: Nausea, vomitting, constipation, diarrhoea, parasthesia (tingling sensation with no long term physical effect), intrahepatic cholestatic jaundice,  cholecystitis, pancreatitis, agranulocytosis, aplastic anemia, hemolytic anemia, thrombocytopenia, epidermal necrolysis, purpura, necrotising vasculitis

3.4 Comparative Information

-At equipotent doses, all thiazides and related diuretics are effective in reducing BP. Indapamide is no less likely than ther others to cause hyponatremia and hypokalemia.

-Often, thiazides are used in combination with ACE-inhibitors, ARBs, other potassium-sparing diuretics (triamterene and amiloride)

*Indapamide is available alone or as a combination product with an ACE inhibitor (Perindopril)

*Do Not start treatment with combination products. Reserve them for patients stabilised on similar doses of single ingredient products.

3.5 Counselling AND Practice Points 

-Patient may feel dizzy on standing when taking this medication.

-Get up gradually from sitting/lying down to minimise this effect. Sit or lie down if necessary.

*Practice Points

-May be given with loop diuretics in severe heart failure to increase diuresis. Use small, intermittent doses with careful monitoring, seek specialist advice.

-Use low doses (e.g. up to 25 mg hydrochlorothiazide). High doses increase the likelihood of metabolic adverse effects without an additional anti-hypertensive effects.

*Diuretic Induced Hypokalemia

Reduce risk by minimising dose of thiazide or related diuretic

-Less likely when also taking an ACE-inhibitor or ARB (because ACE-inhibitors/ARBs retain potassium)

-May be difficult to correct if hypomagnesemia is present

-When potassium levels <3.5mmol/L, consider using potassium supplements (not preferred since each 600mg tablet contains only 8mmol of K+, daily requirement 20-60mmol daily) or potassium-sparing diuretics (easier to use)

3.6 Types of Thiazide Diuretics

  • Chlorthalidone/Chlortalidone

Indications: (a) Hypertension, (b) Edema associated with Heart Failure or hepatic cirrhosis (c) Nephrogenic Diabetes Insidipus (accepted)

-Counselling: Taken once a day usually in the morning (qd am)

  • Hydrochlorothiazide

Indications:

(a) Hypertension: (in combination with amloride, triamterene) (in combination with ACE-inhibitors: enalapril, fosinopril, quinapril) (in combination with ARBs: Candesartan, Olmesartan, Eprosartan, irbesartan, telmisartan, valsartan) (in combination amlodipine and valsartan)

(b) Edema associated with heart failure

(c) Hepatic cirrhosis or nephrotic syndrome (includes combination with amiloride and with triamterene) 

(d) Accepted indications: Prevention of renal calculi associated with hypercalciuria

Precautions: High doses of hydrochlorothiazide may cause hypokalemia. If there is a history of kidney stones, avoid using triamterene or potassium chloride.

Counselling: Taken once daily in the morning. If patient is taking it twice a day, take the first dose in the morning and the second dose before 6pm.

  • Hydrochlorothiazide + Triamterene

Mechanism of action: Triamterene inhibits sodium absorption in the distal tubule by blocking sodium channels. As a result, it interferes with sodium/potassium exchange and reduces urinary potassium excretion

Indications: (a) Hypertension (b) Edema associated with heart failure, hepatic cirrhosis or nephrotic syndrome

-Precautions: Hyperkalemia (contraindicated), Treatment with drugs that can increase potassium concentration (ACE-inhibitors-Avoid combination and avoid monitoring potassium concentration–>contraindicated). Kidney stones (avoid use-increased risk of triamterene stones). Contraindicated in renal and hepatic impairment.

Adverse effects specific to this combination:

1) Hyperkalemia, hypomagnesemia (Common)

2) Kidney stones (usually with high doses), megaloblastic anaemia (inhibition of dihydrofolate reductase), blood dyscrasias, photosensitivity (Rare)

*Counselling points: Taken once a day in the morning. If patient is taking it twice a day, take the first dose in the morning and second dose before 6pm. DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE ON THIS MEDICATION UNLESS TOLD OTHERWISE BY DOCTOR!!!

-Practice points: Maximum dose in the manufacturer’s product information leads to an unnecessarily high dose of hydrochlorothiazide (100mg) however,no more than 25 mg required daily to treat hypertension

  • Indapamide

Indication: Hypertension (in combination with perindopril)

Practice points: Although still common, the risk of hypokalemia is less than 15mg controlled release tablet than with 2.5mg conventional tablet, their anti-hypertensive is similar.

Acronym: CHITs

3.7 Drug Interactions

Hydrochlorothiazide:

1) Bile acid binding resins (Bile acid binding resins may decrease hydrochlorothiazide absorption and its therapeutic effect. Give resin at least 1 hour before or 4-6 hours after hydrochlorothiazide.

Thiazides:

1) ACE-inhibitors

2) Loop Diuretics

3) NSAIDs-May reduce renal function, reduce diuretic (inhibits synthesis of renal prostaglandins, thus reducing the anti-hypertensive effects) and hypotensive effect and increase risk of nephrotoxicity. *Avoid combination or monitor BP, renal functoin and weight. Adjust dosage accordingly. Low-dose aspirin is unlikely to be a problem.

4) Lithium (All diuretics decrease the clearance of LI+, increases risk of toxicity. *Thiazide diuretics are often prescribed with lithium for lithium-induced diabetes insipidus. Close monitoring required.

*******************************************************************************************************************************************

Potassium Sparing Diuretics

4. 1 Mechanism of action

-Inhibits sodium absorption in the collecting tubules by blocking sodium channels.

-Thus, this interferes with sodium/potassium exchange and reduce urinary potassium excretion.

-Weak diuretics when used alone, may cause severe hyperkalemia especially in the presence of renal impairment or if used with ACE-inhibitors, ARBs, Aldosterone antagonists or potassium supplements.

4.2 Comparative information

  • Amiloride: used to prevent diuretic induced hypokalemia, reduces magnesium loss. It is preferred over potassium supplements because of greater convenience and tolerability.

-Also used in combination with hydrochlorothiazide. The combination products have an unnecessarily high content of hydrochlorothiazide (no more than 25mg needed for hypertension)

  • Triamterene: Similar to amiloride but does not reduce magnesium loss. It also inhibits dihydrofolate reductase and may cause megaloblastic anemia.

-Triamterene only used in combination with hydrochlorothiazide.

4.3 Types of K+ sparing diuretics

1. Amiloride (A milo ride)

Indications: (a) Prevention of diuretic induced hypokalemia. (b) Edema due to heart failure (c) Hepatic cirrhosis or nephrotic syndrome, as an adjunct (used in combination to potentiate effects of other drug) to thiazide or loop diuretic (d) Primary hyperaldosteronism (Accepted indication)

*Can be used in combination with hydrochlorothiazide for hypertension and edema due to heart failure or hepatic cirrhosis.

Precautions:

1) Hyperkalemia (potassium >5mmol/L)-contraindicated

2) Debilitated patients with cardiopulmonary disease or uncontrolled type 1 Diabetes-Increased risk of hyperkalemia and respiratory or metabolic acidosis

3) Treatment with drugs that can increase potassium concentration, e.g. ACE inhibitors (increases risk of hyperkalemia-avoid combination)

4) Contraindications: Renal impaired, Hepatic impaired (Hepatic cirrhosis, hyperchloremic metabolic acidosis, hepatic encephalopathy)-Risk is incresaed when amiloride is used with other diuretics.

5) Elderly. More susceptible to postural hypotension and hyperkalemia.

6) Pregnancy. Avoid use, treatment during pregnancy may result in electrolyte disturbances in fetus (CAT C-AUS)

7) Breastfeeding. Safe to use.

***Always monitor potassium concentration

Adverse side effects associated with amiloride

1) Hyperkalemia

2) Hyponatremia

3) Hypochloremia (especially when combined with thiazide diuretics)

4) Nausea, vomitting, Constipation

5) Impotence

6) Dizziness

7) Muscle cramps

*Listed above are the common side effects

*Infrequent side effects: Diarrhea, anorexia, dry mouth, abdominal pain, flatulence, polyuria, postural hypotension, palpitations (due to hyperkalemia), rashes, joint/muscle pain, increased plasma creatinine

*Rare side effects: Jaundice, eosinophilia, itching, encephelopathy, paraesthesia, increased intraocular pressure

Counselling and Practice Points

-Patient may feel dizzing on standing when taking this medication. Get up gradually from sitting or lying to reduce this effect, sit or lie down if necessary. DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE ON THIS MEDICATION UNLESS TOLD TO DO SO BY DOCTOR!!!

-Amiloride is not required routinely in patients taking thiazide or loop diuretics (Reserve for use if hypokalemia occurs, serum potassium <3.5mmol/L)

-Amiloride is preferred to potassium supplements to prevent diuretic induced hypokalemia because of greater convenience and tolerability

*Can be used in combination with hydrochlorothiazide

4.4 Drug Interactions

1) [Amiloride Specific] NSAIDs-May cause or increase risk of hyperkalemia. Also, it reduces renal function. *Monitor serum potassium and creatinine, particularly in the elderly and patients with renal impairment. Low dose aspirin is unlikely to be a problem\

2) [Triamterene] NSAIDs-Same as above but  appears to be an increased risk of renal impairment when indomethacin is used concurrently. *Monitor serum potassium and creatinine, particularly in the elderly and patients with renal impairment.

*******************************************************************************************************************************************

 Class 5: Loop diuretics

5.1 Mechanism of Action

-Inhibits reabsorption of sodium and chloride in the thick ascending limb of the loop of Henle.

-This site accounts for retention of approximately 20% of filtered sodium. Therefore, they are potent diuretics.

*Produce a rapid and intense diuresis and have a short duration of action (4-6 hours). They are effective over a wide dose range with a dose-related response.

5.2 Clinical Indications

1. Edema associated with heart failure

2. Hepatic cirrhosis

3. Renal impairment

4. Nephrotic syndrome (a nonspecific kidney disorder characterised by a number of diseasesproteinuriahypoalbuminemia and edema. It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of high levels of protein passing from theblood into the urine)

*NOTE NOT INDICATED FOR HYPERTENSION !

5.3 Precautions

1. Allergy to specific loop diuretics -Contraindicated

2. Gout- May be aggravated by diuretic induced hyperuricemia (too much uric acid)

3. Treatment with ototoxic  drugs (damage to the ear)-Use combinations cautiously, especially in renal impairment

4. Electrolyte imbalance

-Contraindicated in severe sodium and fluid depletion

-Concurrent treatment with potassium lowering drugs (hypokalemia may occur) *Careful potassium monitoring required

5. Renal impaired

-Contraindicated in anuria (lack of urine <45ml of urine per day)

-Higher doses of loop diuretics are usually required in impairment. Renal function may worsen. *Careful monitoring of creatinine clearance and electrolyte levels is required.

-Treatment with nephrotoxic drugs (e.g. lithium, cyclosporine) increases risk of nephrotoxicity with loop diuretics.  Use combinations carefully, especially in renal impaired.

6. Hepatic impaired

-In patients with Hepatic impairment, diuretic induced electrolyte imbalance may lead to hepatic encephalopathy.

7. Elderly

-Elderly are more susceptible to electrolyte imblance (e.g. hypokalemia) and postural hypotension.

8. Children

Frusemide is used most commonly. Limited information for ethacrynic acid and bumetanide.

9. Pregnancy *AVOID USE, may cuase electrolyte disturbances in fetuses, possible neonatal thrombocytopenia (CAT C-AUS)

10. Breastfeeding

-Use with caution (unlikley to usppress lactation) ??? Meaning control doses?

5.4 Adverse Effects/Side Effects (Usually dose-related)

1. Electrolyte imbalance (Hyponatremia, hypokalemia, hypomagnesemia)

2. Dehydration (Loss of too much water)

3. Uric Acid accumulation (Hyperuricemia), Gout (may occur)

4. Dizziness, Postural hypotension, Syncope (Associated with rapid loss of blood volume)

*Above are the common ones.

*Infrequent side effects: Dyslipidemia, Increased creatinine concentration, hypocalcemia, rash

*Rare: Tinnitus, vertigo, deafness (especially with rapid IV administration), acute pancreatitis, jaundice, thrombocytopenia, hemolytic anemia, agranulocytosis, interstitial nephritis, exfoliative dermatitis, Stevens-Johnson syndrome, bullous eruptions.

5.5 Comparative information

-Frusemide is the only loop diuretic available in oral and IV formulations

-Bumetanide may be used in patients allergic to furosemide/Frusemide but cross-reactivity may occur.

-Ethacrynic acid can be used in patients allergic to both frusemide and bumetanide but has a greater risk of ototoxicity and other adverse effects

5.6 Counselling points and Practice points

-Medicine should be taken once daily in the morning. If patient is taking it twice a day, take the first dose in the morning and the second dose during lunchtime.

-Patient may feel dizzy upon standing when taking this medicine. Sit down or lie down if necessary.

-Role of loop diuretics in hypertension is limited (thus not indicated) to the management of excess salt and water retention inadequately controlled by other anti-hypertensive treatments.

*Treatment Heart Failure patients

-Start with a low dose then adjust according to clinical response! Use the lowest effective maintenance dose.

-Combine with an ACE-inhibitor

-If hypotension occurs, decrease dose of diuretic before that of the ACE-inhibitor (i.e. Ace-inhibitor prioritised)

-Usually given once daily in the morning although there may be better clinical response if drug is given twice daily (Second dose is midday and diuresis may interfere with sleep if given after 6pm)

-Higher doses necessary in refractory heart failure (defined as symptoms of CHF at rest or repeated exacerbations of CHF despite “optimal” triple-drug therapy)

Consider:Trial of IV frusemide may be more effective than increasing oral doses

Consider: Increase diuretic effect by adding a thiazide diuretic (use small intermittent thiazide doses with careful monitoring, seek specialist advice)

*Monitor weight and electrolytes

-Hypokalemia is less likely when diuretics are used with ACE-inhibitors or ARBs (K+ retention) than when used alone.

5.7 Types of Loop diuretics

  • Bumetanide

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome

*Adverse effects: Myalgia (Rare)

*Note: 1mg bumetanide has a diuretic effect equivalent to 40mg oral furosemide

  • Ethacrynic Acid

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome

*Precautions: Renal Impaired Patients (due to increased risk of ototoxicity, accumulation of ethacrynic acid may occur because of reduced excretion)

*Adverse effects: GI toxicity (nausea, vomitting, diarrhea, GI hemorrhage), hallucinations, inapprorpiate behaviour, mania [All rare adverse effects]

  • Furosemide/Frusemide

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome (d) Severe hypercalcemia (with adequate rehydration) [Accepted indication]

Note: The high ceiling effect of furosemide (substantial diuresis-up to 20%)  makes treatment of edema associated with CHF appropriate but not hypertension.

-Dose equivalence: Oral bioavailability of frusemide is about 50%. However, it may be lower in severe heart failure and renal disease. Thus, individualise dose according to clinical response.

-Administration advice: Avoid ototoxicity by giving IV no faster than 4mg/min.

-Practice points: In acute decompensated heart failure, continuous and bolus infusions appear to be equally effective.

*Bolus infusion:  administration of a medicationdrug or other compound that is given to raise its concentration in blood to an effective level

5.8 Drug Interactions

-Loop diuretics are potentially ototoxic and nephrotoxic. Administratoin with other drugs may add to toxicity.

1) NSAIDs

-Reduce Renal function and may reduce diuretic effect.  Also increases risk of nephrotoxicity, monitor BP, renal function and weight. increase diuretic dose accordingly if NSAID cannot be avoided. Low-dose aspirin is unlikely to be a problem

2) Li+

3) ACE-inhibitors

4) ARBs

5) Thiazide diuretics-Synergistic effect with loop diuretics which may cause profound diuresis and serious electrolyte disturbance. Monitor BP, electrolytes and renal function closely and use small/intermittent thiazide doses.

6) Glucocorticoids- Can amplify hypokalemia produced by loop diuretics.

6) Furosemide Specific Drug Interactions: Sevelamer (drug used to treat high levels of phosphate in blood). Reduce frusemide’s absorption, decreasing its efficacy. Monitor for its clinical effect. Giving it 1 hour before, or 3 hours after sevelamer may minimise interaction. Continue to monitor carefully if trying this approach.

*******************************************************************************************************************************************

Class 6: Aldosterone antagonists

Spironolactone

Eplerenone

6.1 Mechanism of action

-Inhibits sodium absorption in distal tubule/collecting tubule by antagonising aldosterone.

-Increases sodium and water excretion. Reduces potassium excretion, weak diuretics (only 0.1-2% of Na+ reabsorbed)

-Aldosterone may contribute to pathophysiology of heart failure by reducing its activity (using Aldosterone antagonists may help)

6.2 Clinical Indications

1) Heart Failure. Aldosterone antagonists improve survival and decrease hospitalisations for heart failure when used with standard treatment

-Spironolactone has been studied in severe (NYHA class III or IV) heart failure and eplerenone in mild heart failure (NYHA class II). No direct comparison trials exist.

-Spironolactone is less expensive than Eplerenone (More appealing to patients?) 

2) Primary Hyperaldosteronism and Refractory edema (Only Spironolactone approved)

-Only spironolactone approved for these indications. Refractory edema associated with secondary hyperaldosteronism (e.g. ascites)

3) Acne and Hirsutism treatment in women.

-Anti-androgenic effects.

6.3 Adverse Effects/Side effects

1) Hyperkalemia (K+ sparing diuretic) especially in renal impairment or if used with ACE inhibitors, ARBs, potassium sparing diuretics or potassium supplements.

2)Endocrine adverse effects (Only for spironolactone, NOT eplerenone) -Gynaecomastia (develop of breasts in men), menstrual abnormalities and sexual dysfunction/impotence.

6.4 Drug Interactions

*Eplerenone is more likely than spironolactone to be affected by drug interactions 

*Eplerenone is metabolised by CYP3A4. Thus any drug which inhibits this enzyme will increase eplerenone’s concentration. Any drug which induces CYP3A4 will decrease its concentration, thus decreasing efficacy.

*Consider using spironolactone if necessary or monitor/alter eplerenone doses appropriately.

(A) Spironolactone drug interactions

  • Digoxin (Spironolactone increases digoxin concentration)
  • Low dose spironolactone is used with ACE-inhibitors in patients with severe heart failure but careful K+ level monitoring is necessary.

(B) Eplerenone drug interactions

  • Itraconazole (Anti-fungal) (Inhibits CYP3A4)-Contraindicated
  • Amiodarone (Increases eplerenone’s concentration)
  • Diltiazem (Increases eplerenone’s concentration)
  • Erythromycin (Increases eplerenone’s concentration)
  • Fluconazole (Increases eplerenone’s concentration)
  • Ketoconazole (Greatly Increases eplerenone’s concentration)-Combination is contraindicated, use spironolactone instead
  • Saquinavir (Increases eplerenone’s concentration)
  • Verapamil (Increases eplerenone’s concentration)

6.5 Types of Aldosterone Antagonists

6.5.1 Spironolactone

Indications: (a) Primary hyperaldosteronism (b) Refractory edema associated with secondary hyperaldosteronism (e.g cirrhosis of the liver) (c) Hirsutism in females (d) Heart failure (Accepted clinically)

Precautions

1. Hyperkalemia (potassium <5mmol/L) Contraindicated

2. Debilitated patients with cardio-pulmonary disease or uncontrolled type 1 diabetes (increased risk of hyperkalemia and of respiratory or metbaolic acidosis)

3. Treatment with drugs that increase potassium concentration (e.g. ACE-inhibitors, ARBs) *Avoid combination or monitor potassium concentration.

4. Renal impaired (Contraindicated in renal failure, avoid use in severe impairment)

5. Hepatic impaired (Patients with cirrhosis, spironolactone may cause the following if metabolic derangements occur: Renal failure, hyperchloraemic metabolic acidosis, hepatic encephalopathy).  Risk is greater when spironolactone is used with other diuretics.

6. Pregnancy *Avoid use, may cause feminisation of male fetus (CAT B3-AUS)

7. Breastfeeding-Seems to be safe to use

  • Adverse effects (Spironolactone specific)

– Hyperkalemia, hyponatremia, hypochloremia (especially when combined with thiazide diuretic), weakness, headache, nausea, vomitting, mastalgia (breast pain) [Common]

GI cramps, diarrhoea, ataxia, drowsiness, confusion, impotence, gynaecomastia, menstrual irregularities, mild acidosis, renal impairment [Infrequent]

-Agranulocytosis, hepatotoxicity, rash, lichen planus, lupus-like syndrome, cutaneous vasculitis, urticaria (hives), alopecia (loss of hair from the head or body), chloasma (facial pigmentation), osteomalacia [Rare]

  • Practice points

*Reserve the use of spironolactone for hirsutism in females for whom other treatments are not suitable.

-In heart failure, spironolactone is used with an ACE-inhibitor, loop diuretic and in some cases Digoxin. 

*Monitor potassium levels each week for the first month, then each month for 2 months, then every 3 months and when indicated clinically.

6.5.2 Eplerenone

Indications: (a) Reduces Risk of cardiovascular death in patients with heart failure and left ventricular impairment within 3-14 days of an acute MI (in combination with standard therapy) (b) Mild heart failure (Accepted indication)

-Special Precautions: Hyperkalemia (potassium levels >5.5 mmol/L)-Contraindicated 

Diabetes and/or proteinuria-Increased risk of hyperkalemia

Important drug interactions  (eplerenone-specific):

1) Ketoconazole, Itraconazole (Contraindicated-CYP3A4 inhibitors)

2) Treatment with drugs that can increase potassium concentration (e.g. ACE-inhibitors, increases risk of hyperkalemia). Potassium-sparing diuretics (Contraindicated)

*Monitor K+ Concentrations

3) Renal impairment (If Creatinine Clearance is <50ml/min, it is contraindicated). (Creatine clearance 30-50ml/min, can be used at lower doses)

*Carefully Monitor K+ Concentrations

4) Hepatic impairment (Contraindicated in severe hepatic impairment)

5) Pregnancy (CAT B3-AUS)

Adverse effects associated:

-Hyperkalemia, hypotension, angina, weakness, vomitting, altered renal function, increased creatinine concentration (Common)

-Orthostatic hypotension, angina, weakness, vomitting and hyponatremia (Infrequent)

Practice points:

-Check potassium concentration at baseline, within 1 week, then 1 month after starting treatment. Adjust dosage accordingly. Then check every 3 months and when clinically indicated.

*Stop treatment or reduce dose if hyperkalemia occurs

***Underutilising or omitting a diuretic is a frequent cause of Resistant hypertension (a type of high blood pressure that does not respond well to traditional medical therapy)

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s