Diuretics Flashcards
DIURETICS MoA
•Crucial for the management of CV risk
and renal disease
● Increase the excretion of Na+ and water
-Decrease re-absorption of Na+ from the filtrate - Increased water loss is secondary
Diuretics Types
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazide diuretics
- Potassium sparing diuretics
LOOP DIURETICS
Examples
Most powerful diuretics
Capable of causing excretion of 15–25% Na+
Examples: furosemide; bumetanide
LOOP DIURETICS
MOA
MOA: Act on the thick ascending limb
Inhibit the Na+/K+/2Cl− carrier (Cl− binding site)
Incompletely understood vasodilator effects
Sulfonamide loop diuretics examples
Furosemide, bumetanide, torsemide
Non-sulfonamide loop diuretic
Example
Ethacrynic acid
Used for diuresis in patients allergic to sulfa drugs
(more ototoxic)
LOOP DIURETICS
Urine levels
Increase delivery of Na+ to distal nephron
>Increase excretion of K+, H+, Ca2+ and Mg2+ >Decrease excretion of uric acid
LOOP DIURETICS
Clinical uses
1) Tx of HTN complicated by renal impairment (thiazides preferred if renal works fine.)
2) hypercalcaemia tx after replacement of plasma volume w/ iv NaCl soln.
3) They’re used with dietary salt retention AND with other diuretic classes, in tx of salt + water overload ass. W/ :
- acute pulmonary oedema
- chronic heart failure
- liver cirrhosis complicated by ascites(to treat ascites which are from fluid retention)
-nephrotic syndrome
- renal failure
ADVERSE EFFECTS of loop diuretics
Hypovolaemia and hypotension
Hyponatraemia
Hypokalaemia
Metabolic alkalosis
Hypomagnesaemia
Hypocalcaemia
Hyperuricaemia
Renal impairment
•Unwanted effects unrelated to the renal actions of the drugs are infrequent
-Dose-related hearing loss
-Idiosyncratic allergic reactions (e.g. rashes, bone marrow depression) are uncommon
-Sulfa allergy
Contraindications of loop diuretics
•Severe hypovolemia •Dehydration •Hypokalaemia •Hyponatraemia •Hepatic encephalopathy •Gout
THIAZIDE DIURETICS Examples
bendroflumethiazide, hydrochlorothiazide
Other drugs acting on the distal tubule:
Chlortalidone, indapamide, metolazone
THIAZIDE DIURETICS
-Less powerful than loop diuretics
-Preferred in uncomplicated hypertension
-Better tolerated than loop diuretics
-Reduce risk of stroke and heart attack associated with hypertension
THIAZIDE DIURETICS: MOA
,
Inhibit the distal tubular Na+/Cl − co-transport system by binding to the Cl− site
Natriuresis with loss of sodium and chloride ions in the urine
Decreased blood volume leads to fall in BP
THIAZIDE DIURETICS
Pk/PD
● Contraction in blood volume stimulates
renin secretion
-Limits anti-hypertensive effects of the diuretic on blood pressure
-Combination with ACEI’s/ARB’s is beneficial
-May also balance potassium levels
● Thiazides also have a vasodilator effect
-May contribute to BP reduction in later stages
THIAZIDE DIURETICS urinary levels
● Increased excretion of Na+, K+, H+ and
Mg2+ balance (qualitatively similar to loop diuretics)
● In contrast to loop diuretics, thiazides
reduce Ca2+ excretion
-May be advantageous in older patients at
risk of osteoporosis
● Synergistic effect with loop diuretics
CLINICAL USES of THIAZIDE DIURETICS
-HTN
- mild ❤️ failure (loop diuretics preferred)
-severe resistant oedema (metolazone, used w/ loop diuretics)
- to prevent recurrent tone formation in idiopathic hypercalciuria
- nephrogenic diabetes insipidus (malfxn of ADH, therefore we get dilute urine)
ADVERSE EFFECTS of thiazide diuretics
•Increase in urinary frequency
•Hyponatraemia - Warning
•Hypokalaemia (drug interactions) - Contraindication
•Hypomagnesemia
•Excretion of uric acid is decreased
-PK interaction: compete with uric acid for the
organic anion transporter (OAT) -> Warning
• Alkalosis
● Impaired glucose tolerance
-Hyperglycemia
● Hyperlipidemia (except indapamide)
● Erectile dysfunction
● Encephalopathy in severe liver disease
● Idiosyncratic reactions are rare
-Thiazides are also sulfa drugs
POTASSIUM SPARING DIURETICS ALDOSTERONE ANTAGONISTS MOA
Aldosterone (you retain Na, you lose K+)
•Enhances Na+ reabsorption and promotes K+
excretion
•Stimulates Na+ channels and induces their
synthesis
•Induces synthesis of Na+ /K +- ATPase
ALDOSTERONE ANTAGONISTS
Examples
spironolactone, eplerenone
ALDOSTERONE ANTAGONISTS
PK/PD
● Limited diuretic action when used singly
● Combined with loop diuretics or thiazides
●Marked antihypertensive effects
●May prevent hypokalaemia
● Prolong survival in heart failure
CLINICAL USES of K+ sparing diuretics
ADVERSE EFFECTS
POTASSIUM SPARING DIURETICS
•Hyperkalaemia, which is potentially fatal -> Contraindication
● Monitoring may be needed -> Be aware of drug interactions
● Gastrointestinal upset
● Gynaecomastia, menstrual disorders and
testicular atrophy
-May be used in female hirsutism
-Eplerenone has less anti-androgen effects
OTHER POTASSIUM SPARING DIURETICS
Examples
MoA
Adverse effects
Examples: triamterene and amiloride
•Limited diuretic efficacy
•MoA: They act on the collecting tubules and collecting ducts
-Inhibit Na+ reabsorption by blocking lumenal sodium channels
•May be given with loop diuretics or thiazides to maintain potassium balance
Adverse effects: •Hyperkalemia: contraindication
•Triamterene has been identified in kidney stones
Its etiological role is uncertain
CARBONIC ANHYDRASE INHIBITORS MOA
-Decrease H+ formation in proximal convoluted tubule cell
-Decrease Na+/H+ anti-port
-Increase Na+ and HCO3- in lumen
-Increase diuresis
CARBONIC ANHYDRASE INHIBITORS
Examples
acetazolamide, dorlozamide
CARBONIC ANHYDRASE INHIBITORS
Urine levels
Increase excretion of bicarbonate with accompanying Na+, K+ and water
Increased flow of alkaline urine (metabolic acidosis)
CARBONIC ANHYDRASE INHIBITORS
Clinical uses
Not used as a diuretic
Glaucoma: reduce the formation of aqueous humor
Idiopathic intracranial hypertension
Metabolic alkalosis
CARBONIC ANHYDRASE INHIBITORS
ADVERSE EFFECTS
Bicarbonaturia and acidosis
Hypokalemia
Hyperchloremia
Paresthesias
Renal stones (calcium precipitation in alkaline urine) NH3 toxicity (alkaline urine)
Acetazolamide is a sulfonamide
-Rashes, blood dyscrasias and interstitial nephritis can occur
-Cross-allergenicity with: all loop diuretics (except ethacrynic acid), thiazides, sulfa antibiotics,
celecoxib
HYDRALAZINE MoA
-Acts on arteries and arterioles predominantly
-Interferes with action of IP3 on Ca2+ release from SR
-Increases cGMP levels
•Decrease in BP
-Accompanied by reflex tachycardia and increased CO
HYDRALAZINE Clinical Uses
Short-term treatment of severe hypertension in
pregnancy
Heart failure (with nitrate)
Severe hypertension
ADVERSE EFFECTS of Hydralazine
Edema
Headache
Systemic lupus erythematosus-like symptoms
Reflex tachycardia
Can be co-administered with a beta-blocker to prevent reflex tachycardia
Contraindicated in angina and coronary artery disease (CAD)
BETA-BLOCKERS: MOA
SNS stimulation increases CO
Ventricle:
● Increased force of contraction cAMP
● Increased stroke volume
SA and AV node:
● Increased heart rate
Beta blockers reduce CO and BP
BETA-BLOCKERS
Less well-tolerated
Evidence supporting use in hypertension is weak Recommended for hypertensive patients with other indications for beta-blockers: angina, heart failure, post-MI
Labetalol: Also has α-1 adrenergic receptor blockade properties.
Safe and licensed to use in pregnancy
α1-BLOCKERS
MoA
Norepinephrine acting on α-1 adrenergic receptors on vascular smooth muscle cells leads to constriction
α1-BLOCKERS
Examples
-Doxazosin, prazosin, terazosin
Also improve symptoms of benign prostatic
hyperplasia (BPH): improve urine outflow
α1-BLOCKERS
Adverse effects
Postural hypotension
-Avoid in pre-existing postural hypotension (warning)
Reflex tachycardia
Urinary incontinence
Impotence
CENTRALLY-ACTING ANTIHYPERTENSIVES
Methyldopa
Methyldopa used for hypertension during pregnancy
Lack of documented side effects on baby
Centrally acting α2 agonist
Decreases sympathetic outflow: decreased TPR and HR
Methyldopa
Troublesome side effects
Sedation, depression, dry mouth, diminished libido,
parkinsonian symptoms, hyperprolactinemia, bradycardia, sinus arrest
Less common: hepatotoxicity, drug-induced lupus
Not as commonly used anymore
Also positive Coombs test
-May cause hemolytic anemia
HYPERTENSIVE EMERGENCY
● Clevidipine/Nicardipine ● Hydralazine ● Labetalol ● Nitroprusside ● Fenoldopam
NITROPRUSSIDE MoA
-Acts equally on arterial and venous smooth muscle
.-Acts by releasing nitric oxide (NO)
-Has to be administered IV
Little clinical usefulness except in hypertensive
emergencies
-Continuous monitoring for hypotension
NITROPRUSSIDE
-Prolonged use may cause thiocyanate accumulation and toxicity
-Weakness, nausea, inhibition of thyroid function -Hydrolyzes to cyanide in solution, especially in light
FENOLDOPAM
Selective dopamine (D1) agonist
Coronary, peripheral, renal, splanchnic vasodilation
Increases natriuresis
Decreased BP: can cause hypotension and tachycardia
Short-term management of severe hypertension in hospital > Improves renal perfusion
Its effect is similar in magnitude to IV nitroprusside
Lacks thiocyanate toxicity
Slower in onset/offset
PULMONARY ARTERIAL HYPERTENSION (PAH)
May be idiopathic or associated with other disease Increased pulmonary pressure can result from
Increased cardiac output
Vasoconstriction
Structural narrowing of pulmonary resistance arteries
Occlusion of pulmonary arteries by recurrent pulmonary
emboli Cellular proliferation and hypertrophy may follow Can progress to right heart failure
PA H D R U G S
•Treatment approach
-Calcium channel blockers (e.g. nifedipine)
-May benefit a small number of patients
•Drugs that antagonize endothelin
-Endothelin-1 receptors mediate pulmonary
smooth muscle constriction and proliferation
•Drugs that potentiate NO
•Prostanoids
ENDOTHELIN RECEPTOR ANTAGONISTS
Examples
Endothelin receptor antagonists (e.g. bosentan, ambrisentan, sitaxentan)
ENDOTHELIN RECEPTOR ANTAGONISTS
Clinical Use + MoA
Clinical Use: Orally for less severe stages of disease MOA: Antagonize effects on endothelin receptors (vasodilation, proliferation inhibition)
ENDOTHELIN RECEPTOR ANTAGONISTS
Adverse effects:
headache, flushing, hypotension
Hepatotoxic (monitor liver function tests)
Endothelins may affect development of the
cardiorespiratory system
Antagonists are teratogenic (contraindication)
SILDENAFIL
MoA+ clinical uses
MOA: PDE V inhibitor
Inhibits breakdown of cGMP
Pulmonary artery relaxation
Clinical Uses:
Erectile dysfunction
PAH
SILDENAFIL Adverse effects:
Adverse effects: headache, flushing, dyspepsia, cyanopia
Risk of life-threatening hypotension in patients taking
nitrates
Should not be taken if high risk of hypotension (recent stroke, recent acute coronary syndrome)
PROSTANOID AND ANALOGUES
Examples
Epoprostenol
● Prostacyclin (PGI2)
● Given as long-term IV infusion
● Improves survival
Prostanoid analogues
● Examples: iloprost, treprostinil, beraprost
● Parenteral routes of administration e.g. intravenous, subcutaneous or inhaled
● Used in more severe stages of disease
Adverse effects: flushing, jaw pain, cough, bronchoconstriction
