Diuretics are pharmacological agents used to regulate fluid volume in the body by acting on different sites within the nephron to alter the retention and excretion of various ions such as sodium, chloride, potassium, and water.
RENAL IMPAIRMENT
Results in a decreased GFR and hence proteinuria, hypoalbuminemia and low oncotic pressure. This low oncotic pressure drives fluid into the intersitium. The decreased intravascular volume activates RAAS system causing Na+ retention and H20 reabsorption.
CIRROHSIS
Due to either chronic inflammation (alcohol) or hepatotoxic insult results in fibrosis. This causes occlusion of outflow causing increased pressure in the portal vein resulting in portal hypertension. This causes ascites formation and a decreased intravascular volume. This decrease in intravascular volume activates RAAS resulting in Na+ retention and water reabsorption
HEART FAILURE
This is when either the LV or RV doesn't pump out a significant CO. This results in a "percieved" fluid depletion causing activation of the SNS and RAAS resulting in an increase in venous pressure and oedema formation
RAAS
DRUGS THAT ACT ON THE RAAS SYSTEM:
Aliskiren: enzymatically cleaves renin thus reducing BP. contraindicated in pregnant women with high BP due to foetal malformations and neonatal death. Other SE include renal artery stenosis (reduced GFR & filtration). Long T1/2 but low oral bioavailablity.
CERL (captopril, enalapril, ramipril & lisinopril): active compounds vs prodrugs, t1/2, 2 ways they decrease BP & increase cough, other SE (CAPTOPRIL)
LCVp (losartan, candesartan, valsartan): AGII receptor antagonists. Inhibt AGII from carrying out natruetic & vasoconstrictive roles. Used in cases where ACE inhibitors SE are not tolerated e.g. dry cough. Tx HF & high BP. Oral agents with t1/2 of 6,8,10hrs
ACTIVATION:
B1 adrenoceptor activation | Decreased Na+ in distal tubules of kidneys | Hypoperfusion of renal artery
Activated when ANGIOTENSINOGEN (liver) turned into ANGIOTENSIN I by the enzyme RENIN (aspartyl enzyme secreted by the smooth muscle of the JXG of the kidney).
ANGIOTENSIN I is converted to ANGIOTENSIN II by ACE (endothelium of the lungs and kidneys).
Results in activation of SNS | Vasoconstriction which increases BP | Na+, Cl-, H2O retention and reabsorption which increases perfusion| ADH secretion | Aldosterone secretion which increases tubular reabsorption of Na+, Cl-, H20 & excretion of K+
Ultimately the increase in vascular volume negatively feedbacks inhibiting renin
What senses
Plasma Tonicity?
Circulating Volume?
Circulating volume is sensed by baroreceptors in the:
carotid sinus and the aortic arch. There are also stretch receptors in the atria.
Upon activation it results in activation of SNS, RAAS and ADH release. This causes vasoconstriction, Na+, Cl-, H20 retention and reabsorption, K+ excretion and increase in vascular volume
Plasma Tonicity is sensed by osmoreceptors in the hypothalamus. It causes the posterior pituatary gland to release ADH and additionally it stimulates thirst resulting in free water intake. ADH activates V2 receptors in the collecting duct resulting in an increased expression of aquaporin 2 channels in the collecting duct causing H2O reabsorption.
Diuretics
drugs that act on FOUR different sites in the nephron causing the retention of Na+, Cl- & H2O and the excretion of K+ (except for K+ sparing diuretics).
banned in sports because they cause 1) dilute banned substances 2) weight loss
effects of diuretics are 1) diuresis 2) altered pH 3) altered ionic concentration in blood & plasma
ALDOSTERONE ANTAGONISTS e.g. spironolactone, eplerenone
They have are pro-drugs and upon conversion to it's active metabolite it has a slow onset (2-3 days). It is well absorbed.
Normally aldosterone binds to intracellular receptors and results in the transcription of genes encoding for Na+ channels and Na+/K+ ATPase, thus increasing their expression. This results in reabsorption of Na+ and H2O and increases the secretion of K+ and protons.
Thus when aldosterone antagonists such as spironolactone and eplerenone compete with aldosterone for binding at these intracellular receptors, it reduces the formation of Na+ channels and Na+/K+ ATPase. This results in Na+ and H2O loss but it spares K+ & protons.
It is often given in conjuction with a thaizide/loop diuretic to treat hypertension and exudative oedema (HF, LF, RF). Also used to tx hyperaldosteronism
SE include gynaecomastia, menstrual disorders and sexual dysfunction because spironolactone can bind to other steroid receptors however epleronone is more selective so the SE are minimised
Na+ CHANNEL BLOCKERS e.g. amiloride, triamterene
Triamterene has a short t1/2 of 1-2 hours and Amiloride has a t1/2 of 6-9 hours
Blocks Na+ channels in the luminal membrane in the collecting duct. This decreases Na+, K+ exchange and hence the loss of K+.
Hence there is a secretion of Na+, Cl- and H2O leading to hypovolemia, lowering of BP & treatment of transudative oedema (HF, LF, RF).
SE include hyperkalaemia and metabolic acidosis due to increased K+ & proton retention, additionally GIT upset (perhaps to increased H+?)
THIAZIDES e.g. hydrochlorothiazide, bendroflumethiazide, chlortalidone
Hydrocholorothiazide and bendroflumethiazide t1/2 is less than 4 hours whilst chlorthalidone is 24 hours and is used overnight to treat rises in BP
Block the Na+/Cl- transporter on the apical membrane in the DCT. This results in loss of Na+, Cl-, K+ & H20 however there is a decrease in the Ca2+ leading to hypercalcaemia.
This results in hypovolemia and inodilation resulting in an decrease in BP.
Side effects include hypokalaemia which can result in arrythmia and digoxin toxicitiy | metabolic alkalosis | hypercalcaemia which can result in arrythmias| hypovolemia which can result in orthostatic hypotension, arrythmia and shock | hyperglycaemia which can unmask diabetes | gout | hypersensitivity which can result in bone marrow suppression, dermatitis but is it rare
first line treatment of hypertension (due to inodilatory and hypovolemic). also used to treat transudative oedema (along to furosemide)
LOOP DIURETICS e.g. Furosemide & Bumetanide (40x more potent).
They are administered either orally or paraenterally and they reversibly inhibit Na+/K+/2Cl- co transporter found on the luminal membrane in the ascending loop of henle.
This results in a retention of Na+, Cl-, H20 and also Mg3+ and Ca2+ paracellularly.
Side effects include: hypokalemia and metabolic alkalosis due to more Na+ presented to the collecting duct stimulates the exchange of K+ and protons for Na+. This means that loop diuretics are given in combination with K+ sparing.
Hypocalcaemia however this is only clinically significant with the long term use of loop diuretics.
Hypovolaemia which can lead to orthostatic hypotension, arrythmias and shock.
Ototoxicity especially if given with combination with aminoglycosides
Excaberates gouts.
Used to treat 3 most common causes of transudative oedema (HF, liver failure [hypoalbuminemia oedema] and renal failure [nephrotic syndrome] )
Hypercalcaemia
Subtopic
CA inhibitors e.g. Acetazolamide (pro-drug)
it has a short half life (2-4 hours) and a high oral bioavailability (95%)
it works by reversibly inhibiting CAII & CAIV thus increasing Na+ and bicarbonate in the distal parts of the nephron. This initially causes an acute decrease in plasma volume but this is inaffective because main Na+ reabsorption occurs in the looop of Henle.
side effects include: renal calculi, worsens respiratory acidosis (COPD), caused metabolic acidosis.
uses: treat closed angle glaucoma because it decreases the rate of aqeuous humour formation. also used to treat altitude sickness and epilepsy.
OSMOTIC DIURETICS e.g. mannitol
small hydrophillic substances that primarily act in the proximal tubule.
they are filtered through the glomerulus and they are not well reabsorbed due to large molecular size; this leads to increased osmolality of tubular fluid and thus decreased water reabsorption.
due to their ability to increase H2O excretion and not Na+ secretion, they're not useful in treating oedema caused by Na+ retention e.g. HF. they are however used in the treatment of cerebral oedema and hence can decrease ICP.
