Pharmacology of CV Drugs 4

What are diuretics? (1)

Drugs which increase the excretion of salts (mainly NaCl) and water by the kidneys. Kidneys designed to filter large quantities of plasma (4% of plasma CO), reabsorb substances body must conserve, excrete substances to be eliminated

1 of 37

What are diuretics? (2)

Diuretics act by reducing Na/Cl reabsorption in nephron, also decreases water reabsorption via osmotic effect. 99% of Na/H2O filtered by kidneys is normally reabsorbed so even a small decrease in reabsorption will greatly increase urine volume

2 of 37

What are the clinical uses of diuretics? (1)

Oedematous conditions (loop diuretics, K+ sparing diuretics), HF (increase venous pressure due to reduced cardiac function), renal disease (protein lost via kidneys, plasma [protein] falls)

3 of 37

What are the clinical uses of diuretics? (2)

Hepatic disease (liver produced less albumin, plasma [protein] falls). Jv (movement of water from plasma to tissues) proportional to delta P - delta II. Hypertension (thiazide type diuretics) - reduced blood volume/CO, many diuretics dilate arteries

4 of 37

Describe the hydraulic and osmotic pressures in the microvasculature (1)

Pressure outside (0 mM Hg), pressure inside (20 mM Hg), hydrostatic pressure gradient (movement to outside). Osmotic pressure gradient caused by pressure inside (more protein/less concentrated water 27 mm Hg), pressure outside (10 mM Hg)

5 of 37

Describe the hydraulic and osmotic pressures in the microvasculature (2)

Water moves into capillary down osmotic pressure gradient. Small net H2O filtration returned to blood via lymphatic system. If sufficient, an increase in net H2O filtration causes oedema

6 of 37

Outline the reabsorption of Na in the kidney

125 mL/min in blood, Na and H2O excreted in urine (1 mL/min). Na reabsorption due to Ang II and aldosterone, H2O reabsorption follows due to ADH. Blood volume decreases, protein concentration increases, reduce oedema

7 of 37

Give an overview of nephron function (1)

20% plasma filtered at glomerulus (capillaries). Proximal tubule (2/3 water and salts reabsorbed, glucose/amino acids reabsorbed, HCO3 reabsorbed, H+ secreted, weak acids and bases (most diuretics) secreted

8 of 37

Give an overview of nephron function (2)

Loop of Henle. 25% Na reabsorbed, water not reabsorbed, urine becomes dilute, medullary interstitium becomes hypertonic due to countercurrent multiplication mechanism

9 of 37

Give an overview of nephron function (3)

At distal tubule, Na reabsorption. Collecting duct, Na reabsorption and K secretion regulated by aldosterone, water reabsorption in the presence of ADH. Urea also reabsorbed

10 of 37

Diuretics target which areas on the nephron? (1)

Loop diuretics target loop of Henle (ascending limb). Thiazide diuretics target distal convoluted tubule. K+ sparing diuretics target transporter at collecting duct

11 of 37

Describe the mechanisms for Na reabsorption in the kidney (1)

Proximal tubule NHE3 (60-70% Na reabsorbed). Loop of Henle (NKCC2, 20-30% Na reabsorbed, loop diuretics used). Distal tubule (NCCT, 5-7% Na reabsorbed, thiazide diuretics used). Collecting duct (ENaC, ROMK, K+ sparing diuretics used)

12 of 37

Describe the mechanisms for Na reabsorption in the kidney (2)

Na-K ATPase pump maintains concentration gradients

13 of 37

Describe features of loop (high ceiling) diuretics (1)

E.g. furosemide, torasemide. Block NKCC2 in thick ascending loop of Henle. Strongly inhibits Na reabsorption. Causes powerful diuresis because kidneys have a diminished capacity to create a hypertonic medullary interstitium

14 of 37

Describe features of loop (high ceiling) diuretics (2)

Needed to drive ADH-induced water reabsorption. Some solute which passes into medullary interstitium and draws water out of collecting ducts now remains in tubular fluid and draws water with it. Vasodilating effect (opening of K+ channels)

15 of 37

Describe the Na transport pathways in the thick ascending limb of the loop of Henle (1)

Na pump on basal surface. NKCC at luminal surface inhibited by loop diuretics e.g. furosemide. Na removed by Na-K ATPase pump and some by Na-HCO3- transporter. Cl diffuses out via CLCN channels, K diffuses back via ROMK channels at luminal surface

16 of 37

Describe the Na transport pathways in the thick ascending limb of the loop of Henle (2)

So can re-enter cell. Tight junction impermeable to water but allows diffusion of cations e.g. calcium and magnesium driven by positive potential

17 of 37

Describe features of loop (high ceiling) diuretics II (1)

Used for oedematous conditions (HF, hepatic cirrhosis). Potential adverse effects - hypokalaemia (due to increased Na-K exchange in collecting tubule). Metabolic acidosis (decreased plasma volume, contraction alkalosis/decrease plasma volume

18 of 37

Describe features of loop (high ceiling) diuretics II (2)

But no increase in HCO3- excretion. Depletion of plasma Ca/Mg (decreased potential gradient across TAL, less reabsorption, use for hypercalcaemia. Ototoxicity (deafness, uncommon), due to Cl handling of NKKCC2, resembles a Cl channel in inner ear

19 of 37

Describe features of loop (high ceiling) diuretics II (3)

Hypovolaemia (too much diuresis), hyperuricaemia (can precipitate gout). Similar effects seen with loss of function mutations to NKCC2 e.g. in neonatal Barrter syndrome

20 of 37

Outline the history of thiazide diuretics (1)

Sulphanilamide (anti-bacterial) caused diuresis (blocked carbonic anhydrase). Use of carbonic anhydrase inhibitors as diuretics (but caused metabolic acidosis). Introduce chlorothiazide (modified SUL)

21 of 37

Outline the history of thiazide diuretics (2)

Development of thiazide like drugs with non-thiazide structure but similar properties. Shown to block Na/Cl reabsorption in distal tubule

22 of 37

Describe features of thiazide type diuretics (1)

Medium efficacy (e.g. indapamide, bendroflumethazide, metolazone). Blocks Na/Cl co-transport in distal convoluted tubule, reduce plasma volume, venous return, CO. Also reduce TPR by unknown mechanism

23 of 37

Describe features of thiazide type diuretics (2)

Adverse effects - hypokalaemia, hyperglycaemia, hyperuricaemia, erectile dysfunction, hyponatraemia

24 of 37

Describe the Na transport pathways in the distal tubule (1)

Na pump on basal surface. Electroneutral Na/Cl co-transporter at luminal surface inhibited by thiazide diuretics. Na pump exchanges Na for K and Cl diffuses out via channels. K diffuses back through channels on basolateral surface

25 of 37

Describe the Na transport pathways in the distal tubule (2)

Both in distal tubule and loop of Henle, K transport across epithelium is not dependent on Na reabsorption

26 of 37

What is the effects of hydrochlorthiazide?

A fall in BP due to transient decrease in CO then a fall in TPR

27 of 37

Describe features of diuretics and K+ loss (1)

Thiazide and loop diuretics increase delivery of Na and fluid to collecting tubule. Increases Na uptake and coupled secretion of K+ and H+ in collecting tubule

28 of 37

Describe features of diuretics and K+ loss (2)

Increases K+/H+ secretion, causes hypokalaemia (cardiac arrhythmias) and metabolic alkalosis. Prevent hypokalaemia with K+ sparing diuretic or K+ supplement (with loop diuretic)

29 of 37

Outline the mechanism which causes hypokalaemia (1)

Na-K pump generates low Na in principal cell, Na enters cell down conc gradient via ENaC. K moves out of cell via ROMK, K+ excreted or enters type A intercalated cell (H+ also enter). Creates metabolic acidosis

30 of 37

Outline the mechanism which causes hypokalaemia (2)

K and H secretion coupled to Na reabsorption. Aldosterone upregulates Na pump and Na channels via protein synthesis (promotes Na reabsorption and K secretion by affecting phenotype). Amiloride and triamterne block ENaC (bloc Na reabsorption

31 of 37

Outline the mechanism which causes hypokalaemia (3)

Spironolactone antagonises aldosterone (takes a few days to effect to occur)

32 of 37

Describe features of K+ sparing diuretics (1)

Not used on their own due to limited diuretic effect and tendency to cause hyperkalaemia resulting inhibition of K+ secretion. Mainly used with loop/thiazide diuretics to enhance diuresis and prevent hypokalaemia. Also used an anti-hypertensives

33 of 37

Describe features of K+ sparing diuretics (2)

Spironolactone (MRA) - competitive aldosterone receptor antagonist, pro-drug (main metabolite - 17a-thiomethylspironolactone), very slow onset of action (days), most useful if aldosterone levels elevated (primary aldosteronism/secondary to HF)

34 of 37

Describe features of K+ sparing diuretics (3)

(hepatic cirrhosis). Has cardiac effect, not due to diuresis. Eplerenone is an alternative. Amiloride and triamterene (block collecting tubule ENaC, decrease Na reabsorption and K secretion)

35 of 37

What are the side effects of K+ sparing diuretics? (1)

Spironolactone and eplerenone (mineralcorticoid antagonists) - hyperkalaemia, GI upset, effects on other steroid receptors can cause gynecomastia, menstrual disorders, testicular atrophy (less common with eplerenone)

36 of 37

What are the side effects of K+ sparing diuretics? (2)

Triamterene and amiloride - hyperkalaemia, GI upset, but less common than with MRA. Hyperkalaemia can be very dangerous - co-administration of MRA with K+ supplements is contra-indicated (study)

37 of 37

Get Revising

Pharmacology of CV Drugs 4

Other cards in this set

Card 2

Front

Back

Card 3

Front

Back

Card 4

Front

Back

Card 5

Front

Back

Comments

Similar Pharmacy resources:

Other cards in this set

Card 2

Front

Back

Card 3

Front

Back

Card 4

Front

Back

Card 5

Front

Back

Comments

Related discussions on The Student Room

Similar Pharmacy resources: