Antihypertensive - Diuretics and RAAS system blocker

Question 1

what are the 3 tubular targets of diuretics and rank their effectiveness according to names

Answer 1

1. Loop diuretics: thick ascending limb = most effective
   ie furosemide
2. thiazide = distal convoluted tubule = second effective
   ie hydrochlorothiazide, chlorthalidone
3. K sparring diuretics = least effective, works at collecting duct
   ie. aldosterone receptor antagonist - spironolactone
   ie amiloride

Question 2

describe the mechanism of action of thiazide

Answer 2

Target: NaCl transporter at the apical membrane of distal tubule

normal mechanism: NaCl transporter = tubular Na into cell
basolateral: KCL and Na/KATPase remove NaCl = water follows

when blocked
less NaCl reabsorption = less water = volume loss = no odema/ hypertension

activates Ca/Na exchanger: on basolateral membrane: increase Ca absorption = good for osteoperosis

Question 3

describe mechanism of loop diuretic resistance

Answer 3

1. reduced renal blood flow = reduced GFR = less drug delivered to site of action
2. increased Na absorption at proximal tubule = less left to reabsorbed = less drug target at proximal tubule
3. reduced renal blood flow = increase endogenous organic acids = compete for transporters to carry drug to target

Question 4

describe mechanism of ARB and ACE inhibitors resistance

Answer 4

1. ARB = AT1 receptor blocked = remove AngII negative feedback = increased renin
   = increased Angiotensinogen conversion to AngII
2. Alternative mechanism for aldosterone sythesis ie (K level and ACTH)
   = aldosterone has +feedback effect
   = ACE inhibitor effectiveness

= renin inhibitor used

Question 5

what are the examples of ARB and ACE inhibitors. which class is better and why

ARB selectivity

Answer 5

ACE inhibitor: captopril
ARB: losartan, valsartan = selective for AT1
(AT2: vascular smooth muscle relaxation

ARB better as it blocks downstream of RAS system: as AGII is the main executor

Question 6

what are the side effects of ARB or ACE inhibitor x4

Answer 6

1. hypotension
2. acute renal failure
3. preganancy careful = fetal hypotension, congenital malformation, renal failure
4. irritating cough
5. hyperkalaemia due to reduced aldosterone action

Question 7

what are the mechanisms of action of K sparring diuretic

Answer 7

normal:
basolateral : Na/KATPase creates gradient
Apical: Na channel = passive
K channel = passive
there is also net hagative charge in tubular fluid: repels Cl-
= more into blood

basolateral: HCO3/Cl- exchanger: more Hco3 reabsorbed
apical: H-ATPase: H excreted

increased in Na enhances these process: alkalosis and K loss

blocked: K preserved (hyper), acidosis,

Question 8

what are the targets and side effects of : amiloride and spironolactone

Answer 8

spironolactone: sex hormone receptor affinity = impotence, gynaecomastia, irregular menstrual
amiloride: targets apical K channel and Na Channel

Question 9

what are the mechanisms of action of loop diuretics

Answer 9

targets: apical na/k/2cl transporter
basolateral: KCL and NA/KATPase removes Na = water reabsorbed
K leak gradient into tubule: repel positive: Ca++ and Mg++ reabsorbed

Question 10

what are the side effects of loop

Answer 10

ontotoxicity, hypovolaemia (hyperuremia, hyperlipidaemia, hyperglycaemia), loss K (collecting duct lots of Na enhance process), alkalosis, loss of ions