Manipulating Renal Physiology

Question 1

What haem problem may occour 2ndry to kidney damage?

Answer 1

Anaemia d/t lack of EPO

Question 2

Functional unit of the kidney?

Answer 2

Nephron

• glomerulus, bow mans
• PCT
• loop of henle (descending , ascending thin AND thick ascending) and vasa recta
• distal tubule
• connecting tubule, collecting tubule (cortical and medullary portions) collecting duct

Question 3

Outline set up of the glomerulus

Answer 3

• 2 set sof capillaries in series (afferent and eggerent arteriole either side of 1st capillary bed)
• high pressure glomerular capillaries
• glomerular basement membrane
• podocytes of visceral epithelium (slit pores)

Question 4

functions of the PCT

Answer 4

• returns 70% filtered load to plasma
• non-selective reabsorption
• SODIUM cotransport (glucose, aas, hydrogen ions (bicarb reabsorption) phosphate (PTH and FGF regulated) chloride flux, water follows passive)

Question 5

How does the Loop of Henley function? What is its purpose and what is the fluid leaving the loop like?

Answer 5

• counter current (salt and creatinine)
• descending loop impermeable to SALT, ascending loop impermeable to WATER
• thick ascending limb active transport Na, K, Cl out of tubule (no water)
• vasa recta (glomerular tubular feedback)
• HYPOtonic fluid leaves loop of henle, enters distal tubule
• animals with more concentrated urine have longer loops

Question 6

Where is the Macula densa situated and what is its function|?

Answer 6

• in distal convoluted tubule
• passes right next to afferent arteriolar, senses chloride passing per unit time to signal glomerulus and regulate GFR
• glomerular tubular feedback

Question 7

Blood supply throug kidney

Answer 7

Afferent Arteriole, glomerulus, efferent Arteriole, tubular

Question 8

Renin secreted by what?

Answer 8

Modified smooth muscle, afferent Arteriole

Question 9

What stimulates renin secretion?

Answer 9

• reduced stretch
• signals from macula densa (if ^ flow, v renin, ^ adenosine to constrict arterioles)
• sympathetic nerves

Question 10

Actions of renin ?

Answer 10

Cleaves ATsinogen -> AT1, cleaved by ACE -> AT2

Question 11

Effects of AT2?

Answer 11

^ BP

• constricts efferent aa
• enhances Na and water absorption (PCT)
• stimulates aldosterone secretion (encourages salt conservation)

Question 12

What effects will ACE inhibitors (benazepril) or Ang2 R blockers (telmisartan) have in the kidney?

Answer 12

• Inhibits RAAS but only if this system has been activated anyway
• ie. could v GFR -> ^ creatinine if dehydrated or over-diuresed
• if normal healthy little effect on kidney
• useful in CKD to v hyperfiltration (stop lossof important things through kidney) -> expect creatinine to rise slightly but not excessively (shouldn’t make animal ill)

Question 13

Where is the site of action of aldosterone?

Answer 13

Distal tubule (regulation of sodium resorption and therefore potassium excretion)

Question 14

What does aldosterone stimulate?

Answer 14

• more Na channels inserted and sodium pumps
• more K channels inserted
• Distal tubule site of fine control of acid base balance (regenerating bicarbonate used as buffer, carbonic anhydrase needed)
• H+ ions secreted by protion pump and buffered in urine by phosphate (net bicarb reclaimed)

Question 15

What effect may inhibiting the aldosterone system have?

Answer 15

• ^ blood potassium

Question 16

Where does PTH act? What does it do?

Answer 16

Regulates resorption of Ca in distal tubule ensuring right amount excreted
PTHs actions on phosphate reabsorption occour in proximal tubule

Question 17

Effects of ADH? Where does it act?

Answer 17

Inserts more Water channels and ^ urea permeability

• acts on connecting tubule, collecting tubule and collecting duct
• as duct passes through concentrated medulla, water reabsorbed if ADH present and urine concentrated
• urea recycled to be used as concentration gradient

Question 18

Why may Urea and creatinine levels change independently?

Answer 18

(Urea will be maintained to help concentrate urine so will rise disproportionate to creatinine which is excreted proportionally to GFR)

Question 19

What effects creatinine and urea level

Answer 19

Urea meat consumed

Creatinine muscle mass

Question 20

Connecting tubule, collecting tubule and duct

Answer 20

• sensitive to ADH (covered on another slide)

Question 21

Principles of mechanism of diuretic function

Answer 21

• most direct action on nephron (later sections not really bowmans)
• inhibit sodium chloride reabsorption to increase salt and water excretion
• counter act salt and water retention in heart failure
• activate renin secretion

Question 22

Functions of the kidney

Answer 22

• excretion nitrogenous waste
• regulation water, electrolyte, minerals and acid base
• production activation hormone s (calcitriol, active vit D3, epo) q

Question 23

What site of action would you give ACE inhibitors as diuretics?

Answer 23

PCT

Question 24

Where do loop diuretics act?

Answer 24

on ascending LOH from tubule side

Question 25

What type of drugs are loop diuretics and how do they reach their site of action?

Answer 25

- highly plasma protein bound so must reach site of action by active secretion in PCT

Question 26

Which are the most efficacious diuretic class?

Answer 26

Loop diuretics (25% filtered load can be lost)

Question 27

What other actions do loop diuretics have?

Answer 27

- pulmonary venodilator action if given IV (so good if animal drowning in pulmonary oedema) - ^ renal flow rate (hence GFR) ^ Ca loss so used for hypercalceamia

Question 28

Most commonly used loop diuretic?

Answer 28

Furosemide

Question 29

How long does furosemide take for onset, when is peak action and duration?

Answer 29

- IV: 5 min, peak effect 30mins, duration 2hrs | - oral: 1 hr, peak effect 2 hrs, duration 6hrs

Question 30

Where do thiazide diuretics act? How do they work?

Answer 30

- early DCT | - bind Cl- bit of NaCl transporter

Question 31

How efficacious are thiazides?

Answer 31

- PROMOTE 10% LOSS of filtered load (less efficacious than loop diuretcis)

Question 32

What side effects may thiazides have?

Answer 32

Promote calcium retention in humans (don't know wh) | - anti-hypertensive effects including vascular action

Question 33

Egs of thiazides used in dogs?

Answer 33

- chlorothiazide | - hydrochlorothiazide

Question 34

What is the bioavailability of thiazides? Time of onset, peak activity and duration of action?

Answer 34

- orally active - onset within 1hr - peak @ 4hrs - duration 6-12hrs

Question 35

How do potassium sparing diuretics work? Are they powerful diuretics?

Answer 35

- act on collecting tubule, inhibit action of aldosterone | - weak on their own, work syndergistically with other diuretcis, used mainly to prevent K loss

Question 36

Egs of potassium sparing diuretics? How do these work?

Answer 36

- Spironolactone competitive antagonist of aldosterone | - Triamterene and amiloride non-competitive inhibitors (block Na channels)

Question 37

Potential adverse effects of K+ sparing diuretics? Which type of diuretic is most likely to cause this?

Answer 37

> Hyperkalaemia - esp. non-competitive inhibitors - competitive (ie spironolactone) will eventually be overcome by ^ levels aldosterone if K+ needs to be excreted, but non-compeotive wont

Question 38

What other effects does spironolactone have?

Answer 38

- death from progressive HF and sudden cardiac causes decreased (not sure of this mechanism??) - minimal side effects

Question 39

Explain beneficial effects of aldosterone R antagonists to the heart failure patient FURTHER READING

Answer 39

-

Question 40

General adverse effects of diuretics

Answer 40

- volume v and circulatory impairment | - synergistic with vasodilators that reduce pre-load

Question 41

How can adverse effects of diuretics be overcome?

Answer 41

- ID cases that are PRELOAD depenedant - monitor HR, BP, muscle strength - reduce dose when congestion resolved - Hypokalaemia (furosemide) - Hypomagnesaemia (Thiazides) - Hyperkalaemia (K sparing diuretics) - HYPONATRAEMIA - very poor prognosis if seen, can occour with all diuretics, indicates refractory HF d/t inappropriate ADH secretion - hypochloraemic metabolic alkalosis (furosemide and thiazide)

Question 42

What causes hypokalaemia and hypomagnesaemia and why are these important for HF patients?

Answer 42

- caused by hyperaldosteronism | - exacerbate ventricular arryhythmias and digoxin toxicity

Question 43

How do NSAIDs affect renal activity?

Answer 43

- Renal PGs are natriuretic (salt losing) - NSAIDs -> exacerbated salt and water retention in HF (reduces diuretic efficacy) - COX1 and COX2 equally

Question 44

How may the pharmacokinetics of diuretics be affected?

Answer 44

- onset of action faster with IV - duration of action shorter with IV - bioavailability poorer with RSHF

Question 45

Which combinations of diuretics are synergistic?

Answer 45

- Loop + thiazide - Loop/thiazide + K sparing - Vasodilator + diuretic

Question 46

What do effective diuretics promote ?

Answer 46

K+ and Mg2+ loss by activating RAAS

Question 47

What is torasemide?

Answer 47

More potent form of furosemide