Manipulating Renal Physiology Flashcards
What haem problem may occour 2ndry to kidney damage?
Anaemia d/t lack of EPO
Functional unit of the kidney?
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
Outline set up of the glomerulus
- 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)
functions of the PCT
- 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)
How does the Loop of Henley function? What is its purpose and what is the fluid leaving the loop like?
- 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
Where is the Macula densa situated and what is its function|?
- 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
Blood supply throug kidney
Afferent Arteriole, glomerulus, efferent Arteriole, tubular
Renin secreted by what?
Modified smooth muscle, afferent Arteriole
What stimulates renin secretion?
- reduced stretch
- signals from macula densa (if ^ flow, v renin, ^ adenosine to constrict arterioles)
- sympathetic nerves
Actions of renin ?
Cleaves ATsinogen -> AT1, cleaved by ACE -> AT2
Effects of AT2?
^ BP
- constricts efferent aa
- enhances Na and water absorption (PCT)
- stimulates aldosterone secretion (encourages salt conservation)
What effects will ACE inhibitors (benazepril) or Ang2 R blockers (telmisartan) have in the kidney?
- 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)
Where is the site of action of aldosterone?
Distal tubule (regulation of sodium resorption and therefore potassium excretion)
What does aldosterone stimulate?
- 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)
What effect may inhibiting the aldosterone system have?
- ^ blood potassium
Where does PTH act? What does it do?
Regulates resorption of Ca in distal tubule ensuring right amount excreted
PTHs actions on phosphate reabsorption occour in proximal tubule
Effects of ADH? Where does it act?
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
Why may Urea and creatinine levels change independently?
(Urea will be maintained to help concentrate urine so will rise disproportionate to creatinine which is excreted proportionally to GFR)
What effects creatinine and urea level
Urea meat consumed
Creatinine muscle mass
Connecting tubule, collecting tubule and duct
- sensitive to ADH (covered on another slide)
Principles of mechanism of diuretic function
- 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
Functions of the kidney
- excretion nitrogenous waste
- regulation water, electrolyte, minerals and acid base
- production activation hormone s (calcitriol, active vit D3, epo) q
What site of action would you give ACE inhibitors as diuretics?
PCT
Where do loop diuretics act?
on ascending LOH from tubule side
What type of drugs are loop diuretics and how do they reach their site of action?
- highly plasma protein bound so must reach site of action by active secretion in PCT
Which are the most efficacious diuretic class?
Loop diuretics (25% filtered load can be lost)
What other actions do loop diuretics have?
- 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
Most commonly used loop diuretic?
Furosemide
How long does furosemide take for onset, when is peak action and duration?
- IV: 5 min, peak effect 30mins, duration 2hrs
- oral: 1 hr, peak effect 2 hrs, duration 6hrs
Where do thiazide diuretics act? How do they work?
- early DCT
- bind Cl- bit of NaCl transporter
How efficacious are thiazides?
- PROMOTE 10% LOSS of filtered load (less efficacious than loop diuretcis)
What side effects may thiazides have?
Promote calcium retention in humans (don’t know wh)
- anti-hypertensive effects including vascular action
Egs of thiazides used in dogs?
- chlorothiazide
- hydrochlorothiazide
What is the bioavailability of thiazides? Time of onset, peak activity and duration of action?
- orally active
- onset within 1hr
- peak @ 4hrs
- duration 6-12hrs
How do potassium sparing diuretics work? Are they powerful diuretics?
- act on collecting tubule, inhibit action of aldosterone
- weak on their own, work syndergistically with other diuretcis, used mainly to prevent K loss
Egs of potassium sparing diuretics? How do these work?
- Spironolactone competitive antagonist of aldosterone
- Triamterene and amiloride non-competitive inhibitors (block Na channels)
Potential adverse effects of K+ sparing diuretics? Which type of diuretic is most likely to cause this?
> 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
What other effects does spironolactone have?
- death from progressive HF and sudden cardiac causes decreased (not sure of this mechanism??)
- minimal side effects
Explain beneficial effects of aldosterone R antagonists to the heart failure patient FURTHER READING
-
General adverse effects of diuretics
- volume v and circulatory impairment
- synergistic with vasodilators that reduce pre-load
How can adverse effects of diuretics be overcome?
- 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)
What causes hypokalaemia and hypomagnesaemia and why are these important for HF patients?
- caused by hyperaldosteronism
- exacerbate ventricular arryhythmias and digoxin toxicity
How do NSAIDs affect renal activity?
- Renal PGs are natriuretic (salt losing)
- NSAIDs -> exacerbated salt and water retention in HF (reduces diuretic efficacy)
- COX1 and COX2 equally
How may the pharmacokinetics of diuretics be affected?
- onset of action faster with IV
- duration of action shorter with IV
- bioavailability poorer with RSHF
Which combinations of diuretics are synergistic?
- Loop + thiazide
- Loop/thiazide + K sparing
- Vasodilator + diuretic
What do effective diuretics promote ?
K+ and Mg2+ loss by activating RAAS
What is torasemide?
More potent form of furosemide
