Diuretics Flashcards
(40 cards)
1
Q
Diuretics
A
- Drugs that increase the rate of urine flow
- Effectively achieved by increasing Na+ (+an anion) excretion-water follows
- Used to adjust the volume/composition of body fluids
- Increasing the excretion of sodium and as an effect the excretion of water
- Generally use to change plasma volume or composition of the blood
- Makes the patients pee more!
2
Q
The 6 different classes of diuretics
A
- Carbonic anhydrase inhibitors
- Osmotic diuretics
- Loop diuretics
- Thiazides
- Na+ channel (ENaC) inhibitors (Potassium sparing)
- Aldosterone antagonists (Potassium sparing)
3
Q
Ways that water can move across the membrane
A
- water pores (transcellular)
- paracellular (this route can drag solutes with it! Especially important for cations (e.g. Ca2+, Mg2+))
4
Q
Carbonic anhydrase Inhibitors
A
- Historically important in understanding renal function: how the proximal tubule works, lots of sodium gets reabsorbed in the proximal tubule
- Weak diuretics: even though these drugs act in the proximal tubule where sodium is 80-90% reabsorbed
- acetazolamide, diclorphenamide
- Bc even if you block reabsorb. of sodium in proximal, the rest of the nephron will compensate
- Many side effects
- Main clinical use: treatment of glaucoma
5
Q
Glaucoma
A
Glaucoma: increased intraocular pressure
- cloudiness of the cornea (and the anterior chamber would likely be as well)
- blood vessels (sclera: white outer layer of eyeball) are engorged/prominent
- normally the cornea is anhydrous, but with glaucoma you get water in it because pumps arent working to keep water out with so much pressure on the eye
- globe was enlarged
- mydriasis–> dilation of the pupil
6
Q
Carbonic Anhydrase Enzyme
A
- Think about the acid base lectures!
- Carbonic Anhydrase catalyzes the reaction:
CO2 + H2O <–> H2CO3 <—> HCO3- +H+
(Bi-directional process)
- In the proximal tubular cells themselves and on the brush border: reason it is there is so that patient can reclaim bicarbonate
- Luminal & basolateral membranes & cytoplasm
- NaHCO3 reabsorption & acid secretion
7
Q
Mechanism of Action for Carbonic Anhydrase Enzyme and Bicarbonate reabsorption
A
- Blood gets filtered at the level of the glomerulus and within the blood there is some bicarbonate. If animal tends to eat more H+ ions (highly acidic), it is going to need to reclaim more bicarbonate from the tubular lumen
- Do so by harnessing the Na+/H+ antiporter on side of tubular lumen: sodium ions are being absorbed and H+ ions are moving into tubular lumen
- H+ ions and bicarbonate combine by action of carbonic anhydrase in the tubular lumen (really occurs on the brush border)
- That generates carbon dioxide and water that can move into the tubular epithelial cells
- Then the process occurs in the opposite direction by carbonic anhydrase to release bicarbonate and a proton (into epithelial cell)
- Basically H+ ion is taken from the cell into the tubular lumen and bicarbonate is reabsorbed back into the body by a Na+/HCO3- symporter
8
Q
Mechanism for Carbonic Anhydrase Inhibitors
A
- Normal net effect by carbonic anhydrase is for H+ to be lost and for bicarbonate to be reabsorbed
- If we give the patient a CAI:
- Increase in HCO3- excretion
- increased urine pH, make urine more alkalitic (less acidic/H+ protons)
- metabloic acidosis
- By recuing the amount of Na+ being re-absobed, we are causing increased water excretion as well
9
Q
Mech of CA inhibitor
A
10
Q
Side Effects of using Carbonic Anhydrase inhibitor
A
- Weak Diuretics: they act very proximally
- When you give them, more sodium (that is not being absorbed in the proximal tubule) actually makes it to the Juxtaglomerular Apparatus which causes a feedback
- Increased sodium and chloride delivery to JGA with reduce renal blood flow and glomerular filtration rate (RBF and GFR reduced)
- Makes urine more alkaline so you can get possible stones precipitating (urolithiasis)
- Can get hypokalaemia (lowered K+):
- increased distal delivery of Na+
- These are now rarely used systemically! They are used topically
11
Q
Topical Use of Carbonic Anhydrase Inhibitor
A
- Formation aqueous humor is caused by CA
- Ciliary body
- Formation of HCO3- moves Na+ (&H2O) into eye: glaucoma issues
- Catalyzed by carbonic anhydrase. this is what we are looking to inhibit with CAI. not the kidney!
- By giving it topically, we are avoiding side effects to the kidneys as would happen if we continued to give systemically
12
Q
Osmotic Diuretics
A
- Freely filtered at the glomerulus
- Inert-negligible tubular reabsorbtion. these are not really reabsorbed
- they are in the tubular lumen and create an osmotic effect
- Increase osmolarity of tubular fluid (& plasma)
- Increases excretion of almost all electrolytes (Na+, K+, etc.)
- Mannitol: One of the only classes that increases the excretion of water over and above the normal amount that would follow sodium –> Relative Water Diuresis
13
Q
Mechanism of Action for Osmotic Diuretics
A
- Osmotic diuretics: these drugs keep water with them and increase excretion because of that (more minor part of mech though)
- Major site of Action: Loop of Henle
- Expand ECF and inhibit renin release
- Increases RBF and reduces medullary tonicity (muscle tone)
- Secondary Osmotic effect in tubules limiting Na absorption
- Increase renal blood flow particularly through the medulla, increase RBF in the medulla in the vasa recta in the loops of Henle, reduce a concentration gradient so the patient cant really reabsorb water
14
Q
Osmotic Diuresis
A
15
Q
Clinical Uses of Osmotic Diuretics
A
- Acute Glaucoma: but topical therapies now generally preferred
- Acute kidney injury (renal failure): draws in lots of fluids and maintains the movement of fluid through the tubules. This prevents dying cells from sloughing off into the lumen and creating obstructions. but questionable efficacy since timing can be off
- Raised intracranial pressure/cerebral oedema: Where these are used most often
- given intravenously and increase vascular volume and excrete that volume and draw fluid out of tissues (brain)- effects can be quite marked (temporarily)
16
Q
Side Effects and Limitation
A
- Cause volume expansion, cannot be used if the patient is over-hydrated or anuric. If patient already is over hydrated due to issues in excretion
- May cause pulmonary oedema (heart can’t pump efficiently enough, fuid pushed into air space (alveoli) in lungs)
- Contra-indicated with intracranial haemorhage
- If you have bleeding in your brain, blood will take mannitol with it and mannitol that leaks into tissues is going to pull lots of fluid into the brain and make patients worse
- Car crash injuries, be careful
17
Q
Loop Diuretics
A
- What is used in the clinic day to day!
- Furosemide
- potent diuretics
- Most commonly used diuretics in veterinary medicine
- Inhibit Na+K+2Cl- symporter in the thick ascending limb of the loop of Henle
- Can be administered by a variety of routes: IM, IV, sub Q, orally
- Use in congestive heart failure often
- Dobermans commonly get dilated cardiomyopathy: condition in which the heart’s ability to pump blood is decreased because the heart’s main pumping chamber, the left ventricle, is enlarged and weakened
- Primary failure of the heart pump
18
Q
Pathophysiology Heart Failure
A
- Cardiac dysfunction
- Abnormal haemodynamics: fluid gets into alveoli and essentially “drowns” patient
- Neurohormonal activation
- Renal Retention Na & H2O: works on kidney to encourage more re-absorbtion of Na and H2O. It thinks that the patient is volume depleted
- Increased pulmonary capillary hydrostatic pressure
- Pump is failing
- Kidneys poorly diffused
- Kidney responds by producing renin
- And activating PNS and trying to reabsorb everything to help with fluid
- this increases hydrostatic pressure in the capillaries
- alveolis should really be air only
–> give diuretics to aid in this
- use in both acute and chronic heart failure
- Use in loop diuretics to get rid of the sodium and water
19
Q
Mecahnism of Action Loop of Henle
(Loop Diuretics)
A
- Work at Thick ascending loop of Henle
1. Sodium is normally moving from tubular lumen down its concentration gradient into the tubular epithelial cell by a K+/2Cl-/Na+ symporter
2. there is an ion channel that allows K+ to escape back out again from cell to tubular lumen (potassium concentrations are much lower than Na+ so we need escape mech for K to get back into the lumen –> would run out of K ions to use to move through symporter (rate limiting)
3. Sodium and Potassium are then reclaimed by the body from the epithelial cell
4. Because potassium escapes back into tubular lumen and the sodium and 2Cl- continue through: you get hyperpolarization on the tubular lumen side and depolarization on the basolateral membrane
5. this gradient is important because it causes a paracellular flux of cations (Na+, Ca2+, Mg2+): those are reabsorbed along with water
- Hyperpolarization to Depolarization = gradient for cations
20
Q
Mecahnism of Action: Loop Diuretics
A
- increase excretion of Na+ and Cl- (might just use them for that, diuretic effect)
- Prevent formation hypertonic medullary interstitium
- Increase excretion Ca 2+ and Mg2+ (can use in patients with hypercalcaemia as an emergency treatment)
21
Q
Side Effects and Limitations to Loop Diuretics
A
- Can be almost to effective: can deplete the patient of fluid
- typically related to diuretic efficacy
- Abnormalities of fluid and electrolyte balance
- Hypochloremic alkalosis
- Hypo-Mg2+ and Hypo-Ca2+ (if you give a lot)
- Hypokalaemia: increased distal delivery of sodium
22
Q
Thiazides
A
- not used in clinics very often : Don’t use that much in veterinary patients, sometimes for management of heart failure once patient has become refractory to previous drug. because most of sodium is absorbed in PDT, but then more sodium will make it to the distal tubule if these patients are previously treated)
- Has greater effect if other diuretic has already been used
- Inhibits Na+-Cl- symport in the distal convoluted tubule (DCT)
- Commonly used in human medicine for the treatement of hypertension (High BP)
- Also treatment oedema associated wth heart failure & cirrhosis (scarring of liver, increase flow?)
23
Q
Mechanism of Action: Thiazides
A
- Acts in the distal convoluted tubule
1. there is a sodium/Chloride symporter in cell/tubular lumen interface
2. thiazides inhibit that symporter therefore preventing further reabsorption of Na+
3. Increase Na+/Cl- excretion and Decrease Ca2+ excretion - The controlled reabsorption of calcium also occurs here
- can use to keep calcium stones from forming
24
Q
Hypertension in Veterinary Patients
A
- cat that has blood in the eye (hyphemia or intraoccular haemorrhage) –> blood in the anterior chamber as a consequence of hypertension –> consequence of hypertension
- most have it as a result of chronic kidney disease, tend not to use these drugs for hypertension due to that factor
25
Veterinary Use of Thiazides
* Quite limited
* Not used for treatment of hpyertension due to lack of efficacy and risk of hypovolaemia (decreased blood volume due to renal failure)
* Not very potent as more than 90% of sodium has already been absorbed at DCT
* Additive therapy, refractory HF
* Prevent calcium oxalate urolithiasis
26
Na+ channel (ENaC) inhibitors and Aldosterone antagonists
* **Potassium sparing diuretics!**
27
Inhibitors of Epithelial Cell Na Channels (ENaC)
**not used much in clinics**
* **Potassium sparing diuretics**
* _Amiloride_
* Principal cells in late distal tubule and collecting duct
28
Mineralocortioid Antagonists
| (aldosterone antagonist)
* **Most used in clinic of this type diuretic**
* **Potassium sparing!**
* _Spironolactone, eplerenone_ (more used in humans)
* Epithelial cells in the late distal tubule and collecting duct
29
Distal Tubule/collecting duct Mech of Action
(ENaC Inhibitor)
* In distal nephron
1. Have epithelial sodium channel and in distal tubule epithelial cells, when a sodium is taken into the cell by the channel, it is usually exchanged for a potassium ion which then goes into the tubular lumen and is excreted
- Thats why any diuretic that works proximal to this point will result in more sodium being deliverd to this apparatus and therefore more K+ will be exchanged and excreted
2. there is also an electrogenic potential that develops. Creates a electrical gradient that is towards the tubular lumen since Na+ is being absorbed and this means the animal excretes more H+ ions (through an ATPase)
* **Diuretics with proximal sites of action increase delivery of Na+ to the distal tubule tend to increase K+ and H+ excretion**
30
Mechanism of Action ENaC Inhibitor
* give patient **amiloride or something that inhibits sodium channel in DCT or collecting duct**
* will have diuretic actions and increase potassium content as it will be excreted less
* Increases Na+ excretion
* Decrease H+ and K+ excretion
31
Side Effects of ENaC Inhibitor
* Limited diuretic potency
* contra-indicated in hyperkalaemia: don't use if your patient already has high K+ values!
* **Clinical Use:**
****-Infrequent in vet med
-Sometimes used as a second diuretic in refractory oedema
32
Aldosterone Effects
* Aldosterone Binds to the Mineralocorticoid receptors (MR) and then to hormone response elements
* regulates the expression of aldosterone induced proteins which includes the sodium channel!
* Net effect is to increase Na conductance of the luminal membrane and Na pump activity (reabsorption!)
* Lumen negative - secretion K+ and H+
* Similar outcome as amiloride (ENaC inhibitor), but different mechanism
33
Aldosterone Antagonists
* similar effects to other potassium sparing diuretics
* Again, typically have limited diuretic efficacy, but often used for ascites (proteinacous fluid in the abdomen)
* May have additional benefits due to anti-fibrotic (reduce connective tissue accumulation in organs) effects, particularly in the myocardium
* Can use for hepatic cirrhosis for this reason as well
34
Why use Aldosterone Antagonists?
* Only diuretics to get to site of action via basolateral membrane (not luminal)
* Other drugs are excreted via organic anion transporters into tubular lumen. liver failure can produce toxic metabolites that can inhibit this process
May limit efficacy of diuretics in hepatic cirrhosis
* Also reduces the risk of hypokalaemia - which can lead to hepatic coma. good to use potassium sparing for these patients!!
* **Spironolactone**
35
Prerenal Azotemia
PRERENAL:
\*An azotemia as a result of reduced renal perfusion (blood flow to kidney).Loss of blood or dehydration
(Most common cause of acute renal failure)
Urine:
- oliguria (very small urine output)
- high USG (urine specific gravity): density of urine to water
36
Renal (Intrarenal) Azotemia
* **Kidney is at fault**
* RENAL(kidney is at fault) :
\*An azotemia due to parenchymal renal disease (disorder affecting glomeruli)
-Acute Renal Failure
Urine:
- variable amount
- low USG: more water density than urine (lack of filtering at glomeruli!)
- quite dilute urine
- the tubules arent working, so not concentrating properly. Cant just blame on dehydration
37
Postrenal azotemia
POSTRENAL:
\*An azotemia caused by interference with the excretion of urine
-urine cant be excreted so it just builds up
Urine:
- anuria (non passage of urine)
- high USG (**if you take from bladder**), just not being urinated
38
Uric Acid
* birds and reptiles excrete uric acid where as mammals excrete urea (birds excrete a bit of urea as well)
* Uric acid takes the most energy to excrete, but saves a lot of water loss. Ammonia excretion takes the least amount of E, but uses the most water (marine)
39
Why are birds and reptiles so susceptible to gout?
* No loop of Henle. Uric acid is really concentrated as it is meant to conserve water. If theres no water---\> get crystals (due to dehydration)
* Caused by uric acid crystal deposits, reptiles and birds always produce uric acid. So if there water imbalance or dehydration, they can get more vulnerable to these deposits. If they are dehydrated they won't excrete uric acid properly and it will deposit throughout the body . Pre-renal? Not enough blood flow
* Levels are above saturation point (improper diet)
40
Different types of gout
* _Primary_: abnormal protein breakdown in liver (too much ammonia waste products)
* _Secondary_: improper diet, dehydration, kidney disease causing excess amount in body
How to treat?
Alter diet, surgical removal, increase hydration
**Vegetarian**-need to feed entirely vegetarian, no protein (more waste product resulting from aa breakdown in the liver from protein. Some systems will get saturated with uric acid and cannot excrete effectively)
**Carnivores**- need to feed animal based protein diet, but just lower protein
