Renal Pharmacology Part 2 Flashcards
What are the most effective, or high ceiling, diuretics?
High ceiling diuretics
Furosemide (Salix®, Disal®), bumetanide
(Bumex®), ethacrynic acid (Edecrin®)
High ceiling diuretics act at _______ ______, in the ______ ascending limbs.
MOA: Binds and impairs the function of the ______ (reduce up to ____% of ______ reabsorption)
Henle‘s loop, thick, NKCC, 25, sodium
Which loop diuretics act at the NKCC in the mTAL?
Furosemide
Bumetanide
Ethacrynic acid
K can move to tubular lumen or interstitium.
Cl has one chance, the Cl channel at BL membrane. CL enters interstitium, whihic becomes more negative than the lumen. The differenc ebetween lumen and interst –> drrives movement of + ions Mg, Ca, sodium, and K. Move through tigh junctions and can diffuse through spores via paracellular pathway.
If you block Na reabsorption and paracellular movement of Ca and Mg. 65% of Mg is absorbed in mTAL, whihc is critical.
_________ (_________ derivative) is the most popular loop diuretic in veterinary medicine (tablets, boluses, injections).
- It increases ______ and ______ excretion with the urine → ___ ECF
- Blockage of the ?
- Disruption of the _________ ______ system
- Possess ________ effects at low doses
Furosemide, sulfonamide, sodium, chloride, ↓, tubulo-glomerular feedback, countercurrent, multiplier, antioxidant
ECF = intersttiial fluid, wihc we want to remove to prevent edema.
Block feedback; NKCC is a functional component of glomerular feedback. NKCC is in macula densa cells and this is the only way they can detect how much sodium enters cells so they can adjust GFR. ? is not able to communicate with glomerulus, so the GFR will keep going b/c you are blokcing the tubularglomerular feedback.
System: Is it important for the process of the counter current multiplying mechanism? Blood flows via vasorecta on one side it flows down and the ubular fluid flows up. Vasa recta goes up, blood flows upwards, and then the descending loop of henle makes fluid flow down. The other aspect is the increased osmolarity in the medullary interstitium.
Osmolality of interstiiium goes down when block NKCC whihc impairs urine concentration system maanged by countercurrent system, which is good because we want to get rid of the water.
Furoesemid specifically –> antiox. It can act as a free radical scavenger, making free radicals less harmful
Furosemide bioavailability ~____% (dogs); _______ plasma protein binding; half-life _____ (? h); max onset ____ h; duration _____h
Good absorption through the ____ tract (______ very slow) Withdrawal in meat and milk = ____ h
Side effects: excretion of (3?), _______,
________ appetite, _________ (impaired electrolyte transport). Not recommended in _________ or __________ animals
Furosemide bioavailability ~77% (dogs); high plasma protein binding; half-life short
(1.5-3 h); max onset 1-2 h; duration 2-4 h
Good absorption through the GI tract (horses very slow)
Withdrawal, meat and milk, 48 h
Side effects: excretion of calcium, magnesium, and potassium, lethargy,
decreased appetite, ototoxicity (impaired electrolyte transport). Not
recommended in pregnant or lactating animals
furoesmide comes not from filtration but from active secretion
Mg and K becuase of excess fo sodium at the CD?
The pig pictured below is suffering from what condition?
What medication is typically used to treat this condition?
Edema disease, head, pig. The skin of the eyelids, snout, and submandibular area are edematous as a result of production of angiotoxin by Escherichia coli, which increases the permeability of capillaries.
Furosemide indications:
Edema in general (udder, cattle; pulmonary; liver disease; cardiovascular, etc)
The cow pictured below is suffering from what condition?
What medication is typically used to treat this condition?
Udder edema, 2-y old Holstein Friesian heifer. The heifer had calved a few days previously
Furosemide indications:
Edema in general (udder, cattle; pulmonary; liver disease; cardiovascular, etc)
The horse pictured below is suffering from what condition?
What medication is typically used to treat this condition?
Furosemide _______ pulmonary vascular pressure and is used to treat ________-
induced pulmonary hemorrhage in horses
During exercise, cardiac ________ increases 6 to 8 times → high _____ atrial pressure → pulmonary capillaries → blood vessels _____ in order to ___ PVR and eventually ______
Signs:
pulmonary ________, _____, ________ of the pulmonary ______, intra-alveolar ______, and presence of blood in the ______
Furosemide lowers pulmonary vascular pressure and is used to treat exercise-
induced pulmonary hemorrhage in horses
During exercise, cardiac output increases 6 to 8 times → high left atrial pressure → pulmonary
hypertension → blood vessels dilate in order to ↓PVR and eventually rupture
Signs:
pulmonary hypertension, edema, rupture of the pulmonary capillaries, intra-alveolar hemorrhage, and presence of blood in the
airways
Furosemide indications:
- Udder edema, cattle: 1 mg/kg IM or IV; 5 mg/kg PO
- Diuresis with acute renal failure: 5-20 mg/kg IM, IV, PO, 8-12 h or as needed. Adjust to lowest dose possible. Very low urine production in ARF, so you need to make patient urinate ASAP, so make patient urinate. Use furosemide (first choice).
- Hypertension: 1-2 mg/kg; maximum of 8 mg/kg for acute renal failure, PO 12 h
EIPH: 0.5-1 mg/kg IV no later than 4 h prior the race - Hydrocephalus, brain edema: 0.5-2 mg/kg PO 12 h
- Ascites from hepatic failure: 1-2 mg/kg PO, SC 12-24
Hypercalcemia: 1-2 mg/kg IM, IV, PO, SC 8-12 h; 5 mg/kg IV as needed; 2-5 mg/kg
IV to effect. Reduce reabsorb of Ca in TAL
What happens as a result of treating conditions with furosemide long term?
Treating long term with furosemide causes detrimental effects to K in the blood. Either use a potassium sparing diuretic or check electrolytes.
Potassium sparing in image
- List two examples of Potassium sparing diuretics.
- Potassium sparing diuretics function to?
- Triamterene and amiloride
- Impair the electrogenic sodium reabsorption in the late DT and CD. Reduced sodium reabsorption causes less potassium to leave the cell → spare of
potassium
… However, the limited elimination of sodium makes these drugs less effective in
wasting sodium and they are usually combined with another diuretic
- List two examples of Potassium sparing diuretics
- _____ bioavailability, ___-____% in humans
- Side effects: May save too much ____ –> ________)
- Contraindications?
- Treatment with _______
- Indication and doses: As a ________, 1-2 mg/kg, ___ every 12 h
- Triamterene and amiloride
- Oral bioavailability, 50-60% in humans
- Side effects: May save too much K –> hyperkalemia)
- Contraindications: Hyperkalemia.
- Treatment with NSAIDs
- Indication and doses:
As a diuretic, 1-2 mg/kg, PO every 12 h
- List an example of a Potassium sparing diuretic that also acts as an Aldosterone antagonists.
- Receptors for this diuretic are located where?
- Describe the MOA.
- What does this diuretic NOT require to reach its site of action?
- Spironolactone
- Spironolactone is an antagonist of aldosterone receptors in the late DCT and CDs
- It causes calcium excretion in the urine
- Spironolactone does not require active secretion at the PT in order to reach its site of action
Spirinolactone bind to the ___________ receptor in the renal tubules, blocking the synthesis of __________. This reduces _____ reabsorption and ____ and ____ secretion –> diuresis and the potential for the patient to develop _________. ________ is also excreted in the urine.
Spirinolactone bind to the mineralcorticoid receptor in the renal tubules, blocking the synthesis of aldosterone. This reduces Na+ reabsorption and K+ and H+ secretion –> diuresis and the potential for the patient to develop hyperkalemia. Calcium is also excreted in the urine.
The target, mineralocorticoid receptor (MR) is the receptor for aldoesterone, in the CD in the principal cells. MR receptor is in the cytosol, not membrane bound, so aldosteroen diffuses into cell, moves to nucleus and induces transcription of genes that will produce ENAC. At the same time, aldosterone will also induce activity of Na, K, ATPase. What stimulates rebaospriton of Na ithout stimulating movement of Na at ? membrane. Aldosteorne does oth? so sodium can leave the cell.
Spironolacton e will difuse into the cell. Comes fro the blood, and reaches the target/ Binds to MR and prevents ldosterone from binding to receptor so that this process does not happen. No Aldosteorne receptor complex, no translcoation to nucleus, no gene transcripton., and finally less Na/K/ATPase
Amiloride ?
Causes Na and Ca elimination.
Spironolactone
- ______ protein binding and ____ bioavailability (60-70%), _____ half-life (1.4 h)
- Side effects:
- Contraindicated in ?
High protein binding and high bioavailability (60-70%), short half-life (1.4 h)
Hyperkalemia, metabolic acidosis, gastritis, diarrhea, drowsiness, lethargy, ataxia.
gastric ulcer!
Aldosterone antagonists indication and
doses
1. ________, 1-2 mg/kg (D); maximum of 4 mg/kg PO every 12 h
2. Diuretic, heart _____ 2-4 mg/kg PO 24, 1-2 mg/kg (D) PO every 12 h
3. Primary __________, hepatic ________ 1 mg/kg (C) PO every 12
h, 12.5 mg (C) PO every 24 h
4. Name a popular combination of this aldosterone antagonist and another medication
Ascites, failure, hyperaldosteronism, insufficiency
Spironolactone/hydrochlorothiazide –> may use K sparing and thiazide combo; very popular combo
Diuretic, antihypertensive agent 2 mg/kg PO every 12-24 h
What diuretics are used in a case of congestive heart failure?
Thiazide and
loop diuretics
*check
potassium!
What diuretics are used to treat liver cirrhosis?
Ascites (hyperaldosteronism)
Spironolactone
Hyperaldosteronism –> liver cirrhosis
What diuretics are used to treat nephrotic syndrome?
Hypoalbuminemia + proteinuria + edema
Less protein binding of the drug
and reduced distribution to
action site
Binding to albumin in the tubular
lumen reduces action
Effects of ADH (aka ?)
Either increased ECF __________ or decrease in blood ________ stimulate hypothalamic osmoreceptors which has two important effects:
o ______ release, which stimulates water _________ by the kidneys (urine concentration)
o Stimulation of the thirst center to promote fluid _______
arginine vasopressin, AVP
Either increased ECF osmolality or decrease in blood volume stimulate hypothalamic osmoreceptors which has two important effects:
o ADH release, which stimulates water reabsorption by the kidneys (urine concentration)
o Stimulation of the thirst center to promote fluid intake
List the ADH receptors
ADH receptors:
V1a: glomerulus and renal
medulla
V1b: inner medulla
V2: mTAL, DCT, CDs (AQP2)
The receptors for ADH are called?
- How does only water get through the AQP2?
V receptors, or Vasopressin receptors (b/c ADH is also called vasopressin).
V2 are relevant for aquaporins. Not every aquaporin is responsive to ADH, only AQP2.
Argenine vasopressin/AVP will bind to V2 –> form cAMP –> pKa –> phosphorylation of target proteins –> translation –> more AQP2. AQP 2 is packed in vesicles which then migrate to apical membrane via sorting and then fuse with the apical membrane in place.
- Size and charge via the selectivity filter.
AQP3 and 4 enable the water molecules to leave the cell.
List the ADH stimulants
- Vinca alkaloids
- Cyclophosphamide
- Tricyclic antidepressants
- Isoproterenol
List the ADH inhibitors
GEM
- Ethanol
- Mineralocorticoids
- Glucocorticoids
Therapeutic use of recombinant ADH in diabetes insipidus centralis
(Desmopressin acetate, several commercial names, off-label use, it may
cause increase of von Willebrand factor as well)
Therapeutic use of recombinant ADH in diabetes insipidus centralis
(Desmopressin acetate, several commercial names, off-label use, it may
cause increase of von Willebrand factor as well)
The onset of effect of ADH stimulants is ~___ h; duration ___-___ h. Intranasal drops, oral tablets (monitor urine ____!)
The onset of effect of ADH stimulants is ~1 h; duration 8-12 h. Intranasal drops, oral tablets (monitor urine SG!)
_____________ is also used in water deprivation tests
Desmopressin
What is the Carter-Robbins test?
You deprive your patient of water for some time and then give them water. In a normal patient the SG will go down but then when you give them saline (NaCl) the SG should go up.
In a patient with diabetes insipidus centralis, the NaCl will not change the SG. Will remain low forever. If you administer ADH, and observe a significant change in SG, the animal for sure has diabetes insipidus centralis. Therapy is desmopressin.
For nephrogenic diabetes insipdus the therapy would be Thiazide diuretics.
When are uroliths formed?
Calcium oxalate (~___%)
Calcium phosphate/ magnesium-ammonium phosphate (~___%)
Uric acid or urate (___–____%)
Xanthine or cystine (<__%)
Uroliths (kidney stones) are formed when concrement-forming substances reach a concentration in the urine that lie above their solubility threshold
Calcium oxalate (~50%)
Calcium phosphate/ magnesium-ammonium phosphate (~30%)
Uric acid or urate (25-30%)
Xanthine or cystine (<5%)
What is Cystine urolithiasis?
Solubility _________ as urine pH _______
oxidized form of cysteine
Solubility increases as urine pH increases
Cystine crystals are ___________ in shape and _____ in terms of thickness. They are ____ in color (?). Produced in _____ urine (human and dog). ___________ in ammonia but _________ in acetic acid
Cystine crystals are hexagonal in shape and flat in terms of thickness. They are clear in color (colorless). Produced in acidic urine (human and dog). Soluble in ammonia but insoluble in acetic acid
Cystine urolithiasis
Struvit (?): the most common kidney stone in dogs and cats (also ?).
Typical _________ shape; _____ color. Soluble in ______ _____. Urine pH ___
Struvit (ammonium-magnesiumphosphate): the most common kidney stone in dogs and cats (also rabbits and Guinea pigs). Typical „coffin lid“ shape; lack color. Soluble in acetic acid. Urine pH 7
Struvite
Calcium oxalate
Calcium oxalate is the _________ common stone in _____ (also ____ and ______). Produced in _______, ______, as well as in _______ urine.
_______ shape. _____ color, insoluble in ______ ______
Calcium oxalate is the second most common stone in cats (also dogs and horses). Produced in acidic, neutral, as well as in alkaline urine. „Envelope“
shape. lack color, insoluble in acetic acid
Urate (_______ urate, _______ urate).
_______ or _______ in shape, _____-colored. Produced in _____ or ______ urine and in ____ amounts (_____-colored urine)
Urate (sodium urate, ammonium urate):
Round or amorphous in shape, red-colored. Produced in acidic or neutral urine and in big amounts (red-colored urine)
Urate
What are the prerenal causes os urolithiasis?
Increased filtration and excretion of stone-producing substances (e.g., hypelcalciuria and phosphaturia). Increased mobilization from bone (excess of PTH or calcitriol)
What are the renal causes of urolithiasis?
abnormal renal reabsorption, release of ADH (enhanced urine
concentration
What are the post-renal causes of urolithiasis?
pH of the urine. Phosphates are easily dissolved in acidic urine (phosphate stones are found in alkaline urine). Uric acid is more soluble in alkaline urine (uric acid stones is found in acidic urine)
What are the effects of urolithiasis?
Hydronephrosis is the swelling of a kidney due to a build-up of urine
NH3 = ammonia
How do you treat cystin urolithiasis?
Dietary management (low methionine diet)
Solubilization
Urine alkalinization (sodium bicarbonate, potassium citrate)
How do you treat calcium oxalate urolothiasis?
Difficult to dissolve
Stimulation of calcium reabsorption (thiazide diuretics, potassium citrate)
How do you treat urate urolithiasis?
Diet (low protein)
Urine alkalinization (sodium bicarbonate, potassium citrate)
Allopurinol (xanthine oxidase inhibitor)
Beginning of Part 3!!!!
Nephrotoxicity and infectious causes that are the most common in veterinary medicine
- Ethylene glycol, lilies (cats), raisins and grapes (dogs)
- Aminoglycosides
- Amphotericin B
- Cisplatin
- Contrast agents
- NSAIDs
- ACE inhibitors
Ischemic injury causes:
- Dehydration (persisting vomiting and diarrhea)
- Shock
- Hypotension
- cardiac output failure
- Thrombosis
What are the causes of renal IRI?
Why so much oxygen and ATP for the kidney? How is urine production such a high energy-consuming process?
What is this energy used for?
What happens if O2 and energy supply are interrupted?
What role do ROS and RNS play in IRI?
Describe the pharmacological management used for acute renal failure.
Fluid therapy
Rapid replacement of fluid deficit (4-6 h)
% dehydration x BW (kg) = liters required
0.9% NaCl
Low-sodium fluids (0.45% saline/2.5% dextrose; lactated Ringer‘s
solution/2.5% dextrose in hypernatremia or cardiac insufficiency
Check urine output (aim should be 1-2 ml/kg/h), body weight,
hematocrit, plasma protein and sodium concentration
Urine production enhancement
Furosemide (2-3 mg/kg IV q 6-8 h or 1 mg/kg/h constant rate infusion)
(furosemide exacerbates gentamicin toxicity!)
Dopamine (1-5 ug/kg/min IV in combination with furosemide), positive
inotrope, vasodilator, ↑ RBF and GFR
Adverse effects: tachycardia, hypertension, vomiting
Mannitol 20-25% solution (osmotic diuretic), ↓ cellular edema, ROS
scavenger
Dextrose 10-20% solution (osmotic diuresis), caloric support, ↑ insulin
Hyperkalemia
Normally improves after fluid therapy and diuresis
Calcium gluconate (10% solution; 0.5-1 ml/kg IV over 10-15 min),
cardioprotective
Dextrose (0.1-0.5 g/kg) or insulin/dextrose (0.25-0.5 U/kg, 1-2 g), ↑
intracellular movement of K+
Metabolic acidosis
Sodium bicarbonate (0.5-2 mEq/kg IV slow), alkalinization of ECF
Nausea/vomiting
Famotidine, ranitidine (H2 antagonists); dolasetron (SR antagonist);
metoclopramide (dopamine antagonist); misoprostol (PG analog)
CKD – General aspects
~30% of cats >12 y; 2nd most common cause of death in cats >5 y (O‘Neill et
al. 2015)
Complex mixture of disorders that cause irreversible lost of nephrons (↓ GFR)
Histological hallmarks: Tubulointerstitial nephritis and fibrosis
Generation and accumulation of ROS (NO, ONOO- .OH, O2-)
ANGII, hypertension
Increased metabolism in the tubular epithelium, anemia, tissue hypoxia,
inflammation (Brown 2008)
ANGII and hypertension
Role of ANGII and mechanical
stress in the generation of ROS in
the vessel wall in patients with
hypertension:
ANGII → NADPH oxidase → O2.-
.NO + O2.- → ONOO-
CKD
pharmacological
management
CKD - Dietary strategies
Low protein (but high quality) and low phosphorus diets help reduce nitrogen
wastes, acid formation, and mineral deposition
Moderate sodium restriction (especially in hypertensive patients)
Control lipid intake to reduce hypercholesterolemia, inflammation, and protect
renal hemodynamic function
Phosphorus binders: Aluminium hydroxide, 30-100 mg/kg/d PO; calcium
acetate, 60-90 mg/kg/d PO; calcium carbonate , 90-150 mg/kg.d PO
Calcitriol (↑ serum Ca++, ↓ PTH), 2.5-3.5 mg/kg/d PO
CKD - Alkalinization
Some animals with already metabolic acidosis may require additional
alkalinization therapy
If serum total CO2 < 15-17 mmol/L → PO alkalinization
If serum total CO2 < 10-12 mmol/L → parenteral alkalinization
Blood gas analysis!
Sodium bicarbonate, 8-12 mg/kg PO q 8-12 h (it adds Na+, check Na+ levels!)
Potassium citrate, 35 mg/kg PO q 8 h (it adds K+ in addition to alkali)
CKD - Anorexia and vomiting
GI effects (uremia): mucosal irritation, impaired GI mucosal barriers, and
hypergastrinemia
Anorexia, vomiting, and diarrhea are common in CKD patients!
Treatment options:
Cimetidine (5 mg/kg PO, IM, or IV q 6-8 h)
Famotidine (0.5-1 mg/kg PO q 12-24 h)
Ranitidine (0.5-2 mg/kg PO q 12 h)
Omeprazole (0.7-1.5 mg/kg PO q 12-24 h)
Sucralfate (mucosal protectant)
CKD - Anorexia-vomiting-hypertension
Metoclopramide (0.2-0.4 mg.kg SC, IM, PO q 8 h)
More effective are serotonin receptor antagonists dolasetron and ondasetron
Maropitant (for dogs, not approved for use in cats), neurokinin type 1 selective
receptor antagonist (motion sickness)
Misoprostol (synthetic PG analog) inhibits gastric acid, pepsin secretion, and
protects the gastric mucosa
Hypertension (due to many factors, among other RAAS and low production of
vasodilators) is treated with ACE inhibitors as a first choice (enalapril,
benazepril) and/or diuretics (furosemide, spironolactone
CKD Phosphate homeostasis
Both calcitriol and PTH are involved in phosphate homeostasis
Regulation of phosphate reabsorption in the kidney is mediated by PTH
From: Sjaastad, Sand, Hove. Physiology of Domestic Animals
Chronic Kidney Disease
CKD - Secondary hyperparathyroidism
Hypocalcemia – hyperphosphatemia – impaired vitamin D → secondary
hyperparathyroidism
↑↑ PTH → ↑↑ mobilization of Ca++ and phosphate from bone
Soft tissue mineralization
Dietary restriction of phosphorus and Ca++ supplementation
Calcitriol supplementatioN
Erythropoietin is an essential hormone for new red blood cells formation (erythropoiesis
Chronic Kidney Disease - Anemia
Progressive, non-regenerative
Apathy, lethargy, poor appetite, and poor body condition
GI blood loss and lack of EPO
Treatment: recombinant human EPO 100 U/kg SC 3x week (check
hematocrit!)
Resistance to EPO. Antibody-mediated
