Drugs Affecting the Kidneys and Micturition

Question 1

functions of the kidneys

Answer 1

Primary function of the kidneys is to regulate the volume (water) and chemical composition (electrolytes, acid-base) of the ECF
n glomerular filtration
n tubular secretion
n tubular reabsorption
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Kidneys also play important role in regulation of arterial blood pressure
n sodium-water balance
n renin-angiotensin-aldosterone system
n vasoactive humoral factors (PGI2, endothelin)
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Other functions
n removal of metabolic wastes, foreign chemicals and several hormones
n elaboration of Vitamin D
n production of erythropoietin

Question 2

what is diuresis?
natriuresis
kaliuresis
chloruresis

Answer 2

n Diuresis…..”increase in urine volume”
n natriuresis: increased renal sodium excretion
n kaliuresis: increased renal potassium excretion
n chloruresis: increased renal chloride excretion

Question 3

do all diuretics act on the same part of the nephron?

Answer 3

Generally each diuretic class acts on specific segments of the
nephron
n loop diuretics: loop of henle
n thiazide diuretics: distal tubule
n K+-sparing diuretics: collecting ducts/tubule
n osmotic diuretics: descending limb of loop of henle

Question 4

Therapeutic use (indications) of diuretics

Answer 4

n maintenance of urine flow in oliguric acute renal failure
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n mobilization of ECF stores; edema or ascites
> congestive heart failure and acute pulmonary or systemic edema
> partiurent edema of mammary gland
> nephrotic syndrome
> hepatic cirrhosis
> iatrogenic fluid overload
n correction of specific ion imbalances
n reduction in intraocular and intracranial pressures
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ensure adequate hydration before using diuretics

Question 5

what must we ensure before using diuretics?

Answer 5

ensure adequate hydration before using diuretics
> don’t want to collapse vascular space

Question 6

classes of diuretics?

Answer 6

loop
Thiazide
K+-sparing
Osmotic

Question 7

most commonly used diuretic; most potent drug class for systemic diuresis

Answer 7

Loop diuretics

Question 8

loop diuretic drugs we use?

Answer 8

• Furosemide, Torsemide
• Furosemide (Salix®, Lasix®, generic), Torsemide (Demadex®, generic)

Question 9

Loop diuretics
- how common? how effective?
- mechanism
- animals used for
- what they treat, how
- potency
- onset time

Answer 9

n most commonly used diuretic; most potent drug class for systemic diuresis
n works as a diuretic by inhibiting the Na+/K+/2Cl- co-transporter in the thick ascending limb of the loop of henle
n licensed for use in dogs, cats, horses, cattle as a diuretic
n most commonly used to treat CHF
> decrease pulmonary pressures and promote
venodilation by vascular PGI2 release
=> critical effect in acute congestive episodes
> most potent diuretic class based on site of action in the loop of henle that is responsible for reabsorbing ~25% of the filtered sodium load
n rapid onset of action after IV administration

Question 10

loop diuretics plus NSAIDs interaction

Answer 10

Concurrent NSAID use can negate the venodilatory and diuretic effects of furosemide which involves NSAID blockade of PGI2 and PGE2 production

Question 11

additional uses of Loop diuretics

Answer 11

n promotes calcium excretion–used for hypercalcemia
n parturient edema; promote urine flow in oliguric acute renal failure
n EIPH in horses ????

Question 12

adverse effects of loop diuretics

Answer 12

n ototoxicity; potentiated by aminoglycosides
n hypokalemia and digoxin toxicities
n dehydration, hypotension and electrolyte disturbance

Question 13

commonly used thiazide diuretics

Answer 13

• Hydrochlorothiazide
• Trichlormethiazide (Naquasone)

Question 14

Hydrochlorothiazide - what kind of drug?
- mechanism? potency? effects?
- caution?
- use in vet med
- diabetes interaction

Answer 14

Thiazide Diuretics
n works as a diuretic by inhibiting the Na+/Cl- co-transporter in the distal tubule n moderately potent diuretics; less than loop diuretics
n also decrease renal excretion of calcium
> caution in hypercalcemic patients
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n less use of hydrochlorothiazide in veterinary medicine
> may be added to loop diuretics for additive effects
> parturient edema (mammary gland and other structures)
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n paradoxically decreases urine output in diabetes insipdus (nephrogenic DI)

Question 15

Trichlormethiazide
- type of drug
- properties
- use

Answer 15

Thiazide Diuretics
- licensed for use in veterinary patients
n similar in properties to hydrochlorothiazide; also has dexamethasone
n inflammatory conditions in horses; parturient edema in cattle

Question 16

K+-sparing Diuretics are primarily indicated in what cases?

Answer 16

Primarily indicated to spare potassium wasting

Question 17

K+-sparing Diuretics drugs commonly used

Answer 17

• Spironolactone (generic)
• Eplerenone (Inspra®)

Question 18

Spironolactone, Eplerenone
- what type of drugs?
- mechanism
- efficacy
- cautions

Answer 18

K+-sparing Diuretics
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n aldosterone receptor antagonists ie mineralocorticoid receptor antagonists
n block effects of aldosterone in the late distal tubules and collecting ducts
> aldosterone promotes sodium and water retention at the expense of excreting K+ and H+ ions
> aldosterone activates mineralocorticoid receptors in tubules; increases sodium channels and pumps; antagonists blocks mineralocorticoid receptors
> weak diuretics
> may be added to other diuretic classes
n aldosterone antagonists effective only in presence of aldosterone !!
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n caution with hyperkalemia; hyponatremia also possible

Question 19

Osmotic Diuretics properties, types used

Answer 19

low molecular weight substances freely filtered by the glomerulus, but poorly absorbed from the tubule fluid; generally pharmacologically inert
n mannitol; most commonly used osmotic diuretic; given IV
n glycerol; given by oral administration

Question 20

Mannitol
- type of drug
- what it does, admin
- uses
- contraindications

Answer 20

n creates a hypertonic urine
n site of action is whole tubule, but primarily descending limb of loop of henle
n poorly absorbed orally hence given parenterally (IV)
n increases free water mobilization over sodium excretion
n uses include:
> oliguric acute renal failure
> increased intraocular and intracranial pressure
> promote excretion of toxins
n contraindicated in cranial bleeding and significant pulmonary edema

Question 21

Hypokalemia and metabolic alkalosis relationship to diuretic therapy

Answer 21

Diuretics generally promote the increased delivery of NaCl to the distal tubules and collecting ducts
> distal exchange of Na+ for H+ and K+ yielding potential hypokalemia and metabolic alkalosis
> ensure adequate K+ intake in the diet
=> addition of a K+-sparing diuretic

Question 22

Factors that can limit diuretic responses

Answer 22

nTolerance from long-term diuretic administration
n Reduced RBF and inadequate delivery of drug to site
n Proteinuria and increased fraction of bound drug

Question 23

Drugs used to treat motor disorders of micturition target what broad issues

Answer 23

§ Urine storage; leakage
§ Urine voiding; retention, incomplete emptying

Question 24

Physiology of Micturition
- important muscles and components for urination
- how the muscles work for contraction / relaxation ie. what neuro control

Answer 24

1. Bladder
2. Bladder wall with smooth muscle (detrusor)
   - Involuntary muscle
   § sympathetic (relaxation)
   § parasympathetic (contraction)
3. Internal Sphincter
   - Involuntary muscle
   § sympathetic (contraction)
   § parasympathetic (relaxation)
4. External Sphincter
   - Voluntary muscle
   § sympathetic (contraction)
   § striated (contraction)
5. Urethra

Question 25

Disorders of Micturition
- classification

Answer 25

Classification/mgmt. of disorders based on bladder and urethral function
- Hypocontractile Bladder
- Hypercontractile Bladder
- Hypertonic Urethra
- Hypotonic Urethra

Question 26

Hypocontractile Bladder
- cause and signs

Answer 26

caused by:
n neurological lesions
n acute or chronic overdistension
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signs: urinary retention and urine overflow is observed

Question 27

drugs used for hypocontractile bladder?
mechanism?
contraindications?
reversal?
when most effective

Answer 27

Cholinomimetics used to promote bladder emptying
n Bethanechol (generic, Duvoid®); muscarinic (M3) receptor agonist
> contraindicated in urethral obstruction
> a-adrenergic antagonists & striated muscle relaxants can be given prior to promote urethral relaxation and maximal urine flow
> atropine is antidote to adverse effects
n most effective in atony secondary to overdistension

Question 28

Hypercontractile Bladder cause, signs

Answer 28

caused by:
n neurological lesions
n chronic inflammation
n congenital disorder and tumors
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signs:
n filling of the bladder decreased
n involuntary contractions of bladder at lower filling pressures and volumes; pollakiuria

Question 29

Hypercontractile Bladder therapy is aimed at what? what drugs are used

Answer 29

• therapy is aimed ideally at underlying cause eg. Infection
• motor agents are used to reduce symptoms
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• Oxybutynin, Propantheline
• Imipramine

Question 30

Oxybutynin use for disorder of micturition
- mechanism
- adverse effects
- similar drug

Answer 30

for hypercontractile bladder
n muscarinic antagonist; anti-spasmodic
n drowsiness, constipation and urine retention are adverse effects
n Others: Propantheline (Pro-Banthine®)

Question 31

Imipramine use for disorder of micturition?
- type of drug? mechanism?
- when used
- other actions
- adverse effects

Answer 31

for Hypercontractile bladder
n classified as a tricyclic antidepressant
n inhibits amine (serotonin and norepinephrine) reuptake in prejunctional neurons…. results in increases in their levels and effects
n used in dogs and cats for urinary incontinence
n other actions include central and peripheral anticholinergic effects
n adverse effects include tremors, seizures, tachycardia

Question 32

Hypertonic Urethra signs (and causes)

Answer 32

signs: urinary retention
n increased resistance to urine outflow and functional obstruction
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caused by:
n neurological lesions
n inflammation

Question 33

drugs used to solve Hypertonic Urethra

Answer 33

• a-adrenergic blockers
  > Prazosin
  > sildosin
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• Striated muscle relaxants
  > diazepam
  > dantrolene

Question 34

use of a-adrenergic blockers for disorders of micturition?
- mechanism?
- adverse effects?
- which drugs are used? differences between them

Answer 34

for Hypertonic Urethra
n decrease internal sphincter resistance; more effective in dog, as cats have smooth
muscle limited to the proximal third of the urethra and more skeletal muscle n some may also decrease external sphincter resistance via central effects
n adverse effects include hypotension, reflex tachycardia, and GI disturbances
n Prazosin (generic, Minipress®); oral capsules
n Silodosin (Rapaflo®)
> oral capsules; highly selective a1a adrenergic antagonist; more selective for
urethral smooth muscle; less adverse effects on the CV system
> less experience with silodosin at this time

Question 35

Striated muscle relaxants used for what disorder of micturition

Answer 35

used in cats and dogs with functional urethral obstruction

Question 36

Diazepam use in disorders of micturition, mechanism

Answer 36

for hypertonic urethra
-centrally-acting relaxant
nDiazepam produces centrally mediated effects that are dose-dependent starting with anxiolytic effects, followed by relaxation, sedation and anticonvulsant effects at increasing doses
nWorks by enhancing GABAA receptor activity
nRare idiosyncratic hepatotoxicity in cats following oral administration

Question 37

Dantrolene use in disorders of micturition, mechanism, adverse effects?

Answer 37

for hypertonic urethra
-peripheral-acting relaxant
nProduces skeletal muscle relaxation most likely by interfering with release of
intracellular calcium from skeletal muscle sarcoplasmic reticulum
nCan cause hepatotoxicity in humans but incidence in veterinary patients is unknown

Question 38

hypotonic urethra signs, (Cause)

Answer 38

signs:
n poor outlet resistance leading to urinary leakage
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caused by:
n neutered dogs and cats; hormone responsive
n neurological lesions or inflammation

Question 39

types of drugs used for Hypotonic Urethra

Answer 39

Reproductive hormones
- Diethylstilbesterol
- Estradiol
- Testosterone
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a-adrenergic agonists
- phenylpropanolamine
- ephedrine
- pseudoephedrine

Question 40

Reproductive hormones used for treating hypotonic urethra, adverse effects?

Answer 40

n estrogen often effective in females
> Diethylstilbesterol (Stilbestrol®) licensed in spayed dog, cats
> Estradiol licensed for use in spayed dogs
> adverse effects include bone marrow suppression, alopecia and induction of estrus and tumors possible

n Testosterone can be used similarly in males
> aggressive behaviour, perianal and prostatic disease possible

Question 41

a-adrenergic agonists for what disorder of micturition?
- mechanism
- which drugs?
- uses, adverse effects?

Answer 41

hypotonic urethra
- stimulate a-adrenergic receptors directly and promote release of norepinephrine; increase sphincter tone
n phenylpropanolamine (Proin®, Propalin®), ephedrine, pseudoephedrine
n phenylpropanolamine approved for use in dogs for urinary incontinence
n equally effective in males and females
n adverse effects; tachycardia, excitability & anorexia