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VETM 443 Pharmacology > Renal Pharmacology > Flashcards

Renal Pharmacology Flashcards

1
Q

List the functions of the kidney

A

A WET BED

acid base balance
water balance
electrolyte balance
toxin removal
blood pressure control
erythropoietin production
vitamin D metabolism

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2
Q

What structures make up the renal corpuscle

A

bowmans capsule and the glomerulus (capillaries)

Blood is filtered to ultrafiltrate

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3
Q

What is allowed through into the ultrafiltrate at the renal corpuscle and what is blocked?

A

Allowed
- water
- Na
- K
- Ca
- glucose and sucrose
- urea
- vitamins
- fatty acids and amino acids

Blocked
- RBC
- plasma proteins and anything bound to a carrier protein (Ca/Fe/hormones/drugs)

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4
Q

What is the function of the proximal convoluted tubule

A

It has osmolarity similar to plasma and removed
- Na
- Cl
- glucose
- amino acids

These products are removed actively

water is removed passively because it will follow Na
- 45- 65% Na resorbed

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5
Q

What is the ‘vasa recta’

A

the peritubular capillaries that surround the loop of henle

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6
Q

How much Na is resorbed in the loop of henle as a whole

A

25 - 40%

it has the biggest impact on Na resorption

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7
Q

What are the parts of the loop of henle

A

the thin descending loop

the thin ascending loop

the thick ascending loop

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8
Q

What is the function of the thin descending loop of henle

A

It concentrated fluid and is permeable to water but not solutes

The surrounding environment is highly concentrated with NaCl and so water is removed passively

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9
Q

What is the function of the thin ascending loop of henle

A

It is permeable to Na and Cl but not to water

This means that NaCl will diffuse out of the tubule

The surrounding environment is less concentrated than the lumen

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10
Q

What is the function of the thick ascending loop of henle

A

It creates the concentration gradient by actively pumping out Na

Cl will also be removed passively as a result of Na removal

It creates a hypotonic fluid in the lumen

The tubule is not permeable to water

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11
Q

What is the function of the distal convoluted tubule

A

It receives the hypotonic lumen fluid

It is permeable to water and so water leaves through osmosis (passive)

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12
Q

What is the function of the collecting duct

A

Many nephrons empty into this

It receives fluid that is isotonic to plasma

Water leaves passively in response to the concentration gradient

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13
Q

How much Na is resorbed in the distal convoluted tubule an the collecting duct

A

10%

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14
Q

What are the 5 key principles of kidney function

A

water moves passively

solutes control water movement

Na can move passively or actively

varied permeability to water creates a concentration gradient

intramedullary concentration gradient allows urine concentration

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15
Q

What are the 3 main functions of diuretics

A

mobilize tissue fluid (edema/ascites)

reduce blood volume (reduce hypertension and congestion)

protect kidney function (increases urine flow and reduces toxins)

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16
Q

What is the main goal/mechanism used by diuretics (except osmotic diuretics)

A

increased sodium excretion is followed by water

So to inhibit targets that are responsible for Na resorption it will cause increase urine production

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17
Q

Define natriuresis

A

sodium (and other ion) loss in the urine

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18
Q

List 5 main classes of diuretics

A

carbonic anhydrase inhibitors

osmotic diuretics

loop diuretics

thiazide diuretics

potassium sparing diuretics

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19
Q

In which part of the kidney would a diuretic effect be most impactful

A

the loop of henle because it has the biggest impact on sodium excretion/retention

The loop of henle can compensate for changes in the proximal tubule

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20
Q

Do diuretics rely on drug concentration in the tubular lumen

A

Yes they all do except spironolactone

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21
Q

What is the mechanism of action of carbonic anhydrase inhibitors

A

They act on enzymes in the proximal convoluted tubule
- non competitive inhibitor of carbonic anhydrase

  1. inhibit = formation of carbonic acid from CO2 and water
    - normally, carbonic acid dissociates into bicarb (HCO3) and H
  2. low carbonic acid results in reduced H in the tubule cells
    - normally, Na is resorbed from the lumen in exchange for an H
  3. Less H in the tubule = less Na moved out of the lumen
  4. Na remaining in the lumen can combine with HCO3 to form sodium bicarbonate
  5. water secreted to join the sodium bicarb
  6. as more bicarb is excreted = can cause systemic acidosis
  7. systemic acidosis = more H available
  8. Na/H antiporter (exchanger) works again
    = this drug is self limiting
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22
Q

What level of diuretic effect is stimulated by carbonic anhydrase inhibitors? Why?

A

mild because although the Na/H exchange is an important part of water exchange, there are other mechanisms that can compensate
- Na/K antiporter (K substitute for H)
- loop of henle can compensate

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23
Q

List 3 systemic carbonic anhydrase inhibitors

A

acetazolamide*

dichloramphine, methazolamide

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24
Q

List 2 topical carbonic anhydrase inhibitors

A

dorzolamide*
brinzolamide

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25
Q

Which diuretic drug is typically used to manage glaucoma

A

dorzolamide

it reduces the production of aqueous humor

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26
Q

What is acetazolamide usually used for in dogs

A

acute treatment of glaucoma if topical dorzolamide fails first

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27
Q

What is acetazolamide usually used for in horses

A

prevention of hyperkalemic periodic paralysis

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28
Q

What is the route of administration for acetazolamide

A

good PO absorption

29
Q

How is acetozolamide metabolized

A

renal elimination

30
Q

What are the adverse effects of acetozolamide

A

most sensitive = cats

self limiting effect

drowsiness/disorientation (inhibiting CNS carbonic acid anhydrase)

hypersensitivity (sulfonamide derivative)

hypokalemia (K wasting)

metabolic acidosis

worsen - hepatic disease and encephalopathy (reduced ammonia secretion)

31
Q

What is the mechanism of action of osmotic diuretics

A

act on the descending loop of henle

They are low molecular weight solutes
- pass through glomerulus
- increase osmolarity of the tubular lumen
- increase passive diffusion of water out of lumen
- reduce Na resorption (it is diluted in a larger volume of fluid)

inert

32
Q

What is mannitol derived from

A

sugar alcohol, marine algae, trees, mushrooms

33
Q

How is mannitol administered and what formulation strength is it commonly found in?

A

IV solution - warmed (can crystallize at cool temp)
- use a test dose

5-25% (50 - 250mg/ml)

given over 15-30 min

34
Q

What are the effects of mannitol

A

increase cardiac output
reduce rigidity of RBC = increase blood flow
reduce hematocrit

35
Q

What is mannitol used for primarily

A

increased intracranial pressure
- increase blood flow and trigger cerebellar vasoconstriction
- osmotic gradient pulls fluid out of brain
- if the BBB isnt intact = can make it worse (leak or pull fluid in the opposite direction)

renal failure
- induce diuresis
- but dont give if anuric or dont give more if 60 mins has passed without diuresis after initial bolus

36
Q

What 3 things should you consider when giving mannitol

A

IV only

use test dose

make sure tissue barriers are intact
- if nephrotoxins/severe renal ischemia = ineffective

37
Q

What are the adverse effects of mannitol administration

A

hypertonic dehydration*
- must hydrate patient before giving
- hypertonicity will maintain plasma volume = easy to miss

cardiac arrhythmia (loss of electrolyte)

acute hyponatremia (if given too fast)

congestive heart failure and/or pulmonary edema

volume overload (if persistent oliguria)

hyperosmolar/osmotic compensation - cells will make osmotically active molecules
- shouldn’t stop mannitol suddenly - discontinue over the amount of time the patient was in the hyperosmolar state

38
Q

What type of diuretic is mannitol

A

osmotic diuretic

39
Q

What is the normal mechanism of ion (Na/K/Cl) movement in the thick ascending loop of henle

A

Normally,
- Na/K ATPase in the basal membrane of the tubule cells moves Na into renal interstitium = transmembrane gradient
- Na/K/2Cl symporter in lumen membrane uses that gradient to move Na/K/Cl into the cell
- movement of Ka back into lumen and Cl into the interstitium generates a voltage gradient
- voltage gradient moves cations (Mg/Ca/Na) between tubular cells from the lumen to the interstitium = paracellular shunt

40
Q

What mechanism of action do loop diuretics use

A

They act on the thick ascending loop of henle (25% Na resorbed, no water resorbed)
- prevent formation of a hypertonic renal medulla = prevent concentration of urine
- protective against ischemia = reduce renal O2 consumption (less Na resorb)

  1. Na/K/2Cl symporter is blocked
    - Cl is still exported to interstitium = low intracellular Cl
  2. transmembrane potential (voltage) of across the tubule cells is changed
    - disrupt the paracellular shunt (block movement of Na/Mg/Ca)
    - kidney medullary concentrations are altered
  3. water movement is impaired due to concentration gradient alterations
  4. altered Cl increases renin production
    - activate RAAS (due to hypotension) = increase blood pressure and renal perfusion
  5. increased Na in tubular lumen = increased H and K excretion (exchanged for Na in distal tubule)
41
Q

List 3 loop diuretics

A

furosemide*

ethacrynic acid/ torsemide/bumetanide

42
Q

What diuretic mechanism does torsemide use

A

loop diuretic mechanism
also inhibit binding of aldosterone = some impact on RAAS

10x more potent than furosemide

43
Q

What diuretic mechanism does furosemide use and what are its pharmacokintetics?

A

loop diuretic mechanism
- interact with Cl site on the Na/K/2Cl symporter = inhibit

also some carbonic anyhydrase activity

it must go through glomerular filtration and active secretion to reach active site

it is fast acting and only for a short duration (T1/2 = 1h)

It is highly protein bound = proteinuria can impact effect

44
Q

How is furosemide metabolized

A

in the kidney

either via glucuronidation or unchanged

45
Q

What is furosemide used for

A

mobilizing edema and ascites (cardiac/renal/hepatic)

reduce exercise induced pulmonary hemorrhage in horses

renal failure if it acute oliguric (not anuric)

hypercalcemia

46
Q

How is furosemide administered

A

in horses it is given IV only

in dogs it is given IV or PO

use at lowest effective dose

47
Q

What are the effects of furosemide

A

natriuretic/chloruretic/diuretic

potassium wasting*

hemodynamic effect*
- due to prostaglandin
= increase venous compliance, reduce pulmonary artery pressure, increase renal blood flow and GFR

prevent bronchoconstriction

weight loss (water loss)

+/- antiepileptic effect

48
Q

What are the adverse effects of furosemide

A

volume depletion/hyponatremia*

electrolyte abnormalities = impact cardiac/renal (in at risk patients)*

many drug interactions (reduce dose when giving with ACE inhibitor)*
- also NSAID inhibit furosemide response

ototoxic in cat (high dose)

sulfonamide hypersensitivity

hyperglycemia (low K = reduce conversion of proinsulin to insulin)

49
Q

List 3 thiazide diuretics

A

chlorothiazide*
trichloromethiazide*

hydrochlorothiazide

50
Q

What is the mechanism of action of thiazide diuretics

A

They act on the distal convoluted tubule
- inhibit Na/Cl cotransporters on the lumen membrane of the tubule cells
- increase Ca resorption (affect Ca transporter on basal membrane)

Normally, Na/K ATPase on basal membrane creates a concentration gradient that draws Na from lumen into the cell - Cl follows Na
- Cl exits via a Cl channel in basal membrane

  1. inhibition of Na/Cl cotransporter = more Na retain
    - result in excretion of K/Mg/H

also

  1. stimulate Na/Ca exchanger (NCX1) in basal membrane (usually bring Na into cell from ECF and excrete Ca into ECF)
    - create Ca gradient that increases Ca influx via calcium channels in lumen membrane
51
Q

How are thiazide diuretics classified

A

thiazide or thiazide like

52
Q

How does thiazide diuretics compare to loop diuretics

A

They have less diuretic and natriuretic effects

thiazide = moderate diuretic

53
Q

What are thiazide diuretics used for

A

nephrogenic diabetes insipidus (due to ADH resistance)

edema (usually used in conjunction with furosemide)

antihypertensive

54
Q

What is the mechanism of blood pressure reduction via thiazide diuretics

A

acutely it causes reduced plasma volume

chronically it causes decreased peripheral vascular resistance via vasodilation in humans

55
Q

What are the pharmacokinetics (absorption/function/excretion) of thiazide diuretics

A

It is not completely absorbed in the GI of animals

very protein bound*
- not filtered at glomerulus
- access to lumen via proximal tubular secretion

renal excretion (some in the biliary system)

56
Q

What are the adverse effects associated with thiazide diuretics

A

K wasting* (increase arrhythmia risk)

hyperglycemia (due to low K = impair conversion of proinsulin to insulin)

hypercalcemia

hyponatremia, hypo K, Cl

metabolic acidosis

sulfonamide hypersensitivity

57
Q

What patients are thiazide diuretics contraindicated in

A

if they have severe renal disease or hepatic disease

58
Q

Explain why loop diuretics and thiazide diuretics are K wasting?

A

in distal convoluted tubule = More Na in the tubular fluid
- stimulate aldosterone (also RAAS) sensitive Na resorption
- Na resorption is done via exchange for K

59
Q

List 2 types of K sparing diuretics

A

mineralocorticoid receptor antagonists

epithelial Na channel blockers

60
Q

What is the mechanism of mineralocorticoid receptor antagonists

A

they act on the late distal tubule and collecting duct
- block aldosterone binding

  1. inhibit aldosterone binding = prevent subsequent gene transcription
    - gene transcription needed for Na resorption
  2. reduced Na resorption and increased diuresis
61
Q

How are mineralocorticoid receptor antagonists usually administered

A

usually with a loop or thiazide diuretic

62
Q

How long do mineralocorticoid receptor antagonists take to work

A

it is protein bound and metabolized in the liver to an active metabolite

T1/2 in dogs = 1 hours
T1/2 in dogs of metabolite (canrenone) = 16-20h

so peak diuresis occurs days after administration

63
Q

In what situation are mineralocorticoid receptor antagonists most effective

A

if there is hyperaldosteronism
- due to cardiac, liver, or nephrotic syndrome

64
Q

Provide an example of a mineralocorticoid receptor antagonist

A

spironolactone

65
Q

Explain the relationship between liver disease and spironolactone

A

liver disease results in
- reduced albumin/low oncotic pressure = ascites
- increased portal circulatory pressure = ascites
- secondary hyperaldosteronism + Na/water retention = ascites

spironolactone is an aldosterone antagonist

66
Q

What are the adverse effects associated with K sparing diuretics

A

safe

hyperkalemia*
- must be careful when combo with ACE inhibitors

67
Q

What are the 3 main goals of using diuretic combinations

A

have adequate diuresis with minimal adverse effect

increase efficacy (acute renal fail)

tx refractory edema (blocking Na resorption multiple ways can reduce compensatory resorption more distal in the tubular system)

68
Q

Why are renal hemodynamics so important

A

kidney gets 20% of cardiac output but only 5-10% goes to medulla

ion movement is energetically expensive and so the kidney is always on the verge os ischemia

69
Q

What are 3 mechanisms to change hemodynamics in the kidney

A

prostaglandins = increase renal blood flow
- NSAID reduce
- loop diuretic increase

dopamine = increase renal blood flow
- low dose CRI can tx hemodynamic renal fail

diuretics (that reduce Na resorption) = reduce O2 demand and the risk of ischemia

VETM 443 Pharmacology (11 decks)

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