Renal Pharm Part 1

Question 1

ECF (extracellular fluid):
* ~____% of total body water
* Volume of ECF is determined primarily by
total ____+ content (_____ ion in the ECF, and is subject to _____ transport)
* Control of ECF involves _________ and ______ systems, as well as the _____
(RAAS, thirst, diuresis)

Answer 1

ECF (extracellular fluid):
* ~20% of total body water
* Volume of ECF is determined primarily by
total Na+ content (major ion in the ECF, and
is subject to active transport)
* Control of ECF involves cardiovascular and renal systems, as well as the CNS
(RAAS, thirst, diuresis)
Thirst center = hypothalamus
osmoreceptors present here to regulate ADH release.

Question 2

Answer 2

B, C, D

Question 3

Answer 3

C

Malnutrition = low AA in diet –> less proteins
Kidney disease = destruction of glomerular filter or tubular destruction

Question 4

Answer 4

B

Question 5

How do the kidneys maintain ECF (sodium and water)?

Answer 5

Sodium determines osmolality of the fluid
How much water is retained and leaves also determines osmolality.

Question 6

How does the kidney eliminate waste products?

Answer 6

Carrier proteins at proximal tubule, basement membrane apical membrane that eliminate waste products. All waste products are filtered, such as urine and creatinine

Question 7

How do the kidneys participate in Renal Transport?

Answer 7

Proximal tubule is the main site that partiicpates in tranport due to sodium dependent transporters.

Question 8

How do the kidneys participate in the autoregulation of renal blood flow (and systemic blood pressure)?

Answer 8

Renin is produced to maintain blood pressure
1. Tubular glomerular feedback: macula densa will regulate GFR
2. Myogenic reflex: small at local level in a single nephron responds to adjust GFR

Question 9

How do the kidneys participate in Endocrine function?

Answer 9

Kidneys produce hormones
Renin (without renin, no angiotensin)
Calcitriol

Question 10

How do the kidneys participate in Acid-base balance?

Answer 10

Acid to eliminate , bicarb being reabsorbed and vice versa

Respiratory disorders acid base balance disorders

Question 11

These compartments are separated by semi permeable membranes, meaning osmotic pressure can be found in these compartments. Any change in this pressure moves water from one compartment to another.
Na+ is the most important ion in the ECF.

Question 12

How do the proximal tubules reabsorb sodium?

Answer 12

Secondary active transport via:
AA with Na+, Glucose with Na+, K+ with Na+, etc.

Sodium proton exchanger is important for acid base imbalances and is important for bicarb reabsorb

Na+ and K+ exchanger

Question 13

How is sodium reabsorbed via the TAL?

Distally, in the thick ascending limbs, the carrier NKCC picks up ___ Na+, ___ K+ and ___ Cl- at same time. This moves sodium paracellularly, and the interstitial fluid becomes less ___ due to____ channels at basolateral membrane making + ions (___,___) from lumen to interstitium by the paracellular pathway easier. This makes up ___% of Na+ resabsorption.

Answer 13

Distally, in the thick ascending limbs, the carrier NKCC picks up one Na+, one K+ and 2 Cl- at same time. This moves sodium paracellularly, and the interstitial fluid becomes less + due to Cl- channels at basolateral membrane making + ions (Na, K) from lumen to interstitium by the paracellular pathway easier. This makes up 25% of Na+ resabsorption.

Question 14

In the distal segments. 5% of Na+ is reabsorbed. At the apical side?
At the basolateral side?

Answer 14

This is important b/c Aldosterone stimulate ENACC at apical membrane and diuertics work here to stop Na+ reabsorption.

Question 15

Altering sodium reabsorption at more proximal segments of the nephron will also affect the reabsorption of (3?)
► High levels of sodium at the TAL alters the transepithelial potential impacting negatively the paracellular reabsorption of (2?)
► High levels of sodium at the CD will make ___ move outside of the cell via channels into the tubular lumen (↑ ___ ______ = ________)

Answer 15

potassium, magnessium, and calcium
Ca++ and Mg++
K+, K+ excretion, hypokalemia

My notes:
Furosemide is a luce diuretic. It blocks or inhibits the NKCC at the TAL. This is good because we stop Na+ reabsorption and remains in tubular lumen, and Na+ pulls water –> increase diruesis and reduce ECF.

Problem? NKCC is important b/c produces differnece between lumen and interstitium. K+ gets in with NKCC and leaves via K channels. Na+ enters cell with NKCC and elaves via NA, K ATPASE, Cl- enters (2 of them) adn keaves at basolaterla membrane. This is importat b/c maikes intersittium more nevative3 than lumen making paracellular movement of Mg and Ca more efficient since + charged. 70% of Mg is resbaorbed at apracellualr pathway using TAL.

Na+ in the lumen is what we want to get rid of sodium and water but te TAL is connected via DCT to the TAD. At the distal nephron, the ENAC will try to reabsorb all Na that was retained in the lumen. Whwnever Na enters cell, K laves so rhe more Na+ leaves, the greater loss of K. This is why diruetics cause hypokalemia.

Question 16

How is Na+ reabsorption regulated?
There are 3 hormones that stimulate and 3 that inhibit.

Answer 16

Stimulation:
Angiotensin II
Aldosterone
ADH

Hypothalamic neurons tha tproduce ADH project to posterior hypophisis. When osmolality increases or blood vol decreases, neurons send vesicles containg ADH to synaptic terminal and by exocytosis AdH leaves vesicles and enters blood. Goes to kidney –> promotes water retention because ADH stimulates aquporins in colecting ducts. ADH also stimulates areasborb of Na+.

Thirs tcenter in hypothaalmus also is stimuoated to increase water consumption.

Inhibition:
ANP –> produced by ? response to increase vol. so the response of ANP inhibits Na+ reabsorption to get rid of it + water. Inhibits release of Renin and angiotensin, which are importnat for Na+ reaborption.
Nitric oxide
Endothelin-1

Question 17

Answer 17

Autoregulation of renal blood flow:
Macula densa mechanism (tubuloglomerular
feedback) for autoregulation of glomerular
hydrostatic blood pressure
Additionally, there are local myogenic
responses and the systemic RAAS, that
contribute to blood flow regulation. How muhc blood is reaching each glomerulus. Happens at afferent arteriole. Arteriole closes a bit to regulate the amount of bloof.

Question 18

Answer 18

Macula densa is apart of feedback.
These cells are closely related to glomerulus of the same nephron. This response occurs in one single nephron.

If GFR decreases, less NaCL reaching MD cells. This increases renin, angio, and efferent, all of whihc corrects GFR.

At the same time, Decrease in afferent, etc.

Question 19

The PT contains several active transport mechanisms to secrete numerous
waste products and xenobiotics.

Question 20

Some carriers at BL membrane or apical membrane.

Answer 20

From peritubular capillaries –> epithelial cells –> lumen
to get ride of drug metabolites and xenobiotics that are harmful to body.

OA –> MRP2 = apical
OC —> MDR1 = apical

Question 21

Some carriers at BL membrane or apical membrane.

Answer 21

Organic Cations

Question 22

When and how do we reduce the ECF?

Answer 22

When fluid is inappropriately retained (edema)

Edema is accumulation of fluid in the interstitum.

Question 23

List the causes of edema.

Answer 23

Cardiac
Renal
Liver disease
Lymphatic obstruction
High hydrostatic pressure (high blood pressure)
Low plasma oncotic pressure
…
Water and salt retention

Question 24

Edema
Treatment is directed to promote?

Answer 24

renal excretion of sodium (diuretics) followed by water

No diuretics just focus on water elimination.

Question 25

Diuretic are classified according to the mechanism of action into:

Answer 25

1. Where they work:
   * Loop diuretics
   * Carbonic anhydrase inhibitors
   * Thiazides
   * Osmotic diuretics
   * Potassium sparing diuretics
   - make patient save potassium but less effective than Loop diuretics, which makes your patient lose K.

Question 26

How do you determine which diuretic to select?

Answer 26

Which one to select …?
* Underlying disease (cause of ECF
volume retention)
* Mechanism/site of action of the drug
* Side effects

Question 27

The mechanism of action of diuretics is primarily the _________ of NaCl reabsorption and, secondarily, by __________ water reabsorption.

Osmotic diuretics do not work in the ________, meaning they change the _______ ____ but do not have specific receptors in the _______. They do this by pulling water from ____ or ___ and increase ____ and ______ ____ to get ride of excess water. DO NOT act directly on ______. E.g.?

Carbonic anhydrase inhibitors block ____ and ______ reabsorption. E.g.?

Loop diuretics function to block _____ symport in the _____. E.g.?

Thiazide function to block _____ symport.

Aldosterone antagonists function to _______ block ____ channels so ENAC? at ___ E.g. ?

Amiloride: block ____ channels, ENAC?, but this is a ______ effect in contrast to ________.

Answer 27

inhibition, decreasing

kidneys, filtration rate, kidneys, IF, ECS, ECF, filtration rate, kidneys, mannitol

NA, bicarb, Acetazolamide

NKCC, TAL, furosemid

NaCl

indirectly, Na+, CD, Spirinolactone

Na+ , direct, spirnolactone

Question 28

Osmotic diuretics:
Increase the ________ of _______ fluid, enhancing flow of water from ______ to interstitial and intravascular fluids. Examples: ?

Properties:
* Must be _______ filtered in order to pull water into the tubular system and then into the bladder
* Not _______
* Not _________

Answer 28

Osmotic diuretics:
Increase the osmolality of extracellular fluid, enhancing flow of water from tissues to interstitial and intravascular fluids. Examples: Mannitol, glycerin, hypertonic saline

Properties:
* Must be freely filtered in order to pull water into the tubular system and then into the bladder
* Not reabsorbed
* Not metabolized

Question 29

Describe the mechanism of osmotic diuretics.

Answer 29

Question 30

Mannitol
It does not ______ the cells but remains in the _____ → it extracts water from ________ compartments, ↑ ____ volume, ↓ blood _______

No ____ absorption! Must be administered ___ in order to have that effect!
Not __________; elimination half-time ~__ h
Human formulations available

Mannitol is a sugar alcohol that acts throughout the nephron (stronger effect at the loop of Henle)
Sodium loss is small

Answer 30

Mannitol
It does not enter into the cells but remains in the ECF
→ it extracts water from intracellular compartments, ↑ ECF volume, ↓ blood viscosity

No PO absorption! Must be administered IV in order to have that effect!
Not metabolized; elimination half-time ~1h
Human formulations available

Mannitol is a sugar alcohol that acts throughout the nephron (stronger effect at the loop of Henle)
Sodium loss is small

Question 31

Mannitol Indications:
Very popular for ?

Oliguric renal failure (has renal failure and not _________) → 0.25-0.5 g/kg of a 15-25% solution over 15-60 min (repeat every 4-6 h is necessary; contraindicated in patients with ______)

___________ → 1-3 g/kg over 15-20 min (repeat every 4-8 h if necessary)

______ ______ → 1.5 g/kg given once (contraindicated in patients with craneal _________!) May be useful to decrease brain _____/_____ before craneal surgery

Mannitol is not effective in moving fluids from the IF, it’s more for ICS. Why?

Answer 31

Very popular for acute renal failure

Oliguric renal failure (has renal failure and not urinating) → 0.25-0.5 g/kg of a 15-25% solution over 15-60 min
(repeat every 4-6 h is necessary; contraindicated in patients with anuria)

Glaucoma → 1-3 g/kg over 15-20 min (repeat every 4-8 h if necessary)

CNS edema → 1.5 g/kg given once (contraindicated in patients with craneal bleeding!) May be useful to decrease brain mass/volume before craneal surgery

Mannitol is not effective in moving fluids from the IF, it’s more for ICS. Why? Mannitol is distributed in ECF so it is not good for removing fluid from Interstitum. But it does get water to remove from intersitial fluid compartmet into ECF. If we had a drug tat reained in intravsular space, that would be good to remove water from interstitial space.

Question 32

Carbonic anhydrase inhibitors

CA inhibitors target both the ________ and the _______ (membrane-bound) ____. Hydrogen ions are not generated ______ of the cell and are ____ available for exchange with ________. As a result, reduced _______ (and _________) reabsorption
* Elimination of _______ and ________ with the urine
* _______ elimination of acids, _______ pH of the urine (~___) and potential development of ___________ _______

Answer 32

CA inhibitors target both the cytosolic and the luminal (membrane-bound) CA

Hydrogen ions are not generated inside of the cell and are not available for exchange with sodium

As a result, reduced sodium (and bicarbonate) reabsorption
* Elimination of sodium and bicarbonate with the urine
* reduced elimination of acids, increased pH of the urine (~8) and potential development of metabolic acidosis

Bicarbonate is reabsorbed as CO2. This reaction is necessary for proton transport into tubular lumen. If this is blocked, less sodium entering cell. Hydrogen ions not available for exchange with sodium. As a result, sodium reabsorption os reduced and also bicarbonate at the same time.

Question 33

Carbonic anhydrase inhibitors
Sodium that is not reabsorbed will be reabsorbed at _____ segments of the nephron at the expense of a _______ potassium elimination (up to ____% of K+ excreted)

Answer 33

distal, higher, 70

One segment of the nephron can absorb excess Na at expense of K. These are the CD. CD use ? at apical membrane to absorb Na that was not reabsorbed before. This increases K elimination at same time.

Question 34

Carbonic Anhydrase inhibitors
1. Aqueous humor and CSF formation are _____ (useful in ________, primary use)
2. Larger does may ______ gastric acid secretion, affecting the gastric ______
3. Effects RBCS –> increase in ____ levels in ______ tissues and reduced levels in ______ air.
4. May _______ amount of solutes delivered to the macula densa, thereby activating ?

Answer 34

1. reduced, glaucoma
2. reduce, mucosa
3. CO2, peripheral, exhaled
4. increase, tubular glomerular feedback

Other tissues rely on hydration reaction to produce bicarb or transport CO2 as bicarb.

• In the eyes, aqueous humor…
• Protons necessary for formation of HCl acid in the lumen. If use diuretics for a long time, reduce gastric acid ?
• Blocking transport of CO2 as bicarb because you are blocking CA. (air)
• high conc of solutes at macula densa, that will reduce the GFR.

Question 35

Carbonic anhydrase has

• Good _____ absorption
• Half-life = ___ h
• Onset of action in ~____ min; max effects ___-___ h
• Primary indication: _______, 5-10 mg/kg PO q 12 h

Contraindications:
1. ___________ _________
- Can reduce the elimination ____ of _____ bases

Over time, filtered _______ decreases.
- The low amounts of filtered _______ is absorbed by the __________ hydration
reaction → ________.
CA inhibitors can be more effective when used in combination with ?

Answer 35

Good oral absorption; half-life 7 h; onset of action in ~30 min; max effects 2-4 h
Primary indication: glaucoma, 5-10 mg/kg PO q 12 h

Contraindications:
1. Metabolic acidosis
- Can reduce the elimination rate of weak bases

Over time, filtered HCO3- decreases
The low amounts of filtered HCO3- is absorbed by the uncatalized hydration
reaction → refractoriness
CA inhibitors can be more effective when used in combination with loop diuretics or potassium sparing diuretics.

Happens faster with CA, but Hydration reaction can also occur spontaenously without CA help. Over time, diuretics may not work as well because the reaction will keep going independetly of the presence of the carbonic anhydrase.

CA and Loop both increase elimination of K+.
? with thiazide diuretic for long term treatment

Question 36

Thiazide diuretics directly inhibit the ____/____ ___-transport in the __ (_____ effect). By blocking it, blocking reabsorption of ___ and ___ at the same time, therefore they are called ______, which increases _______.

Answer 36

Na+/Cl- co, DT, saluretic, Na, Cl-, saluretic, excretion

Question 37

Thiazide diuretics are less effective in causing Na+ excretion Why?

Answer 37

(most of Na+ reabsorption occurs earlier!) B/c most of Na+ rebabsorption occurs before the distal convoluted tubules. Highest in PCT via secondary active transporters

Question 38

Duration of Thiazide diuretic effect is _________ because of _____ bioavailability, elimination _____-____, and ______. _____ safety margin

Answer 38

variable, oral, half-life, potency, Wide

Question 39

List the side effects of Thiazide diuretics

Answer 39

volume depletion, hypotension, hyponatremia, hypochloremia, hypomagenesemia,
and hypokalemia (b/c of increased reabsorption of Na in DCT via ENAC and leaving of K via RK? channels) (oral potassium supplementation)

Question 40

List the drug interactions of Thiazide diuretics?

May increase effects of ?

Answer 40

reduced effectiveness of anticoagulants, uricosuric drugs, insulin (impaired insulin sensitivity; insulin resistance).

anesthetics, digitalis glycosides, lithium, vitamin D

Question 41

List the indications for Thiazide diuretics?

Answer 41

treatment of early congestive heart failure
Contraindicated in patients with impaired renal function (reduce GFR), hypercalcemia

Not indicated in patients with a reduced GFR because impacts tubular glomerular feedback, which reduces the GFR even further.

Question 42

List the most commonly used Thiazide diuretics and their indications.

Chlorothiazide
- Diuretic 10-40 mg/kg, PO, interval 12 h
- Partial ADH deficiency/diabetes insipidus 20-40 mg/kg, PO, q 12 h

Hydrochloro- thiazide (hydrozide®)
- Diuretic 2-4 mg/kg (D), PO, q 24 h; Antihypertensive agent, 0.5-2 mg/kg, PO q 12-24 h
- Nephrogenic diabetes insipidus, 0.5-5 mg/kg, PO q 12 h
- Hypoglycemia, 2-4 mg/kg, PO q 12

Answer 42

These are the most commonly used thiazide diuretics.

Why do we use diuretics in DI? If DI already causes PU? No one knows; Hypothesis 1–> over time, this diuretics for some reason reduce the GFR. One of the theories, s that it increses Na elomination. For some reason more effective reabsorption of Na in PT. No one knows why this hapens with Thiazide or other diuretics.

Kidneys are not sensitive to ADH in nephrogenic DI.

urine is not as concentrated in DI becuase it is water diruesis not osmotic diuresis.