Download pptx - Diuretics. Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention

Diuretics

Diuretics

Agents that promote natriuresis (salt loss) and diuresis (water loss)

Used to treat hypertension and fluid retention

Salt & Water Balance

2/3 ICF 1/3 ECF

What causes edema?

¼ Plasma

¾ Interstitium

1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body


2/3 ICF 1/3 ECF

What causes edema?

¼ Plasma

¾ Interstitium


When water is added to the system, it distributes evenly: 2/3 to the ICF, 1/3 to the ECFIsotonic fluid, however, stays in the ECF


2/3 ICF 1/3 ECF

I

S

O

T

O

N

I

C

What causes edema?

¼ Plasma

¾ Interstitium

BP

Edema



2/3 ICF 1/3 ECF

I

S

O

T

O

N

I

C

What causes edema?

¼ Plasma

¾ Interstitium



What causes edema?

1. There is a change in capillary hemodynamics favoring the movement of fluid from the vascular to interstitial space

Increased Hydrostatic Pressure

Decreased Oncotic Pressure

Increased Capillary Permeability

Diuretics

Diuretics have profound clinical implicationsThey allow physicians to manipulate salt and water excretion in impaired states of volume/solute regulationLike all great therapeutic interventions, they have the potential to make patients better, and, when not considered carefully, the potential to make patients worse

Diuretics

Act primarily by inhibiting Na channels in the renal tubular system

To reach the tubular lumen, these drugs must be… Ingested and absorbed Effectively circulated Secreted into the renal tubular lumen Bound to the target transporter

Question 1

All of the following are potential obstacles in the diuretic’s migration from pill bottle to apical transporter EXCEPT: A. Low Albumin States B. Pt non compliance C. Renal Failure D. All of these are obstacles to effective

diuresis

Question 2

In patients with nephrotic syndrome, oral diuretics: A. Are not effective, since these patients have

volume retention due to low albumin states and not salt retention

B. Are absorbed more efficiently in the gut C. May bind albumin in the urine instead of

their targeted apical transporters D. Are unable to reach the apical transporters

due to impaired glomerular permeability

Regulation of Urine Content

ADH

Diuretics

Diuretics

Are all diuretics pretty much the same?

Well, they all cause people to pee

But recognize the difference based on the channels being blocked

Favorite test questions focus on “Why is one diuretic better than another in a particular context?”

Diuretics

Class Site Effect Use Side Fx

Thiazides

Loop

K Sparing

Other

Diuretics

LOOP DIURETICS

Representative Example: Furosemide (Lasix)

Onset of action: roughly 30 minutes with PO, 5 minutes with IV

Duration: 6 hours

LASIX = “Lasts Six [Hours]”

Diuretics

LOOP DIURETICS

Representative Example: Furosemide (Lasix)

Site of Action: NaK2Cl transporter in the Thick Ascending Limb

Loop Diuretics

Decrease sodium reabsorption

Impairs the generation of a medullary gradient

Thus… Impairs urine dilution Impairs urine concentration


ADH

NaK2Cl is necessary for:

1. Dilution of Tubular Filtrate

2. Establishing the Hypertonic Medullary Interstitium

3. Providing the concentration gradient by which water is reabosrbed from the collecting duct (urinary concentration)

Effect of Lasix

ADH

Blocking NaK2Cl causes:

1. Impaired dilution

2. No concentration gradient

3. Increased free water excretion

LAS I X

Impaired dilution

Lasix: Let’s see that one more time

Diluting and Concentrating

Diluting and Concentrating

TAL

TAL

Distal Tubule

Collecting Duct

Medullary Interstitium

Loop Diuretics

Decrease sodium reabsorption

Impairs the generation of a medullary gradient

Thus… Impairs urine dilution Impairs urine concentration

Loop Diuretics

NaKCl

Na

K

Calcium

Loop Diuretics

NaKCl

Na

K

Calcium

Loop Diuretics:

Increase excretion of Calcium

Loop Diuretics

Collecting Duct

Na Na

NaNa

K

The increase in Na delivery to the Collecting Duct causes an increase in the exchange of Na for secretion of K/H+

H

Diuretics

LASIX Quick onset of diuresis

Good for acute volume overload Increases urinary calcium excretion

Used to treat hypercalcemia (Malignancy, Hyperparathyroidism)

Increases urinary excretion of potassium and hydrogen ions

Used to treat acute hyperkalemia

3 Reasons to love your loop diuretic

Diuretics

LASIX Excessive diuresis can lead to volume

depletion and ARF/hypotension/CV collapse

3 Reasons to think twice

Diuresis

Diuretics


depletion and ARF/hypotension/CV collapse


Diuresis

Diuretics


depletion and ARF/hypotension/CV collapse Can exacerbate calcium based kidney stones Can cause hypokalemia, metabolic alkalosis


Diuretics


Thiazides

Loop

K Sparing

Other

TAL

NaK2Cl

Impairs dilution and concentration

Acute overload, edema, ↑Ca/K

↓serum K, Met Alkalosis, Volume Depletion, ↑U Ca

Diuretics

THIAZIDE DIURETICS

Representative Example: Hydrochlorothiazide (HCTZ)

Onset of action: roughly 2 hours

Duration: 6-12 hours

Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the “most intimidating medication names.”Less effective at GFR < 40

Diuretics

THIAZIDE DIURETICS

Representative Example: Hydrochlorothiazide (HCTZ)

Site of Action: Distal Convoluted Tubule Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the “most intimidating medication names.”Effect: HCTZ impairs urinary dilution,

increases Na excretion in the urine



HCZT


ADH

HCZT

Thiazide Diuretics:

1. Impair Dilution, leading to excretion of salt and water

2. Do not disrupt the concentrating mechanism

Question 3

Why are patients on thiazides more prone to hyponatremia than those on loop diuretics?

A. Thiazides provide greater natriuretic effect than loop diuretics

B. Trick question: They both equally predispose patients to hyponatremia

C. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilution

D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia

DiureticsHow do I choose between a loop diuretic and a thiazide diuretic?

Similarities:

Both will make you pee

Both can result in hypokalemia and metabolic alkalosis

Both can be used for edema and HTN

DiureticsHow do I choose between a loop diuretic and a thiazide diuretic?

Differences:

Loop Thiazide

Concentration/Dilution Impairs both; greater free water excretion

Impairs dilution only; more prone to ↓Na

PotassiumGreater kaliuretic effect; better for Tx of ↑K

Less kaliuresis

CalciumIncreases Ca excretion; better for Tx of ↑Ca

↑Ca reabsorption; better for folks with Ca stones

Unique Superpowers Better in renal failure; Relieves resp distress

Inexpensive; First line agent for HTN

Diuretics


Thiazides

Loop

K Sparing

Other

TAL

NaK2Cl

Impaired dilution and concentration



DCT

Na/Cl cotrnsprt

Impaired dilution Edema, HTN, Ca stones

Hyponatremia, ↓serum K, Met Alkalosis, Volume Depletion

K-Sparing Diuretics

1. Aldosterone Antagonists

Representative Example: Spironolactone

Site of Action: Cortical Collecting Duct

Mechanism: Competes with aldosterone receptor

Pharmacokinetics: Can take between 10-48 hours to reach maximal efficacy

Factoid:

If Peter Griffin (Family Guy) was on a diuretic it would probably be spironolactone, which would account for his gynecomastia

K-Sparing Diuretics

Collecting Duct

Na Na

NaNa

K

Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface

Aldo

K-Sparing Diuretics

Collecting Duct

Na Na

NaNa

Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface

Aldo

Spironolactone is an aldosterone antagonist, thus preventing sodium reabsorption and K excretion

K

K Sparing DiureticsThere’s more to aldosterone than meets the eye…

There are mineralocorticoid receptors in the heart as well

Local production of aldosterone in the heart is proportional to degree of heart failure

Aldosterone may stimulate cardiac fibrosis and hypertrophy (Bad)

Aldosterone Antagonists may be particularly beneficial in the long term management of certain patients with heart failure

K Sparing Diuretics Despite being a weaker diuretic, aldosterone

antagonists have a greater effect in cirrhotics than lasix!

Cirrhotic patients have a poor response to lasix due to their low albumin state and reduced tubular secretion.

Aldosterone antagonists do not require secretion into the tubular lumen, and thus may remain effective despite marginal renal perfusion in the context of cirrhosis

K-sparing Diuretics

2. ENaC Blockers

Representative Example: Amiloride, triamterene

Site of action: Corical collecting duct

Mechanism: Blocks ENaC channels

Pharmacokinetics: Half-life = 3-5 hours

Factoid:

Amiloride was first approved for use in 1967, the same year that Thurgood Marshall was sworn in as the first African American justice of the Supreme Court

Spares potassium by decreasing the lumen-negative gradient that drives the exulsion of K/H into the lumen

K-Sparing Diuretics

Collecting Duct

Na Na

NaNa

Amiloride and triamterene directly block the ENaC channel

Aldo

This makes amiloride an ideal agent for the treatment of patient’s with Liddles Syndrome, in which there is an abundance of “active” ENaC channels expressed in the CCD

K K

K-Sparing Diuretics

Collecting Duct

Li

Li

Li

Li

Li

Factoid:

Certain drugs (trimethoprim, pentamidine) may have mild diuretic effects due to their ability to block reduce the number of open ENaC channels

Question 4

A young bipolar patient with AIDS is seen in clinic. He was recently hospitalized and treated for PCP pneumonia with high doses of Bactrim (trimethoprim sulfamethoxazole). He also takes lithium and a cocktail of antiretroviral drugs. Since the completion of his antibiotic, the patient states that his breathing has improved dramatically, but he notes that he is always thirsty and has urine output of Gaussian proportions.

Question 4 (cont)

The intern blows this off, but since you’ve read this syllabus you hypothesize that…

A. Accumulation of TMX has led to nephrogenic DI B. The patient may have lithium-induced nephrogenic

DI because Bactrim increases the open Na channels available for Li entry into cells

C. The patient may have psychogenic polydipsia and worsening mania due to decreased absorption of lithium during treatment with Bactrim

D. Amiloride my alleviate his symptoms.

Diuretics


Thiazides

Loop

K Sparing

Other

TAL

NaK2Cl

Impaired dilution and concentration



DCT

Na/Cl cotrnsprt

Impaired dilution Edema, HTN, Ca stones

Hyponatremia, ↓serum K, Met Alkalosis, Volume Depletion

CCD Decreased distal Na reabsorption

↓K, CHF, ESLD; Li tox, Liddles

↑ serum K, gynecomastia

“Other” DiureticsCAI Ex: Acetazolamide Blocks carbonic

anhydrase Causes alkaline

diuresis

Applications:

Glaucoma

Prophylaxis of Mountain Sickness

“Other” Diuretics

Osmotic Diuretics Ex: Mannitol Non-reabsorbable polysaccharide Preferential water diuresis

The net effect is akin to putting SpongeBob Squarepants in the lumen of the renal tubule.

Final thoughts

Rebound The kidney is a master at compensation In the absence of salt restriction, the kidney

will adapt to the effect of the diuretic After an initial diuresis, further natriuresis will

be blunted by post-diuretic salt retention Salt restriction is, thus, crucial to continued

diuresis

Downstream Compensation

ADH

LAS I X

As the kidney is an awfully smart fellow, it may try to restore steady-state Na status by increasing reabsorption distal to the site of diuretic action

The addition of a “downstream” diuretic (in this case, something that blocks the distal tubule) will prevent the kidney from reclaiming Na and water

Fortune Cookie:“To fool the kidney, you must think like the kidney”

Clinical Scenarios

For each of the following clinical scenarios, pick the appropriate diuretic: A. Loop B. Thiazide C. Aldosterone Antagonist D. ENaC Inhibitor E. The square root of Misler/(1.73x Kukla)

Clinical Scenarios 60 year old with history of myocardial infarction presents to ER with sudden onset shortness of breath after participating in regional pickle eating contest

Too winded to speak in full sentences

Crackles/Rales on exam, 2+ LE edema, Oxygen Saturation 74% on 5L O2

LASIX

Why? Rapid onset of diuresis, +Pulmonary edema

Result? Symptomatic relief, avoidance of intubation and mechanical ventilation

Clinical Scenarios 48 year old man seen in clinic after experiencing exquisite pain in groin last week. Passed the following Ca-based stone with urination.

Noted to have BP 153/80

Thiazide

Why? HTN, Ca-based stone

Result? Decrease risk for future stone formation, reduce BP, decrease risk of cardiovascular complications/death due to HTN

Clinical Scenarios 12 year old with a strong family history of HTN, noted to have a BP of 188/60. Has been treated with thiazides, beta-blockers, ACE-inhibitors without BP control. Labs show a serum K of 3.1, bicarb of 32.

ENaC Inhibitor

Why? Suspicion of Liddle’s (family history, HTN, low K, metabolic alkalosis)

Result? Reduced blood pressure, decrease in cardiovascular risk from HTN

Clinical Scenarios 63 year old with a history of CHF. Edema is managed with dietary restriction of Na and a loop diuretic, but patient still occasionally short of breath with minimal exertion. Is in clinic for follow up and management of his heart failure.

Aldosterone Antagonist

Why? Class III-IV HF

Result? Decreased mortality at 16-24 months

Clinical Scenarios 62 year old woman with CKD complaining of generalized weakness, intermittent palpitations. Serum K level is 6.8 (normal 3.5-4.5)

Lasix

Why? Kaliuretic effect

Result? Reduction of serum K, prevention of cardiac arrhythmia and death

Clinical Scenarios 69 year old man presents with back pain and anemia. Is found to have Ca 11.6 mg/dL. In addition to hydration with NS and the diagnosis of Multiple Myeloma, what diuretic should be given?

Lasix

Why? Increase Ca excretion

Result? Reduce serum Ca, prevent cardiac, renal, neurologic, musculoskeletal complications of hypercalcemia.

Clinical Scenarios Iron Chef Morimoto shows up in your clinic for a routine check up. He has no significant past medical history. His renal function in intact. Electrolytes are stable. BP is 153/87

Thiazide

Why? Essential HTN

Result? Reduction of future cardiovascular risk, many more years of dominance on “The Iron Chef.”

Clinical Scenarios 47 year old with chronic hepatitis and cirrhosis. Has noted increasing abdominal girth over the last several days despite treatment with Lasix. Serum K is 3.2 (normal 3.5-4.5)

Aldosterone Antagonist

Why? Hypokalemia, improved volume removal in a cirrhotic patient

Result? Mild alleviation of volume retention, improvement in serum K.

Clinical Scenarios The previous patient has a slight improvement in edema and ascites. However, after three days she develops worsening renal function. What could have happened?