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What happens to total body water following Na+ infusion?
It shifts (water moves from the ICF to the ECF)
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What happens to compartmental water balance following infusion of pure water?
The water redistributes equally to both ICF and ECF (water is freely permeant across membranes)
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Why is it important to maintain a relatively constant serum osmolarity?
The brain cannot tolerate small changes in osmolarity (it will swell or shrink)
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Consequences of brain shrinkage
Pulls apart from meninges → hemorrhage, meningeal tears, neuronal/glial tears
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Consequences of brain swelling
Herniation beyond the tentorium → compression of the brainstem
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Why can the brain tolerate minor changes in serum osmolarity?
Blood-brain barrier
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Most dysnatremias are [mild, moderate, or severe] and SNa is in the range [#]-[#] mM
Mild; 125-155 nM
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What kinds of patients most often have dysnatremias?
Hospitalized, institutionalized, or “polypharmacied” patients
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T/F: Dysnatremias are often emergencies and require aggressive treatment
False – most are non-emergent and require only a “tweak” in treatment
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Define osmoregulation
Maintenance of constant Sosm (serum osmolarity)
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What areas of the brain sense changes in Sosm?
- Supraoptic nucleus (SON)
- Hypothalamic thirst nucleus
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Hypothalamic cells can sense Sosm changes of [%] once the level is about [#] mOsm
1%; 285-290 mOsm
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How do these nuclei respond to increased Sosm?
SON
Hypothalamic thirst nucleus
- ADH secretion
- Increase thirst drive
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How do stimuli from the baroreceptor and brainstem nuclei affect ADH release?
Lower the threshold for ADH release
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Stimuli that can lower the threshold for ADH release from the SON
- Decreased PO2
- Decreased BP
- Decreased ECFV
- Pain/stress
- Nausea
- Drugs
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ADH is released from the [anterior or posterior] pituitary
posterior
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Operational definition of euvolemia
Intravascular volume required to maintain the least preload for optimizing stroke volume
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How is preload measured?
Swan-Ganz catheter
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Practical definition of euvolemia
Intravascular volume that maintains stable BP and HR (lying or standing), without peripheral pitting edema or pulmonary vascular congestion
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Diuretics lead to which one?
A. Too much water for the amount of salt
B. Too little salt for the amount of water
C. Too much salt and water, but more water than salt
B. Too little salt for the amount of water
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Cirrhosis leads to which one?
A. Too much water for the amount of salt
B. Too little salt for the amount of water
C. Too much salt and water, but more water than salt
C. Too much salt and water, but more water than salt
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Molecular mechanism for SON response, leading to decreased ADH release
Decreased Sosm → SON cell swelling → closure of stretch-inactivated cation channels → less depolarization → fewer APs → decreased Ca2+ entry at terminal → decreased ADH release
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Molecular mechanism for decreased ADH resulting in decreased urine osmolarity
Decreased ADH binding at V2 receptors in collecting duct → less exocytosis of aquaporins into apical membrane → decreased water permeability → decreased urine osmolarity (urine is more dilute)
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Increased renal free water clearance → [increase or decrease] in Sosm
increase
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4 major causes of hyponatremia
- Stimulus for inappropriate thirst
- Stimulus for massive ADH release
- Salt wasting with water replacement
- Overactivation of CVMP
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Osmolarity of the most dilute urine possible
50 mOsm/L
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ADH release is inappropriate if Sosm falls below [#]
280 mOsm
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CVMP is a [non-osmolar or osmolar] drive for ADH secretion
non-osmolar
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Methods for determining a patient’s volume status
- Weight
- Recent photograph
- Orthostatic BP changes
- Central venous pressure
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How can cancer cause hyponatremia?
Paraneoplastic secretion of an ADH-like substance
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How can CNS inflammation or injury cause hyponatremia?
Cytokine stimulation of SON neurons → ADH release
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How can affective disorders cause hyponatremia?
- Psychotic thirst
- Antidepressants → non-osmotic induction of ADH release
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The urine of a hyponatremic patient should be below [#] mOsm
100 mOsm
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How can you measure renal function?
Serum creatinine
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The urine of a hyponatremic patient should have UNa below [#] mEq/L
20 mEq/L
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A hyponatremic patient should be hyper-osmolar, with Sosm < [#] mOsm
285-290 mOsm
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What could produce a falsely reduced serum sodium?
Hyperlipidemia (lipids take up too much of the non-protein component of blood; if you subtract the lipid component, SNa is normal)
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What hormone might have residual activity if the urine of a hyponatremic patient is not maximally dilute?
ADH
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SIADH
What does it stand for?
It is also called “[?] hyponatremia”
- Syndrome of inappropriate ADH secretion
- Euvolemic
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SIADH occurs in the [presence or absence] of ineffective intravascular volume
Absence
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In SIADH, SNa and Sosm are low enough that [hormone] should be shut off, but it isn’t
ADH
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In SIAD, the urine [is or is not] maximally dilute
is not
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2 possible causes of SIADH
- Osmostat has been reset
- Autonomous ADH secretion (paraneoplastic syndrome)
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SIADH results in primarily [ECF or ICF] overload
ICF
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Is pitting edema often seen in SIADH?
No – SIADH causes an increase in ICF, not ECF
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Describe the following in SIADH:
Volume status
Renal function
Hypothyroid or Addison’s?
Urine osmolarity
Urine sodium
- Euvolemic
- Intact
- No
- Less than maximal (Uosm > 75-100 mOsm)
- UNa > 20 (off diuretics) – not low
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Patients with SIADH [are or are not] in sodium balance, and they put out [too much or too little] water
are; too little
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What is psychogenic polydypsia?
Inappropriate thirst → massively increased water intake
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Excretable sodium load on a normal diet
800-900 mOsm/day
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On a normal diet, what is the maximal volume or urine possible (if it is maximally dilute)?
16-18 L/day
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Excretable sodium load on a poor diet
300 mOsm/day
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Patients with hypovolemic hyponatremia have decreased [?] volume
intravascular
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How can patients develop hypovolemic hyponatremia?
- Loss of fluid from body
- Sequestration of fluid in a third space (e.g., intestinal lumen, lymph, muscle, pancreas, pleural cavity, peritoneal cavity)
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What conditions can result in hypervolemic hyponatremia?
- CHF
- Hepatic cirrhosis
- Nephrotic syndrome
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Chronic use of thiazide diuretics can result in [?] hyponatremia, due to ongoing loss of [?]
euvolemic or hypovolemic; Na+
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Use of thiazide diuretics results in a decrease in intracellular [K+ or Na+] and an increase in intracellular [K+ or Na+]
K+; Na+
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Treat hyponatremia if SNa is less than [?] mEq/L
120-125 mEq/L
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T/F: Hyponatremia might be correctable with simple fluid restriction
True
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When treating hyponatremia, what is the maximum safe rate of SNa increase?
8-10 mEq/day
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2 methods for treating hyponatremia
- Solute loading + loop diuretic (to get rid of hypotonic fluid)
- Aquaresis with ADH V2 receptor blocker
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What are vaptans?
Non-peptide ADH V2 receptor blockers
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Do vaptans produce…
Natriuresis?
Kaliuresis?
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How do vaptans interact with the ADH V2 receptor?
- Bind deep in the GPCR and prevent ADH binding superficially
- Prevent interaction of the GPCR with the G-protein
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Hypernatremia + fluid [intake or restriction] → “eunatremic”
intake
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Hyponatremia + fluid [intake or restriction] → “eunatremic”
restriction
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2 general causes of hypernatremia
- Diabetes insipidus (hypodipsea + urinary concentrating deficit)
- Abnormal loss of hypotonic fluid without access to free water
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Cause of central diabetes insipidus
Reduced ADH secretion secondary to surgery, intrapituitary bleed, head trauma, intracranial malignancy (i.e., damage to the pituitary)
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Causes of nephrogenic diabetes insipidus
- Reduced ADH response due to receptor or aquaporin deficit
- Reduced transport of Na+ or urea into medullary interstitium
- Loss of vasa recta (sickle cell disease)
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Causes of hypernatremia secondary to abnormal hypotonic fluid loss
- Impaired skin integrity
- Intense sweat + fever/heat exposure
- Heat exhaustion or stroke
- Osmotic diarrhea
- Hyperventilatory water loss
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In osmotic diarrhea, the lost fluid is [hypertonic or hypotonic]
hypotonic
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3 drugs that result in nephrogenic diabetes insipidus
- Lithium
- Amphotericin B
- Calcium
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Drug-induced diabetes insipidus results in disruption of the [hormone] pathway, causing decreased insertion of [?] in the apical [nephron segment] membrane
ADH; aquaporins; collecting duct
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How does lithium cause ADH blockade?
Enter cell through ENaC → inhibit adenylate cyclase → interrupt ADH signaling cascade
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How does amphotericin B cause ADH blockade?
Amphotericin B monomers form a non-selective cation channel in the apical membrane of the collecting duct → Na+ enters cell and K+ leaves → loss of K+ causes malfunction of adenylate cyclase → interrupt ADH signaling cascade
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How does calcium cause ADH blockade?
Ca2+ binds its own GPCR in the basolateral membrane → release of an inhibitory G-protein subunit → inhibition of adenylate cyclase → interrupt ADH signaling cascade
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Urinary concentration deficits secondary to lithium/amphotericin B/calcium have a [rapid or slow] onset
rapid
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Treat hypernatremia if serum sodium is > [#] mEq/L
155 mEq/L
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Why must hypernatremia always be treated?
Patients could develop significant CNS pathology
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Maximum rate of SNa decrease when treating hypernatremia
Consequences if SNa decreases too quickly
- 0.5 mEq/L/hr (12 mEq/day) until SNa = 150
- Brain swelling
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Treatment for acute hypernatremia
Infusion of D5W (5% dextrose; essentially “free water”)
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Treatment options for chronic hypernatremia
- ADH agonist (DDAVP)
- SON stimulant
- Mild reduction in GFR (tricky)
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Treatment for a hypovolemic hypernatremic patient
- First, correct hypovolemia with normal saline
- If patient is still hypernatremic, infuse D5W
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During treatment of hypernatremia, rebound will occur if you don’t…
replace urinary and insensible free water loss
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Formula for estimated water deficit in hypernatremic patients
0.45*(lean body weight)*(measured SNa/140 – 1)
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In the formula for estimated water deficit, what does “0.45” represent?
Fraction of body weight that is total body water (in a lean person)
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T/F: The calculated water deficit might not be accurate depending on the BMI of the patient
True
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T/F: Vaptans (ADH receptor antagonists) can be used to treat hypernatremia
True – they are effective in both hypo- and hypernatremia
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Mechanism of vaptans in the treatment of hypernatremia
Vaptans enter cell → bind defective ADH receptor → chaperone the receptors through the ER/Golgi → insertion in the basolateral membrane of the collecting duct
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Mechanism of cGMP phosphodiesterase inhibitors in the treatment of hypernatremia
Raise intracellular [cGMP] → cGMP acts like cAMP → target aquaporins to the apical membrane of the collecting duct
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Example of a cGMP phosphodiesterase inhibitor
Viagra
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Hypernatremic patients have [oliguria or polyuria]
polyuria
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Major cause of hypernatremia in the elderly
Defect in thirst (or lack of accessibility to water)
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