1.

Reticuloendothelial system
In immunology, the ​mononuclear phagocyte system or mononuclear phagocytic 
system​ (MPS) (also known as the reticuloendothelial system or macrophagesystem) 
is a part of the ​immune system​ that consists of the phagocytic cells located in 
reticular connective tissue. 
The spleen is the largest unit of the mononuclear phagocyte system. The monocyte is formed in 
the bone marrow and transported by the blood; it migrates into the tissues, where it transforms 
into a histiocyte or a macrophage. 
Macrophages are diffusely scattered in the connective tissue and in liver (Kupffer cells), spleen 
and lymph nodes (sinus histiocytes), lungs (alveolar macrophages), and central nervous system 
(microglia). The half-life of blood monocytes is about 1 day, whereas the life span of tissue 
macrophages is several months or years. The mononuclear phagocyte system is part of both 
humoral and cell-mediated immunity. The mononuclear phagocyte system has an important role 
in defense against microorganisms, including mycobacteria, fungi, bacteria, protozoa, and 
viruses. Macrophages remove senescent erythrocytes, leukocytes, and ​megakaryocytes​ by 
phagocytosis​ and digestion. 

2.Tutorial 2 Page 3 nomor 1 dan 2

a.After receive laboratory result, what is your conclusion?
K serum pasien dibawah range normal sehingga kita bisa mengatakan bahwa pasien
mengalami hypokalemia. Hal ini dapat terjadi karena pasien mengalami muntah-muntah.
Disaat pasien muntah, akan lambung akan ikut terbuang. Semakin banyaknya asam
lambung yang terbuang, membuat tubuh mengalami kenaikan pH dan terjadi kondisi
metabolic alkalosis. Tubuh akan mengkompensasi peristiwa ini dengan mengambil ion H
dari dalam cell. Proses ini bersifat antiporter, artinya setiap H yang diambul dari dalam cell,
maka harus ada K dalam serum yang harus dimasukan ke dalam cell. Kadar K dalam
seruum akan terus menurun sehingga pasien mengalami kondisi hypokalemia.
Platelet pasien juga mengalami penurunan. Hipotesisnya adalah pasien yang mengalami
diarrhea dapat disebabkan oleh infeksi bakteri. Bakteri penyebab diarrhea dapat berupa
Shigella Dysentriae dan E. Coli. Kedua bakteri ini akan menyebabkan infeksi di epithelial gut
mucosa. Receptor di endothelial akan menginduksi terjadinya proses inflamasi dan terjadi
microvascular thrombosis.

b.What kind of disease or drug can cause hypokalemia

Disease that cause hypokalemia :
1. Gitelman’s Syndrome
2. Severe diarrhea and vomiting
3. Nephritis and renal tubular acidosis
4. Cushing’s Syndrome
5. Hyperaldosteronism
6. Acute alcoholism
7. Heart failure
8. Bartter Syndrome

Drug cause hypokalemia :

1. Diuretics : Acetazolamide, Thiazides, Bumetanide
2. Beta 2- Receptor agonists : Epinephrine, Terbutaline, Albutenol, Overdose insuline
3. Xanthine : Caffeine, Theophyline
4. Antimicrobials : Penicilin, Ampicilin
5. Corticoid and Glucocorticoids : Prednisone, Hydrocortison
6. Laxatives : Sorbitol

4.Tutorial 2 Page 4 nomor 2

Explain the changes of electrical process that is affected by electrolytes, water, and
acid-base balance

Electrolytes : Changes in sodium and potassium levels in the body will affect the electrical
process of the body. Since it will disrupt all the Na/K pumps in the body, which makes an
electrical gradient responsible for the regulation of muscle contraction and heart beats.

Acid - Base : Acidosis causes depression the Central Nervous System, which causes
hypercapnia (acidosis by CO2 increase). Hypercapnia causes diaphragm impairment by
affecting the afferent transmission of signals and reduces cardiac muscle contractility.

Meanwhile Alkalosis causes an overexcitability of the peripheral nervous system and the
central nervous system, the latter happening after the former. Overexcitability in the
peripheral nervous system causes paraesthesia and spasms, which would then become a
respiratory muscle spasm which causes dyspnea. Overexcitability in the central nervous
system causes convulsions that may result in death.
5.Describe the distribution of potassium in the body and in the kidney

7a. Describe the Na/K-ATPase and its role in potassium physiology

Na/K-ATPase = Na K pump​ : energy-dependent and are located in the tubular cell’s basolateral
membrane (di ginjal)
Basolateral membrane: refers to the membrane on the base and sides of the cell. The basolateral
membrane forms a barrier between the cell and the blood and/or other cells. The basolateral
membrane's main function is to transport nutrients from the cell to the blood plasma through
specialised protein transporters
Na/K-ATPase: active transport​ (Na keluar sel, K masuk sel)
Na: Reabsorption di ginjal
-Transport Na+ dari dalam sel ke lateral space. Menjaga intracellular Na+ concentration low while
simultaneously building up Na+ concentration in the lateral space
-Dari total Na yang difiltrasi ginjal, yang direabsorpsi kembali adalah 99,5%:
67%: reabsorpsi di proximal tubule
25%: reabsorpsi di loop of Henle
8%: reabsorpsi di distal and collecting tubules
Setelah Na ditransport keluar dengan menggunakan pump karena melawan gradien konsentrasi, Na
akan bertransportasi secara pasif dari interstitial fluid ke dalam pertibulary capillary blood.

K+: Secretion di ginjal

-Most important substances secreted by the tubules are hydrogen ion, potassium ion, and organic
anions and cations.
-H+ secretion: important in regulation acid-base balance in the body
Body fluids acidic: H+ secretion increases
H+ concentration too low: H+ secretion decreases
-Potassium secretion is controlled by aldosterone
about 98% of K+ is in the intracellular fulid because NaK pump actively transport K+ into the cells.
-Sedikit perubahan dalam jumlah K+ di ECF, akan memberikan efek yang besar di plasma K+
concentrationnya. Perubahan konsentrasi K+ di plasma dapat memengaruhi membrane excitability.
Plasma K+ concentration are tightly controlled by kidneys:
Proximal tubule: actively reabsorbed without regulation
Distal and collecting tubules: actively secreted variablely and subject to regulation
kenapa hanya di distal saja yang sekresi K+?
Yang mempengaruhi adalah lokasi passive K+ leak channels. Di bagian distal dan collecting tubules:
K+ channels ada di luminal membrane, jadi K+ yang ditarik ke dalam sel akan masuk melalui channel
ini dan pindajh ke dalam tubuler lumen sehingga tersekresi
Sedangkan di bagian proximal tubule, K+ channelnya terlatak di basolateral membrane. K+ yang
masuk ke dalam sel dari NaK pump bisa langsung pindah ke lateral space melalui channel ini
sehingga tidak tersekresi
Mechanism of K+ secretion
-K+ secretion in the principal cells of the distal and collecting tubules is coupled to Na+ reabsorption
by the energy-dependent basolateral NaK pump.
Control of K+ secretion
Yang paling berpengaruh: aldosterone
Th is hormone stimulates K secretion by the principal tubular cells late in the nephron while
simultaneously enhancing these cells’ reabsorption of Na. A rise in plasma K concentration directly
stimulates the adrenal cortex to increase its output of aldosterone, which in turn promotes the
secretion and ultimate urinary excretion and elimination of excess K. Conversely, a decline in plasma
K concentration causes a reduction in aldosterone secretion and a corresponding decrease in
aldosteronestimulated renal K secretion. The amount of filtered K excreted in the urine varies from
80% to 1%, depending on the body’s momentary needs. ​Note that a rise in plasma K concentration
directly stimulates aldosterone secretion by the adrenal cortex, whereas a fall in plasma Na
concentration stimulates aldosterone secretion by means of the complex RAAS pathway.​ Thus,
aldosterone secretion can be stimulated by two separate pathways. No matter what the stimulus,
however, increased aldosterone secretion​ ​always promotes simultaneous Na reabsorption and K
secretion​. For this reason, K secretion can be inadvertently stimulated as a result of increased
aldosterone activity brought about by Na depletion, ECF volume reduction, or a fall in arterial blood
pressure totally unrelated to K balance. The resulting inappropriate loss of K can lead to K deficiency.
Clinical Note
Potassium plays a key role in the ​membrane electrical activity of excitable tissues.​ Both increases and
decreases in the plasma (ECF) K concentration can alter the intracellular-to-extracellular K
concentration gradient, which in turn can change the resting membrane potential. The most serious
consequences of​ both K excess and K deficiency are related to their impact on the heart​. Both
conditions result in decreased cardiac excitability, for different reasons. A rise in ECF K concentration
reduces resting potential (makes it less negative), which ​decreases the excitability of neurons​,
skeletal muscle cells, and, most importantly, cardiac muscle cells, by keeping the voltage-gated Na
channels responsible for the rising phase of the cardiac action potential in their inactive (closed and
not capable of opening) state (see p. 92). The cell membrane is unable to repolarize completely after
depolarization to return the channel to its closed and capable of opening conformation. Some Na
channels are more sensitive than others to the depolarizing effect. As more and more Na channels
are inactivated by rising K levels, cardiac excitability progressively decreases. In mild cases, the rate
of rise and amplitude of cardiac action potentials decrease, and conduction velocity slows. In serious
cases, cardiac arrhythmias possibly leading to fatal fibrillation ensue (see p. 320), or alternately death
may result from cardiac arrest. ​A fall in ECF K concentration results in hyperpolarization of nerve and
muscle cell membranes, which also reduces their excitability​. A greater depolarization than normal is
needed to bring the membrane to threshold potential. The manifestations of ECF K depletion are
skeletal muscle weakness, diarrhea and abdominal distension caused by smooth muscle dysfunction,
and abnormalities in cardiac rhythm and impulse​ conduction.

NCBI:
The energy dependent exchange of cytoplasmic Na+ for extracellular K+ in
mammalian cells is due to a ​membrane bound enzyme system, the Na,K-ATPase​.
The exchange sustains a gradient for Na+ into and for K+ out of the cell, and this is
used as an energy source for creation of the membrane potential, for its de- and
repolarisation, for regulation of cytoplasmic ionic composition and for transepithelial
transport. The Na,K-ATPase consists of two membrane spanning polypeptides, an
alpha-subunit of 112-kD and a beta-subunit, which is a glycoprotein of 35-kD. The
catalytic properties are associated with the alpha-subunit, which has the binding
domain for ATP and the cations.
Potassium Physiology
Potassium is crucial to ​heart function and plays a key role in skeletal and smooth
muscle contraction​, making it important for normal digestive and muscular function​.
Potassium is very important in the human body. ​Along with sodium, it regulates the
water balance and the acid-base balance in the blood and tissues​. Potassium enters
the cell more readily than does sodium and instigates the brief sodium-potassium
exchange across the cell membranes. In the nerve cells, this ​sodium-potassium flux
generates the electrical potential that aids the conduction of nerve impulses.​ When
potassium leaves the cell, it changes the membrane potential and allows the nerve
impulse to progress. This electrical potential gradient, created by the
"sodium-potassium pump," helps generate muscle contractions and regulates the
heartbeat. Another of the pump's most important functions is​ preventing the
swelling of cells.​ If sodium is not pumped out, water accumulates within the cell
causing it to swell and ultimately burst.

Potassium is very important in ​cellular biochemical reactions and energy

metabolism​; it participates in the synthesis of protein from amino acids in the cell.
Potassium also functions in carbohydrate metabolism; it is active in glycogen and
glucose metabolism, converting glucose to glycogen that can be stored in the liver for
future energy. Potassium is important for normal growth and for building muscle.

Though sodium is readily conserved by the body, there is no effective method for
potassium kconservation. Even when a potassium shortage exists, the kidneys
continue to excrete it. Because the human body relies on potassium balance for a
regularly contracting heart and a healthy nervous system, it is essential to strive for
this electrolyte's balance.

http://hkpp.org/patients/potassium-health

-Potassium (K+) is the major intracellular cation, with 98% of the total pool being located in
the cells at a concentration of 140-150 mmol/l, and only 2% in the extracellular fluid, where
it ranges between 3.5 and 5 mmol/l.
7b. Describe the effects of hyperkalemia and hypokalemia and outline
treatment
Hypokalemia
Hypokalemia is generally defined as a serum potassium level of less than 3.5 mEq/L
(3.5 mmol/L)
Moderate hypokalemia is a serum level of 2.5-3.0 mEq/L
Severe hypokalemia is a level of less than 2.5 mEq/L. Severe hypokalemia may
manifest as bradycardia with cardiovascular collapse
Causes
Hypokalemia may result from inadequate potassium intake, increased potassium
excretion, or a shift of potassium from the extracellular to the intracellular space.
Increased excretion is the most common mechanism. Poor intake or an intracellular
shift by itself is a distinctly uncommon cause, but several causes often are present
simultaneously
Signs and symptoms
Complaints may include the following:

● Weakness and fatigue (most common)

● Muscle cramps and pain (severe cases)
● Worsening diabetes control or polyuria
● Palpitations
● Psychological symptoms (eg, psychosis, delirium, hallucinations,
depression)
Management
The treatment of hypokalemia has 4 facets, as follows:

● Reduction of potassium losses

● Replenishment of potassium stores
● Evaluation for potential toxicities
● Determination of the cause to prevent future episodes, if possible
Decreasing potassium losses

● Discontinue diuretics/laxatives
● Use potassium-sparing diuretics if diuretic therapy is required (eg, severe
heart failure)
● Treat diarrhea or vomiting
● Administer H2 blockers to patients receiving nasogastric suction
● Control hyperglycemia if glycosuria is present
Replenishment

● For every 1 mEq/L decrease in serum potassium, the potassium deficit is

approximately 200-400 mEq; however, this calculation could either
overestimate or underestimate the true potassium deficit
● Patients with a potassium level of 2.5-3.5 mEq/L may need only oral
potassium replacement
● If the potassium level is less than 2.5 mEq/L, intravenous (IV) potassium
should be given, with close followup, continuous ECG monitoring, and
serial potassium levels
● The serum potassium level is difficult to replenish if the serum
magnesium level is also low
Surgical care
Surgical intervention is required only with certain etiologies, such as the following:

● Renal artery stenosis

● Adrenal adenoma
● Intestinal obstruction producing massive vomiting
● Villous adenoma
Hyperkelamia
Hyperkalemia is defined as a serum potassium concentration greater than
approximately 5.0-5.5 mEq/L in adults. Levels higher than 7 mEq/L can lead to
significant hemodynamic and neurologic consequences, whereas levels exceeding
8.5 mEq/L can cause respiratory paralysis or cardiac arrest and can quickly be fatal.

Signs and symptoms

Many individuals with hyperkalemia are asymptomatic. When present, symptoms are
nonspecific and predominantly related to muscular or cardiac function. Weakness
and fatigue are the most common complaints. Occasionally, patients may report the
following:

● Frank muscle paralysis

● Dyspnea
● Palpitations
● Chest pain
● Nausea or vomiting
● Paresthesias
Hyperkalemia can result from any of the following, which often occur in combination:

● Excessive intake
● Decreased excretion
● A shift of potassium from the intracellular to the extracellular space
Diagnosis

Other tests include the following:

● ECG
● Urine potassium, sodium, and osmolality
● Complete blood count (CBC)
● Metabolic profile
Early ECG changes​ of hyperkalemia, typically seen at a serum potassium ​level of
5.5-6.5 mEq/L​, include the following:
 - Tall, peaked T waves with a narrow base, best seen in precordial leads
- Shortened QT interval
- ST-segment depression
At a serum potassium level of ​6.5-8.0 mEq/L​, the ECG typically shows the following:

● Peaked T waves
● Prolonged PR interval
● Decreased or disappearing P wave
● Widening of the QRS
● Amplified R wave
At a serum potassium level ​higher than 8.0 mEq/L​, the ECG shows the following:

● Absence of P wave
● Progressive QRS widening
● Intraventricular/fascicular/bundle branch blocks
The progressively widened QRS eventually merges with the T wave, forming a sine
wave pattern. Ventricular fibrillation or asystole follows.
Management
The aggressiveness of therapy is directly related to the rapidity with which
hyperkalemia has developed, the absolute level of hyperkalemia, and the evidence
of toxicity. The faster the rise of potassium, the higher the level, and the stronger the
evidence of cardiotoxicity, the more aggressive therapy should be.
If the patient has only a moderate elevation in potassium level and no ECG
abnormalities, treatment is as follows:

● Increase potassium excretion using a cation exchange resin or diuretics

● Correct the source of excess potassium (eg, increased intake or inhibited
excretion)
In patients with severe hyperkalemia, treatment is as follows:

● IV calcium to ameliorate cardiac toxicity, if present

● Identify and remove sources of potassium intake
● IV glucose and insulin infusion to enhance potassium uptake by cells
● Correct severe metabolic acidosis with sodium bicarbonate
● Consider beta-adrenergic agonist therapy (eg, nebulized albuterol, 10
mg, administered by a respiratory therapist); preferred over alkali therapy
in patients with renal failure
● Increase potassium excretion by administering diuretics or
gastrointestinal cation-exchange medications
● Emergency dialysis for patients with potentially lethal hyperkalemia that
is unresponsive to more conservative measures or with complete renal
failure
Medications for increasing potassium excretion include the following:

● IV saline and a loop diuretic (eg, furosemide), in patients with normal

renal function
● An aldosterone analogue, such as 9-alpha fluorohydrocortisone acetate
(Florinef), in patients with hyporeninemia or hypoaldosteronism or solid
organ transplant patients with chronic hyperkalemia from calcineurin
inhibitor use
● Cation exchange resin such as sodium polystyrene sulfonate (SPS;
Kayexalate) or patiromer; retention enema for hyperkalemic
emergencies, oral for patients with advanced renal failure who are not
yet on dialysis or transplant candidates

Surgery
Surgery is typically unnecessary, but the following scenarios may involve surgical
intervention:

● Patients with metabolic acidosis and consequent hyperkalemia due to

ischemic gut: Exploration required
● Patients with hyperkalemia due to rhabdomyolysis: Surgical
decompression of swollen ischemic muscle compartments may be
needed
● Patients without end-stage renal disease who require hemodialysis for
control of hyperkalemia: Placement of a hemodialysis catheter for
emergent dialysis needed
Other causes of hyperkalemia include:

1. Addison's disease​ (adrenal insufficiency)

2. Angiotensin II receptor blockers
3. Angiotensin-converting enzyme (ACE) inhibitors
4. Beta blockers
5. Dehydration
6. Destruction of red blood cells due to severe injury or burns
7. Excessive use of potassium supplements
8. Type 1 diabetes

8. Describe the distribution of sodium in the body​ ​and in the kidney

Total di tubuh 60mmol/kg
Extracellular fluid contains 50% of the total body sodium
Intracellular fluid contains 5% of the total body sodium.
Plasma solid effect : Krn plasma terdiri dari 93% air dan 7%solid
Gibbs-Donnan Effect : Anionic plasma proteins attract sodium into the plasma. An equilibrium
is reached where the sodium concentration in the plasma remains slightly higher, and the
chloride concentration in the plasma is slightly lower (chloride ends up being higher in the
interstitial fluid)

Na+/K+ ATPase activity :Sodium concentration inside the cell is kept artificially low by the
action of Na+/K+ ATPase, which exchanges 3 sodium atoms for every potassium.
Ginjal
9a. Describe the major hormones involved in the regulation of sodium absorption and
excretion in the kidney
9b.Describe the factor involved in the movement of Na+ between the ICF and ECF
i. Influence of Aldosterone
● 75-80% of sodium (NaCl) in renal filtrate is reabsorbed in proximal tubules of kidneys
● Aldosterone aids in actively reabsorbing remaining Na​+​Cl​-​ in distal convoluted
tubule/collecting tubule by increasing tubule permeability; therefore aldosterone promotes
both sodium and water retention
● Mechanism:
○ increase in K or decease in Na in blood plasma renin-angiotensin Mechanism
○ stimulates adrenal cortex to release aldosterone
○ aldosterone targeted towards the kidney tubules
○ increase in Na reabsorption increase in K secretion
○ restores homeostatic plasma levels of Na and K
● Influences on aldosterone synthesis and release:
○ Elevated potassium levels in ECF directly stimulates adrenal cells to secrete
aldosterone
 ○ Juxtaglomerular apparatus of renal tubes release renin in response to:
1. decreased stretch (due to decrease in blood pressure)
2. decreased filtrate osmolarity
3. sympathetic nervous system stimulation
ii. Cardiovascular system
● As blood volume (and pressure) rises, the baroreceptors in the heart and in the large vessels of
the neck and thorax (carotid arteries and aorta) communicate to the hypothalamus
● Sympathetic nervous system impulses to kidneys decrease, allowing afferent arterioles to
dilate; as the glomerular filtration rate rises, sodium and water output increases (causing
pressure diuresis)
● Reduced blood volume and pressure results
iii. Influence of ADH
● Amount of water reabsorbed in the distal segments of the kidney tubules is proportional to
ADH release (increase in ADH secretion = increase in water resorption)
● Osmoreceptors of the hypothalamus sense the ECF solute concentrations and trigger or inhibit
ADH release from the pituitary
● Mechanism:
○ decrease in sodium concentration in plasma (decreased osmolarity)
○ stimulates osmoreceptors in hypothalamus
○ stimulates posterior pituitary to release ADH
○ ADH targeted toward distal and collecting tubules of kidney
○ the effect is increased water resorption
○ plasma volume increases, osmolarity decreases
○ scant urine produced
iv. Influence of atrial natriuretic factor (ANF)
● Reduces blood pressure and blood volume by inhibiting nearly all events that promote
vasoconstriction and sodium and water retention
● In essence, inhibits ADH and Aldosterone production

10a. Describe the Na/K-ATPase and its role in sodium physiology

Na+/K+-ATPase (sodium-potassium adenosine triphosphatase, also known as the Na+/K+
pump or sodium–potassium pump) is an enzyme (an electrogenic transmembrane ATPase)
found in the plasma membrane of all animal cells. It performs several functions in cell
physiology.

The process of moving sodium and potassium ions across the cell membrance is an active
transport process involving the hydrolysis of ATP to provide the necessary energy. It
involves an enzyme referred to as Na+/K+-ATPase. This process is responsible for
maintaining the large excessof Na+ outside the cell and the large excess of K+ ions on the
inside. A cycle of the transport process is sketched below. It accomplishes the transport of
three Na+ to the outside of the cell and the transport of two K+ ions to the inside. This
unbalanced charge transfer contributes to the separation of charge across the membrane.
The sodium-potassium pump is an important contributer to action potential produced by
nerve cells. This pump is called a P-type ion pump because the ATP interactions
phosphorylates the transport protein and causes a change in its conformation.
ATPase is an enzyme that break down ATP to become ADP plus P, that cause opened of
the Na/K channel, so it can cause the Na enter the cell and K is quit from inside.

10b. Describe the pathophysiology and clinical effect of hyponatremia and

hypernatremia and outline treatment
Hyponatremia​ is defined as a serum sodium concentration lower than 136 mmol/L.2 It can
result from a particular laboratory technique or from improper blood collection, excessively
high water intake, or, most commonly, an inability of the kidneys to excrete free water (see
later, “Pathophysiology and Natural History”).3
Hyponatremia refers to a lower-than-normal level of sodium in the blood. Sodium is essential
for many body functions including the maintenance of fluid balance, regulation of blood
pressure, and normal function of the nervous system. Hyponatremia has sometimes been
referred to as "water intoxication," especially when it is due to the consumption of excess
water, for example during strenuous exercise, without adequate replacement of sodium.
Hyponatremia is a condition that occurs when the level of sodium in your blood is abnormally
low. Sodium is an electrolyte, and it helps regulate the amount of water that's in and around
your cells.

Patophysiology

Hyponatremia can result from improper collection of a blood sample from a vein that is being
infused with hypotonic medications. Additionally, if older techniques (e.g., flame photometry
using whole plasma) for sodium measurement are being used, high levels of protein or
triglyceride in the sample can cause the sodium concentration to be falsely low
(pseudohyponatremia).4 Hyperglycemia can also cause hyponatremia, via osmotically
induced water movement from cells into the blood (translocational hyponatremia), resulting
in a relative decrease in serum sodium concentration in the absence of hypo-osmolality. The
sodium concentration should be increased by approximately 1.6 to 2 mmol/L for each
100-mg/dL increase in glucose concentration above 100 mg/dL.4
Excess water intake is a rare cause of hyponatremia. In persons with preserved renal
function, any extra water intake above obligatory water loss is usually excreted in a dilute
urine, hyponatremia does not develop. However, in psychogenic polydipsia, ingesting large
volumes (>15-20 L/day) of water can result in hyponatremia, despite preserved renal
function and diluting ability.
However, most cases of hyponatremia are caused by decreased renal excretion of water,
secondary to persistent action of ADH or the use of medications that interfere with urinary
dilution (e.g., thiazide diuretics and nonsteroidal anti-inflammatory drugs [NSAIDs]). Most of
these clinical disorders (e.g., congestive heart failure, nephrotic syndrome, cirrhosis) share a
reduction in effective arterial blood volume, resulting in persistent ADH activity despite
hypo-osmolar plasma. In addition, acute or chronic renal failure results in reduced functional
nephron mass, decreased glomerular filtration rate, and therefore decreased capacity for
water excretion.
The drugs most commonly associated with the development of hyponatremia are thiazide
diuretics and NSAIDs. The mechanism of diuretic-induced hyponatremia is complex and
includes interference with urinary dilution by the thick ascending loop of Henle and the distal
convoluted tubule, as well as volume contraction–induced increase in ADH secretion.
Hyponatremia occurs almost exclusively with thiazide diuretics because of preservation in
medullary osmolality and urine-concentrating ability. NSAIDs can lead to hyponatremia via a
decrease in prostaglandin-mediated suppression of ADH. Many other drugs can be
associated with hyponatremia via the augmentation of ADH release or action

Hypernatremia
Definition and Causes
Hypernatremia is defined as a serum sodium concentration greater than 145 mmol/L.10 It is
most commonly caused by the loss of water via the skin, urine, or gastrointestinal (GI) tract.
In all cases, loss of access to water or impaired thirst sensation is required to maintain the
hypernatremic state (see later, “Pathophysiology and Natural History”).
Pathophysiology
An increase in serum sodium concentration is almost always a reflection of water loss rather
than sodium gain. Water loss results in the development of plasma hyperosmolality; via
hypothalamic sensors, this acts as a stimulant to thirst and production of ADH. Ultimately,
free water is ingested and reclaimed via the kidneys, and sodium concentration and
osmolality are restored to normal. Thus, the maintenance of hypernatremia requires
diminished thirst sensation or decreased access to water. Even in states of impaired ADH
release or reduced ADH function at the level of the kidneys (e.g., central or nephrogenic
diabetes insipidus), hypernatremia is avoided if thirst is intact and access to free water is
maintained in adequate amounts to compensate for renal losses.
Hypernatremia is not always associated with pure water loss. It can be associated with
concomitant loss of sodium via hypotonic fluids (e.g., diarrheal fluid) or the addition of
hypertonic fluids (e.g., excessive sodium from parenteral nutrition or sodium bicarbonate
infusion).
Hypernatremia causes a loss of intracellular water into the ECF space and can be
associated with cellular shrinkage. In the CNS, this can be catastrophic, with ensuing cell
death or rupture of blood vessels. To protect against cell shrinkage, electrolytes enter into
the ICF, usually in the first few hours. When hypernatremia persists beyond 2 or 3 days, the
cells begin to generate intracellular osmolytes to maintain intracellular fluid (ICF) osmolarity
further and avoid water loss into the ECF.