Kus 10 ahmc

kidneys & urinary system
By Tatek
1

Out line• Introduction
• CKD
– Progression modifying therapies
– therapeutic approach for the management of complications
• Vasopressin and other agents affecting the renal conservation of
water
• Common electrolyte disorders
– Disorders of potassium homeostasis
– Agents used for disorders of sodium, water, & calcium
homeostasis
– Agents used for acid-base disorders
• Diuretics (Reading assignment) 2

kidneys & urinary system Introduction
• Renal “function” includes the processes of
– filtration, excretion, secretion, reabsorption, endocrine,
metabolic
– endocrine (Secretion of renin & erythropoietin )
• In the presence of stages 3 to 5 chronic kidney disease and
moderate to severe acute renal injuries, secretion of
erythropoietin is impaired leading to reduced red blood cell
formation; Renal anemia
– metabolic functions; ( including the activation of vitamin
D3, gluconeogenesis, and metabolism of endogenous
compounds such as insulin, steroids, and xenobiotics.)
• It is common for patients with diabetes and chronic renal failure to have
reduced requirements for exogenous insulin, and supplemental therapy
with activated vitamin D3 (calcitriol) or other vitamin D analogs
(paricalcitol, doxercalciferol) is often necessary to avert the bone loss and
pain associated with renal osteodystrophy.
3

Chronic kidney disease (CKD)
• Quantification of renal function,
• S/S (Lab parameters)
• CKD; Progression modifying therapies
• CKD; Management of complication
6

Chronic kidney disease (CKD)
Quantification of renal function, in CKD KEY CONCEPTS
Damage to the kidney has detrimental consequences on many other
organ systems, particularly once patients develop ESRD.
The stage of chronic kidney disease (CKD) should be determined
for all individuals based on the level of kidney function, independent of etiology,
The glomerular filtration rate (GFR) is the single best indicator of kidney function.↓↓
Persistent proteinuria indicates the presence of chronic kidney disease. ↑↑
Quantitation of urine protein excretion,
Measurement of creatinine clearance is not routinely recommended; . CCr=↓↓
The measurement of a serum creatinine concentration (Scr); Scr=↑↑
Longitudinal assessment of GFR and proteinuria is important
for monitoring the efficacy of therapeutic interventions, such as
angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers, which are used to slow or halt the progression
of kidney disease.
It is apparent that management of CKD requires treatment of multiple secondary
complications. 7

Microalbuminuria 30–300 mg/day albumin
Clinical proteinuria or albuminuria ≥300 mg/day protein
8

CKD; Progression modifying therapies
12

CKD; Progression modifying therapies
13

CKD; Management of complication
• CKD(stage 4 & 5); S/S, Lab results
• Common complication
• Management of complication
18

CKD; Management of complication
20

Chief Complaint “I’m here to check the results of my urine test.”
Robin Morales is a 37-year-old woman with diabetes mellitus who
visited her PCP 1 week ago for a routine physical examination. Her
laboratory tests revealed a serum creatinine of 1.4 mg/dL and spot
urine albumin-to-creatinine ratio (ACR) of >300 mg albumin per
gram of creatinine. These values were elevated over her baseline of
SCr 1.1 mg/dL and ACR 210 mg/g 1 year ago. A 24-hour urine
collection was performed last week, and she was scheduled to return
to clinic today for further evaluation of her kidney function.
PMH;Type 2 DM × 10 years HTN × 4 years Hypercholesterolemia
Meds ; Metformin 1,000 mg po TID × 8 years Glyburide 10 mg po BID × 6 years
Hydrochlorothiazide 25 mg po once daily × 2 y
UA (1 week ago); 1+ glucose, (+) ketones, 3+ protein,
24-Hour Urine Collection
Total urine volume 2.1 L, urine creatinine 62 mg/dL, urine albumin 687 mg/24 h
SCr 1.4 mg/dL K 4.9 mEq/L, Hgb 10.6 g/dL , Hct 36.5% ,
BP 156/94 Wt 82.5 kg, Ht 5'2''
22

QUESTIONS
1.Create a list of the patient’s problem.
2.What are the indicators markers
3.What are the possible causes
4.What is the stage of the disease
5. Goals of the treatment
6.What other clinical conditions require intervention
7.Recommend your therapeutic approaches
8. What are possible complications and how to manage
9. How to prevent progression of the disease
23

VASOPRESSIN SYSTEM
• By selectively regulating solute or fluid reabsorption, the kidneys play
the major role in maintaining the volume and composition of
extracellular fluid, Osmolality/Tonicity.
• How these process regulated ? Stimulus; volume, blood flow to
kidney; Osmolality/Tonicity,
Regulation of Vasopressin Secretion
Hyperosmolality/volume depletion → acOvate posterior pituitary to
release vasopressin/ADH→ vasopressin act on renal collecOng duct
→ to prevent Diuresis → ↑ Absorption of water →use pituitary DI
Hypo Osmolality /hypervolemia → Inhibit pituitary release of
vasopressin/ADH→H2O Loss
Hypovolemia → ↓ blood flow to kidney/↓ BP→ renin released
→ angiotensin II → Aldosterone → sodium retention/potassium
excretion → water retention → ↑ BP 25

VASOPRESSIN SYSTEM
Regulation of Vasopressin Secretion.
• An increase in plasma osmolality is the principal
physiological stimulus for vasopressin secretion by the
posterior pituitary . Severe hypovolemia/hypotension also is
a powerful stimulus for vasopressin release.
• In addition, several endogenous hormones and
pharmacological agents can modify vasopressin release.
Renal Actions of Vasopressin.
• renal conservation of water; Normalize in plasma osmolality
– V2-receptor-mediated antidiuresis
– V2 receptors also increase Na+ transport in the cortical collecting
duct , and this may synergize with aldosterone to enhance Na+
reabsorption during hypovolemia.
– V1-receptor-mediated reduction of inner medullary blood flow
contributes to the maximum concentrating capacity of the kidney
28

DISEASES AFFECTING THE VASOPRESSIN SYSTEM
Diabetes Insipidus (Di).
Central DI
nephrogenic DI
Syndrome of Inappropriate Secretion of
Antidiuretic Hormone (SIADH).
Other Water-Retaining States (Edema).
– In patients with congestive heart failure, cirrhosis,
or nephrotic syndrome
29

Diabetes Insipidus (Di). DI is a disease of impaired renal conservation
of water owing either to an inadequate secretion of vasopressin from
the neurohypophysis (central DI) or to an insufficient renal response to
vasopressin (nephrogenic DI).
Central DI (desmopressin, Chlorpropamide, thiazide diuretic )
• Desmopressin; Antidiuretic peptides are the primary treatment for
central DI, with desmopressin being the peptide of choice. For
patients with central DI who cannot tolerate antidiuretic peptides
because of side effects or allergic reactions, other treatment options
are available.
• Chlorpropamide, an oral sulfonylurea, potentiates the action of small
or residual amounts of circulating vasopressin and will reduce urine
volume in more than half of all patients with central DI.
– The antidiuretic mechanisms of chlorpropamide, carbamazepine, and
clofibrate are not clear. These agents are not effective in nephrogenic DI
• thiazide diuretic usually results in an adequate reduction in the
volume of urine. MOA; not clearly elucidated
30

Nephrogenic DI. ( Amiloride, thiazide diuretics, indomethacin)
• Causes; Nephrogenic DI may be congenital or acquired. Hypercalcemia,
hypokalemia, postobstructive renal failure, lithium, clozapine, demeclocycline,
• Although the mainstay of treatment of nephrogenic DI is assurance of an
adequate intake of water, drugs also can be used to reduce polyuria.
Amiloride ; blocks the uptake of lithium by the sodium channel in the collecting-
duct system and is considered the drug of choice for lithium-induced
nephrogenic.
Paradoxically, thiazide diuretics reduce the polyuria of patients with DI and often
are used to treat non-lithium-induced nephrogenic DI.
– The antidiuretic mechanism of thiazides in DI is incompletely understood
– In patients with DI, a 50% reduction of urine volume is a good response to thiazides.
Moderate restriction of sodium intake can enhance the antidiuretic effectiveness of
thiazides.
A number of case reports describe the effectiveness of indomethacin in the
treatment of nephrogenic DI.
• The mechanism of the effect may involve a decrease in glomerular filtration rate,
an increase in medullary solute concentration, and/or enhanced proximal
reabsorption of fluid. Also, since prostaglandins attenuate vasopressin-induced
antidiuresis in patients with at least a partially intact V2-receptor system, some
of the antidiuretic response to indomethacin may be due to diminution of the
prostaglandin effect and enhancement of the effects of vasopressin on the
principal cells of the collecting duct 31

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH).
(Demeclocycline, 3 %saline +Furosemide)
• SIADH ; inappropriate ↑↑vasopressin, Water intake exceed water
excretion
• SIADH is a disease of impaired water excretion with accompanying
hyponatremia and hypo-osmolality caused by the inappropriate secretion of
vasopressin. The clinical manifestations of plasma hypotonicity resulting
from SIADH may include lethargy, anorexia, nausea and vomiting, muscle
cramps, coma, convulsions, and death.
• the goal of therapy is simply to increase plasma osmolality toward normal.
• Hyponatremia and Hypo-osmolality treatment is by 3 %saline +Furosemide
– Treatment of hypotonicity in the setting of SIADH includes water restriction,
intravenous administration of hypertonic saline, loop diuretics (which interfere
with the concentrating ability of the kidneys), and
• Demeclocycline,; drugs that inhibit the effect of vasopressin to increase
water permeability in the collecting ducts. To inhibit vasopressin's action in
the collecting ducts, demeclocycline, a tetracycline, currently is the
preferred drug
• Although lithium can inhibit the renal actions of vasopressin, it is effective
in only a minority of patients, may induce irreversible renal damage when
used chronically, and has a low therapeutic index. 33

Other Water-Retaining States. (Edema) diuretic
• In patients with congestive heart failure, cirrhosis, or nephrotic syndrome,
effective blood volume often is reduced, and which can trigger compensatory
renal sodium and water retention through the activation of the RAAS renin–
angiotensin–aldosterone axis, vasopressin, and the sympathetic nervous system .
Since hypovolemia stimulates vasopressin release, patients may become
hyponatremic owing to vasopressin-mediated retention of water.
• Nephrotic syndrome is characterized by proteinuria greater than 3.5 g/day per
1.73 m2, hypoproteinemia(<2mg/dl), edema, and hyperlipidemia.
– Patients with nephrotic syndrome commonly develop diuretic resistance.
– Although the delivery of diuretic to the kidney tubules is normal, the presence of large
amounts of protein in the urine promotes drug binding, and thereby reduces the
availability of the diuretic to the luminal receptor sites. In addition, reduced sodium
delivery to the distal tubule secondary to decreased glomerular perfusion may also
alter diuretic effectiveness.
– It is suggested that the impaired natriuretic response may be overcome by using
higher doses to increase the delivery of free drug to the secretory site in the proximal
nephron. Another approach is to use the combination of a loop diuretic with a distal
diuretic.
• Cirrhosis ; secondary hyperaldosteronism( spironolactone and furosemide)
• Patients with cirrhosis should initially be treated with spironolactone in the
absence of impaired glomerular filtration rate and hyperkalemia. Thiazides may
then be added for patients with a creatinine clearance >50 mL/min. For those
patients who remain diuretic resistant, a loop diuretic may replace the thiazide.34

Edema
Edema may develop rapidly as in the setting of acute decompensation
in myocardial contractility which leads to an elevation in
pulmonary venous pressure that is transmitted back to the pulmonary
capillaries resulting in acute pulmonary edema. Edema may
also develop insidiously as in the case of renal sodium and water
retention due to diminished effective circulating volume which
leads to a rise in the ECF volume and edema formation in both
peripheral and pulmonary interstitial tissues.
Edema formation in patients with nephrotic syndrome is primarily
related to renal sodium and water retention. A decrease in
capillary oncotic pressure does not appear to play a major role until
the serum albumin concentration falls to less than 2 g/dL. This is
explained by the fact that both capillary and interstitial oncotic
pressure decrease proportionately above a serum albumin concentration
of 2 g/dL, and thus the transcapillary oncotic gradient is not
significantly altered.
Patients with cirrhosis initially develop ascites as a result of an
increase in the pressure in the portal circulation proximal to the
diseased liver. Sequestration of fluid in the abdominal cavity (ascites)
and peripheral vasodilation as a consequence of increased levels
of circulating cytokines, result in a decrease in the effective circulating
volume, activation of the sympathetic nervous system, and
secondary hyperaldosteronism. Therefore, renal sodium retention
leads to worsened ascites and edema.
Edema
Management of nephrotic edema involves salt restriction, bedrest,
and use of support stockings and diuretics. However, severe salt
restriction is difficult to achieve and prolonged bedrest could
predispose nephrotic patients to thromboembolism. Hence the use
of a loop diuretic such as furosemide is frequently required.
Although the delivery of diuretic to the kidney tubules is normal,
the presence of large amounts of protein in the urine promotes drug
binding, and thereby reduces the availability of the diuretic to the
luminal receptor sites. In addition, reduced sodium delivery to the
distal tubule secondary to decreased glomerular perfusion may also
alter diuretic effectiveness. Large doses of the loop diuretic, such as
160 to 480 mg of furosemide, may be needed for patients with
35

COMMON ELECTROLYTE DISORDERS
€ sodiumsodiumsodiumsodium
€ PotassiumPotassiumPotassiumPotassium
€ calciumcalciumcalciumcalcium
40

POTASSIUM ABNORMALITIES
Roles:
contractility of muscle cells, trans-membrane potential
• Potassium has many physiologic functions within cells,
including
is critical to cardiac & neuromuscular function.
It is also a determinant of the electrical action potential
across the cell membrane.
Proper cardiac conduction ,neuromuscular function
protein and glycogen synthesis and cellular metabolism
and growth.
42

POTASSIUM ABNORMALITIES
Principal regulator:
kidneys,.
hormones, acid-base balance, and body fluid ,
The kidneys excrete 80% of the daily potassium intake
The normal daily amount of potassium excreted in the
urine is generally 40 to 90 mEq/L, but it can vary based on
dietary intake, serum potassium concentration, and
aldosterone activity.
>90% of the potassium in the body is located in the ICF
compartment (150mEq/L).
Only the small EC [K+], 63 mEq (4.5 mEq/L × 14 liters)
43

HYPERKALEMIA: K+ > 5.5 mmol/l
• Hyperkalemia is defined as a serum potassium
concentration greater than 5.5 mEq/L.
• It can be further classified according to its
severity:
mild hyperkalemia (serum potassium 5.5 to 6 mEq/L);
moderate hyperkalemia (6.1 to 6.9 mEq/L); &
severe hyperkalemia (>7 mEq/L).
44

hyperkalemia: K+ > 5.5 mmol/l
[Mild 5.5-6, Moderate 6.1-7 & Severe >7 mmol/l]
Causes
Decreased renal potassium excretion
Renal failure
Hypoaldosteronism
Potassium sparing diuretics- Sprinolactone
Intercompartmental shifts
Acidosis
Medications
Severe injury or surgical stress
Catabolic states
Increased potassium intake
Salt Substitutes
Causes; potassium supplements, Drugs[ACEI, ARB, PSD, BB],
Acidosis, acute renal failure and CKD ; adrenal insufficiency ,
Addison’s disease, and hypoaldosteronism
45

k
ETIOLOGY AND PATHOPHYSIOLOGY
• Hyperkalemia develops when
potassium intake exceeds excretion(i.e., elevated total body
stores), or
when the transcellular distribution of potassium is disturbed
(i.e., normal total body stores).
Generally, there are four primary causes of true
hyperkalemia:
(1) increased potassium intake; potassium supplements
(2) decreased potassium excretion; acute renal failure and
CKD, endocrinologic disorders; adrenal insufficiency,
Addison’s disease, and hypoaldosteronism[↓ aldosterone],
drugs [ACEI, angiotensin receptor blockers (ARBs),
potassium-sparing diuretics]
(3) redistribution of potassium into the extracellular space;
metabolic acidosis, secondary to diabetes mellitus, chronic
renal failure, or lactic acidosis, β-Blockers
(4) tubular unresponsiveness to aldosterone. 46

K
Hyperkalemia Associated with Decreased Renal Potassium
Excretion
CKD
The kidneys excrete 80% of the daily potassium intake.
Therefore when the kidney is unable to excrete potassium
appropriately, as in acute renal failure and CKD, potassium is
retained and often results in hyperkalemia
– endocrinologic disorders, including adrenal insufficiency,
Addison’s disease, and hypoaldosteronism. All of these
disorders involve a decreased production of aldosterone, which
results in the retention of potassium.
Moreover, many drugs can inhibit the kidney’s ability to
excrete potassium by inhibiting aldosterone and thus
contribute to an increase in serum potassium levels.
– Three drug classes in particular have specific effects at the
kidney: angiotensin-converting enzyme inhibitors (ACEIs),
angiotensin receptor blockers (ARBs), potassium-sparing
diuretics,
47

clinical manifestations of hyperkalemia
Cardiovascular Gastrointestinal Neuromuscular
Tall, peaked T waves
Decreased P waves
PR prolongation
ST-depression
QRS widening
Heart block
Asystole
Nausea
Vomiting
Diarrhea
Intestinal colic
Paresthesias
Weakness
Paralysis
Confusion
48

Treatment of hyperkalemia
Involves three approaches:
1. Measures to protect the myocardium
• Calcium gluconate or calcium chloride reverses
membrane effects). Rapid onset
2. Measures to redistribute K+
• Regular insulin 10U in 50ml 50% dextrose IV over 30-
60min
• Sodium bicarbonate (50 - 100mmol IV over 5-10 min).
• B2-agonist - salbutamol 5mg nebulised (beware
tachycardia).
3. Measures to ↑ K+ excreFon.
• Potassium binding resins - sodium polystyrene
sulfonate (Kayexalate): This resin exchanges Na+ for K+
It can be given orally or rectally as a retention enema.
• Dialysis
49

PHARMACOLOGIC THERAPY
Severe hyperkalemia (>7 mEq/L) or moderate hyperkalemia
(6.1 to 6.9 mEq/L), when associated with clinical symptoms
or ECG changes, requires immediate treatment.
Calcium ; Initial treatment of hyperkalemia is focused on
antagonism of the membrane actions of hyperkalemia
calcium Raises cardiac threshold potential
Secondarily, one should attempt to decrease extracellular
[K] by promoting its intracellular movement (e.g., with
glucose, insulin, β2-receptor agonists, or sodium bicarbonate).
Finally, removal of potassium from the body by Diuretics or
hemodialysis may need to be implemented.
• The underlying cause of hyperkalemia should be identified
and reversed, and exogenous potassium must be withheld
51

C
DESIRED OUTCOME of THERAPY
• The goals of therapy for the treatment of hyperkalemia are
to antagonize adverse cardiac effects,
reverse any symptoms that may be present, and
to return the serum and total body stores of potassium to normal.
52

X
HYPOKALEMIA
• Hypokalemia (defined as a plasma [K] <3.5 mEq/L;
NV=4.5) Hypokalemia can be described as
mild (serum potassium 3 to 3.5 mEq/L),
moderate (serum potassium 2.5 to 3 mEq/L), or
severe (<2.5 mEq/L).
When hypokalemia is detected, a diagnostic work-up
that evaluates the patient’s comorbid disease states
and concomitant medications should be initiated.
ETIOLOGY/Causes
Many drugs; Diuretics & Mineralocorticoids, Insulin
overdose & β2-Receptor agonists
diarrhea and vomiting; loss of potassium-rich GI fluid
Hyperaldosteronism
Hypomagnesemia; hypomagnesemia impairs the function of
the Na+-K+-ATPase pump and promotes renal potassium
wasting. 54

Hypokalemia: K+ < 3.5 mmol/liter
[Mild 3-3.5, Moderate 2.5-3 & Severe <2.5 mmol/l]
Causes:
GI losses
– Vomiting (GOO, pyloric stenosis)
– NGT suctioning, intestinal fistulas
ECF → ICF shifts
– Alkalosis (0.1 increase in pH decreases K+ by 0.6 mmol/l)
– Insulin therapy
Inadequate intake
• prolonged administration of K+ free IV fluids or TPN
Excess renal loss
– Hyperaldosteronism, Cushing's syndrome
– Diuretic use
– Renal tubular acidosis 55

CLINICAL MANIFESTATIONS OF HYPOKALEMIA
CARDIOVASCUR NEUROMUSCUR RENAL METABOLIC
Dysrhythmias
ECG changes
Digitalis toxicity
potentiation
Postural
hypotension
Impaired pressor
responses
Muscle weakness
Ileus
Respiratory failure
Hyporeflexia
Confusion
Depression
Polyuria
Concentrat
ing defect
Glucose intolerance
Potentiation of
hypercalcemia,
hypomagnesaemia
56

HYPOKALEMIA TREATMENT
CORRECT PRECIPITATING FACTORS
Increased pH, Decreased [Mg2+], Drugs
Mild hypokalemia (K+ > 2.0 mEq/L)
Oral KCl tablets
Intravenous KCl infusion 40 mEq/L/6hour
Severe hypokalemia (K+ ≤ 2.0 mEq/L, Paralysis, or ECG
Changes)
Intravenous KCl infusion 40 mEq/h
Continuous ECG monitoring
57

x
PHARMACOLOGIC THERAPY; [K (oral/IV), Spironolactone, Amiloride ]
• Oral Potassium supplementation; Potassium Chloride; moderate
• Intravenous potassium use should be limited to
(1) severe cases of hypokalemia (serum concentration <2.5 mEq/L);
(2) patients exhibiting signs and symptoms of hypokalemia such as
electrocardiogram (ECG) changes or muscle spasms; or
(3) patients unable to tolerate oral therapy.
• Intravenous supplementation is more dangerous than oral therapy because it is
more likely to result in hyperkalemia, thrombophlebitis, and pain at the site of
infusion.
ALTERNATIVE THERAPIES; Potassium-sparing diuretics; Spironolactone
• Spironolactone USE; hyperaldosteronism. For pt on loop diuretics
– Potassium-sparing diuretics are an alternative to exogenous potassium
supplementation, especially when patients are concomitantly receiving drugs that are
known to deplete potassium (e.g., diuretics ).
– Spironolactone is especially effective as a potassium sparing agent in patients with
primary or secondary hyperaldosteronism.
• Spironolactone inhibits the effect of aldosterone in the distal convoluted tubule,
thereby decreasing potassium elimination in the urine.
• Amiloride and triamterene act by an aldosterone-independent mechanism;
however, the complete mechanism of their potassium sparing is unknown.
58

group Discussion
1. A patient with serum potassium 2.8 mEq/L, serum Magnesium 1.1 mEq/L and
Asymptomatic. What is the initial therapy you recommend?
2. A patient with serum potassium 7.1 mEq/L, associated with clinical symptoms,
Hyperglycemia & Abnormal ECG (peaked t-waves, widened QRS complex).
What Initial treatment you recommend ?
3. Mechanism of Action & Expected Result of the agent you recommend for initial
treatment at question # 2
4. Enumerate possible cause of Hypokalemia
5. Why some patients receiving diuretics develop hyperglycemia
6. Main hormone(s) that tightly regulate [K] through negative feedback loop
7. Which of the following cause cell shrinkage and water loss then hyperkalemia?
59

SODIUM Role
• Physiologic functions of Na
– Osmolarity (Antidiuretic hormone (ADH)
– ECF volume; (Aldosterone)
– Action potential
62

• Balance is maintained primarily by the kidneys under
the influence of aldosterone.
• Normal [Na+] is 135–145 mmol/liter.
• [Na+] largely determines the plasma osmolality (Posm
is 290–310 mosm/liter) serum osmolality remains
relatively constant (275 to 290 mOsm/kg)
• Antidiuretic hormone (ADH) is released from the
posterior pituitary when the plasma osmolality rises by
1% to 2% or more.
• Hyponatremia or hypernatremia may occur in the
setting of hypovolemia, hypervolemia, or euvolemia.
SODIUM
63

Control of Aldosterone Secretion
64

HYPONATREMIA: [Na+] < 130 mEq/L
• Hyponatremia (defined as a plasma [Na] <130
mEq/L; ) Hypokalemia can be described as mild
moderate severe
– mild hyponatremia (125 to130 mEq/L)
– moderate ( 115 to 125 mEq/L) to
– severe (< than 110 to 115 mEq/L)
Etiology and diagnosis:
Hyponatremia may occur in the setting of hyperosmolality,
iso-osmolality, or hypo-osmolalities
Consequently, it is necessary to measure the urine & plasma
osmolalities & UOP to evaluate patients with hyponatremia.
–
65

CAUSES OF HYPONATREMIA
I. Hyponatremia with normal or high plasma osmolality (pseudo
hyponatremia)
Hyponatremia with normal plasma osmolality
Asymptomatic:
severe hyperproteinemia
Marked hyperlipidemia
Hyponatremia with high plasma osmolality hypertonic hyponatremia,
Caused by other solutes (e.g., hyperglycemia, mannitol)
• Hyponatremia associated with increased serum osmolality, termed hypertonic
hyponatremia, suggests the presence of excess, nonsodium effective osmoles in
the ECF. This is most frequently encountered in patients with hyperglycemia.
Elevated concentrations of glucose provide effective plasma osmoles, resulting
in diffusion of water from the cells into the extracellular compartment thereby
expanding the ECF, which results in decrease in the serum sodium
concentration. For every 100 mg/dL increase in the serum glucose
concentration, the serum sodium level decreases by 1.7 mEq/L, and the serum
osmolality increases by 2 mOsm/kg.
67

CAUSES OF HYPONATREMIA
II. Hyponatremia with low plasma osmolality
(a) Hypovolemic Hyponatremia:
Renal (urine sodium >20 mmol/litre)
Diuretics; Osmotic diuresis (glucose, mannitol)
Renal tubular acidosis
Extrarenal (urine sodium <15 mmol/litre)
Vomiting & Diarrhea, GIT, Skin, Lung
(b) Normovolemic Hyponatremia: (Water excess)
SIADH (common causes ),
inappropriate replacement of sodium-rich fluid
losses with hypotonic fluid e.g. D5W.
(c) Hypervolemic Hyponatremia –CHF; Cirrhosis;
Nephrosis
68

PATHOPHYSIOLOGY Hyponatremia
• Hypervolemic Hypotonic Hyponatremia CHF; Cirrhosis; Nephrosis
• Hyponatremia associated with an increase in ECF volume occurs in conditions in which renal sodium and
water excretion are impaired. Patients with cirrhosis, congestive heart failure, and nephrotic syndrome have
an expanded ECF volume and edema, but a decreased effective circulating volume. This decreased volume
results in renal sodium retention, and eventually ECF volume expansion and edema. At the same time, there
is nonosmotic release of AVP(arginine vasopressin) and retention of water in excess of sodium, thus
perpetuating the hyponatremia
• Euvolemic Hypotonic Hyponatremia SIADH
• Euvolemic hypotonic hyponatremia is associated with a normal or slightly decreased ECF sodium content and
increased total body water and ECF volume. The increase in ECF volume is usually not sufficient to cause
peripheral or pulmonary edema, and thus patients appear clinically euvolemic. Euvolemic hyponatremia is
most commonly the result of the syndrome of inappropriate ADH release (SIADH). In this syndrome, water
intake exceeds the capacity of the kidneys to excrete water, either because of an increased release of AVP
via nonosmotic and/or nonphysiologic processes or enhanced renal sensitivity to AVP. The urine osmolality in
patients with SIADH is generally greater than 100 mOsm/kg, and the urine sodium concentration is usually
greater than 20 mEq/L as a result of the ECF volume expansion. The most common causes of SIADH
• Hypovolemic Hypotonic Hyponatremia; diarrhea, excessive sweating, diuretic use or adrenal insufficiency.
• Most patients with ECF volume contraction lose fluids that are hypotonic relative to plasma and thus can be
transiently hypernatremic. This includes patients with fluid losses caused by diarrhea, excessive sweating,
and diuretics. This transient hypernatremic hyperosmolality results in osmotic release of AVP and
stimulation of thirst. If sodium and water losses continue, more AVP is released as a result of hypovolemia.
Patients who then drink water or who are given hypotonic fluids intravenously retain water and develop
hyponatremia. These patients typically have a urine osmolality greater than 450 mOsm/kg, reflecting the
presence of AVP and formation of a concentrated urine. The urine sodium concentration is <20 mEq/ L when
sodium losses are extrarenal, as in patients with diarrhea, and >20 mEq/L in patients with renal sodium
losses, as occurs in the setting of diuretic use or adrenal insufficiency.
69

CLINICAL MANIFESTATIONS
NEUROLOGIC MUSCULAR GASTROINTESTINAL
Altered consciousness
Coma
Seizures
Cerebral edema
Cramps
Weakness
Loss of appetite
Nausea
Vomiting
70

treatment of hyponatremia
Depends on the etiology and the clinical manifestations.
(a) Hypovolemic hyponatremia: 0.9% NaCl + 3% NaCl
Restore circulating volume (0.9% NaCl).
Severe symptomatic hyponatremia: (Na+ <110 mmol/liter), a 3% or
5% NaCl solution is used to correct to approximately 120 mmol/liter
(b) Euvolemic hyponatremia:
responds to fluid restriction (1,000 ml/day).
Demeclocycline for refractory SIADH
(c)Hypervolemic hyponatremia: (CHF; Cirrhosis; Nephrosis )
Na & water restriction (1,000 ml/day);
tt the cause ; tt= 3 %saline +Furosemide if there is edema
(d)hypervolemic hypotonic hyponatremia;
tt= 3 %saline +Furosemide
(e) It is important for both the short- and long-term
management of the patient to treat
the underlying cause of hyponatremia 71

• Solutes that cannot freely cross cell membranes, such
as sodium, are referred to as effective osmoles. The
concentration of effective osmoles in the ECF
determines the tonicity of the ECF, which directly
affects the distribution of water between the extra- and
intracellular compartments.
• Addition of an isotonic solution to the ECF will result in
no change in intracellular volume because there will be
no change in the effective osmolality of the ECF.
• Addition of a hypertonic solution to the ECF, however,
will result in a decrease in cell volume, whereas
• addition of a hypotonic solution to the ECF will result
in an increase in cell volume. Table 49–1 summarizes
the composition of commonly used intravenous
solutions and their respective distribution into
extracellular and intracellular compartments following
infusion. 73

HYPERNATREMIA [Na+] > 145 mEq/L
Diagnosis:
• It is the result of either to a gain in sodium in excess
of water, or to a loss of water in excess of sodium.
• Patients are categorized on the basis of their ECF
fluid volume status.
74

Etiologies
(1) Hypovolemic Hypernatremia: Net loss of
hypotonic body fluid
– Extrarenal fluid loss (diarrhea, sweat, burn)
– Renal (osmotic diuresis, chronic renal failure)
(2) Euvolemic Hypernatremia:
– Pituitary diabetes insipidus
– Nephrogenic diabetes insipidus
(3) Hypervolemic Hypernatremia:
– Sodium over load
• parenteral administration of hypertonic solutions (e.g., NaHCO3,
saline,).
– Primary hyperaldosteronism and Cushing's syndrome
76

Clinical manifestations
• Symptoms are primarily neurologic.
• Patients presented initially with pyrexia, nausea,
vomiting, lethargy, weakness, & irritability.
• The symptoms may progress to fasciculation, seizures,
coma, & irreversible neurologic damage.
• Dry, sticky mucous membranes are characteristic
• Body temperature is generally elevated & may
approach a lethal level, as in the patient with heat
stroke.
77

TREATMENT Hypernatremia
• DESIRED OUTCOME
• The desired goals for patients with hypernatremia include correction of
the serum sodium concentration at a rate that restores and maintains
cell volume as close to normal as possible, as well as normalizing the
ECF volume in states of ECF volume depletion or expansion.
• Adequate treatment should result in the resolution of symptoms
associated with hypovolemia. Careful titration of fluids and medications
should minimize the adverse effects from too rapid correction. Rapid
correction can result in movement of excessive water into the brain
cells, resulting in cerebral edema, seizures, neurologic damage, and
potentially death. Modulation of dietary sodium intake and sodium
replacement.
• PHARMACOLOGIC THERAPY
– Hypovolemic Hypernatremia
– Central Diabetes Insipidus
– Nephrogenic Diabetes Insipidus
– Sodium over load
– Osmotic diuresis
78

TREATMENT OF HYPERNATREMIA
• Hypovolemic Hypernatremia
Hypovolemia correction (0.9% saline)
Hypernatremia correction (hypotonic fluids)
• Hypervolemic Hypernatremia
Enhance sodium removal (loop diuretics, dialysis)
Replace water deficit (hypotonic fluids)
• Euvolemic Hypernatremia
Replace water deficit (hypotonic fluids)
Control diabetes insipidus
79

Hypovolemic Hypernatremia, 0.9% sodium chloride until 0.45% sodium chloride or 5% dextrose in water (D5W)
Hypovolemic hypernatremia (postural hypotension, tachycardia, and decreased skin turgor) should initially be treated
with 0.9% sodium chloride until hemodynamic stability is restored. An initial infusion rate of 200 to 300 mL/h will likely
be appropriate for many patients. Once intravascular volume is restored, 0.45% sodium
chloride or 5% dextrose in water (D5W) can then be infused to correct the water deficit,
OSMOTIC DIURESIS
Treatment of hyperglycemia-induced osmotic diuresis consists of correcting the hyperglycemia with insulin, as well as
administering 0.9% sodium chloride until signs of ECF volume depletion resolve.
Once hemodynamic stability is restored, the water deficit should be corrected in a manner analogous to that described
for patients with hypovolemic hypernatremia above. The corrected serum sodium
level should be calculated by adding 1.7 mEq/L for every 100-mg/dL
increase in the serum glucose concentration before estimating the
water deficit.
Hypernatremia in patients undergoing a postobstructive diuresis
should be treated with infusion of hypotonic fluids such as 0.45%
sodium chloride at maintenance rates of approximately 1.5 mL/kg
per hour. It is important to avoid the temptation to administer
fluids to replace urine output on a 1:1 volume basis, because this
tends to perpetuate the diuresis.
The serum sodium concentration and fluid status should be
monitored every 2 to 3 hours over the first 24 hours of admission in
patients with symptomatic hypernatremia to permit appropriate
adjustment in the rate of infusion of hypotonic fluids. After symptoms
resolve and the serum sodium is less than 148 mEq
Sodium Overload Tt= loop diuretics + intravenous D5W.
Treatment of sodium overload consists of administration of loop
diuretics to facilitate excretion of the excess sodium, as well as
intravenous D5W. The latter should be infused at a rate that will
decrease the serum sodium at approximately 0.5 mEq/L per hour, or
81

Nephrogenic Diabetes Insipidus
Hypercalcemia and hypokalemia should be corrected, and medications
that contribute to the pathogenesis should be discontinued.
One key goal in treating nephrogenic DI is to induce a mild ECFVd
(1 to 1.5 L) with a thiazide diuretic and dietary sodium restriction
(85 mEq Na+ or 2,000 mg sodium chloride per day), which often
can decrease urine volume by as much as 50% (see Table 52–3)
Central Diabetes Insipidus
Patients with central DI should generally receive AVP replacement
therapy with desmopressin, an AVP. Several medications
with antidiuretic properties have been used successfully in the
management of central and nephrogenic DI (Table 52–3). They can
be used as an alternative to DDAVP or adjunctively.
The desmopressin dose should be adjusted to achieve adequate
urinary concentration during sleep to prevent nocturia, to result in
a daily urine volume of approximately 1.5 to 2 L, and to maintain
the serum sodium concentration in the 137 to 142 mEq/L range
82

Questions
• 1. Main hormone(s) that regulates osmolality; sodium and water
homeostasis, released by the posterior pituitary in response to a rise in
serum osmolality
• 2. Explain MOA of Desmopressin :
• 3. A Patient with severe hyperglycemia, present with signs of volume
depletion, should initially be treated with
• 4. For a patient with SIADH and symptomatic hypotonic hyponatremia, the
most efficient means of correcting the hyponatremia involves
• 5. What IV solution used for fluid & electrolyte replacement cause osmotic
removal of water from intracellular space?
• 6. Hypovolemic hypernatremia patient (present with postural hypotension,
tachycardia, and decreased skin turgor) should initially be treated with
• 7. For a patient with SIADH and symptomatic hypotonic hyponatremia, the
most efficient means of correcting the hyponatremia involves
83

CALCIUM ABNORMALITIES
• Most of the body calcium is found in the bone in the
form of phosphate and carbonate.
• The normal serum level is between 8.5 & 10.5 mg/dL.
• Approximately 40% is non ionized (albumin bounded)
• An additional 10% non ionized fraction is bound to
phosphate & sulphate in the plasma & interstitial fluid
• the remaining 50% is free ionized portion (Active) that is
responsible for neuromuscular stability.
• Acidosis increases the ionized fraction, whereas alkalosis
decreases it.
85

CALCIUM
• In adult humans, the normal serum calcium
concentration ranges from 8.5 to 10.4 mg/dl
(4.25 to 5.2 mEq/L, 2.1 to 2.6 mM) and
• includes three distinct chemical forms of Ca2+:
– ionized (50%),
– protein-bound (40%),
– complexed (10%)
• Thus, whereas total plasma calcium
concentration is approximately 2.54 mM, the
concentration of ionized Ca2+ in human
plasma is approximately 1.2 mM.
86

CALCIUM
• Roles
• Coagulation
• Enzyme function
• Cellular signals
• Muscle and myocardial contraction
• Neuromuscular transmission
• Bone growth and mineralization
87

CALCIUM
Serum [Ca] is tightly regulated by
Parathyroid glands,
kidney, and
Small intestine
88

x
Parathyroid Hormone (PTH)
PTH is a polypeptide hormone that helps to regulate plasma Ca2+ by affecting bone resorption/formation, renal
Ca2+ excretion/reabsorption, and calcitriol synthesis (thus gastrointestinal Ca2+ absorption).
• Physiological Functions. The primary function of PTH is to maintain a constant concentration of Ca2+ in the
extracellular fluid. The principal processes regulated are renal Ca2+ absorption and mobilization of bone Ca2+
• Regulation of Secretion. Plasma Ca2+ is the major factor regulating PTH secretion. As the concentration of Ca2+
diminishes, PTH secretion increases
Conversely, if the concentration of Ca2+ is high, PTH secretion decreases.
Ca2+ itself appears to regulate parathyroid gland growth as well as hormone synthesis and secretion.
Changes in plasma Ca2+ regulate PTH secretion by the plasma membrane-associated calcium-sensing receptor
(CaSR) on parathyroid cells .
Effects on Kidney. In the kidney, PTH enhances the efficiency of Ca2+ reabsorption, inhibits tubular reabsorption
of phosphate, and stimulates conversion of vitamin D to its biologically active form, calcitriol (Figure 61-3;). As
a result, filtered Ca2+ is avidly retained, and its concentration increases in plasma,
• PTH increases tubular reabsorption of Ca2+ with concomitant decreases in urinary Ca2+ excretion.. This action,
along with mobilization of calcium from bone and increased absorption from the gut, increases the
concentration of Ca2+ in plasma
Calcitriol Synthesis.
• PTH powerfully stimulates calcitriol synthesis.
• The final step in the activation of vitamin D to calcitriol occurs in kidney proximal tubule cells. Three primary
regulators govern the activity of the 25-hydroxyvitamin D3-1a-hydroxylase that catalyzes this step: Pi, PTH, and
Ca2+ .
• Reduced phosphate rapidly increases calcitriol production, whereas
• hyperphosphatemia or hypercalcemia suppresses it.
• PTH powerfully stimulates calcitriol synthesis. Thus, when hypocalcemia causes a rise in PTH concentration,
both the PTH-dependent lowering of circulating Pi and a more direct effect of the hormone on the 1a-
hydroxylase lead to increased circulating concentrations of calcitriol.
92

HYPOCALCEMIA CA++ < 8 mg/dL
Causes
Hypoparathyroidism (after thyroid surgery, burns
or sepsis)
Vitamin D deficiency
Nutritional
Malabsorption
Postsurgical (gastrectomy, short bowel)
Inflammatory bowel disease and SI fistulas
Chelation or Precipitation of calcium
Pancreatitis
Rhabdomyolysis
Multiple rapid red blood transfusion
93

CLINICAL MANIFESTATIONS HYPOCALCEMIA
• CVS
– Cardiac dysrhythmias
– ECG changes (prolongation of QT interval, T- wave inversion)
– Congestive Heart failure
– Hypotension
• Neuromuscular
– Skeletal muscle spasm
– Skeletal muscle weakness
– Tetany
– Convulsions
• Pulmonary
• Laryngeal spasm
• Bronchospasm
• Hypoventilation (Apnea)
• Psychiatric (Anxiety, Dementia)
94

TREATMENT OF HYPOCALCEMIA
Administer calcium
IV calcium gluconate (10 ml 10% solution over 10
minutes, followed by continuous infusion (0.3–2.0
mg/kg/h)
500-1000 mg of calcium orally every 6 hours
vitamin D replacement & oral calcium (CaCo3) for
chronic hypocalcemia
Monitor electrocardiogram
95

PHARMACOLOGIC THERAPY calcium gluconate and vitamin D supplementation
A/The initial therapeutic intervention for patients with acute symptomatic
hypocalcemia is to administer 100 to 300 mg of elemental calcium intravenously
over 5 to 10 minutes. This may be provided by the administration of 1 g of calcium
chloride (27% elemental calcium) or 2 to 3 g of calcium gluconate (9% elemental
calcium).
B/Once acute hypocalcemia is corrected by parenteral administration,
further treatment modalities should be individualized according to the cause of
hypocalcemia.
C/Asymptomatic and chronic hypocalcemia associated with hypoparathyroidism
and vitamin D–deficient states may be managed by oral calcium and vitamin D
supplementation.
D/Treatment of hypocalcemia associated with vitamin D–deficient states and
vitamin D supplementation
96

Calcium gluconate & calcium chloride
• A/The initial therapeutic intervention for patients with acute
symptomatic hypocalcemia is to administer 100 to 300 mg of
elemental calcium intravenously over 5 to 10 minutes.
• This may be provided by the administration of 1 g of calcium
chloride (27% elemental calcium) or 2 to 3 g of calcium
gluconate (9% elemental calcium).
• Calcium gluconate is generally preferred over calcium chloride
for peripheral venous administration because calcium
gluconate is less irritating to veins.
• Disadvantages to the use of calcium gluconate are the lower
percentage of elemental calcium per volume and the less
predictable, slightly smaller increase in plasma ionic calcium
compared with calcium chloride.
• Calcium should not be infused at a rate greater than 60 mg of
elemental calcium per minute because severe cardiac
dysfunction may result 98

Clinical use of Calcium
• Calcium carbonate and calcium acetate are used
to restrict phosphate absorption in patients with
chronic renal failure.
• Acute administration of calcium may be life-
saving in patients with extreme hyperkalemia
(serum K+ > 7 mEq/L).
• Calcium gluconate (10 to 30 ml of a 10% solution)
can reverse some of the cardiotoxic effects of
hyperkalemia, providing time while other efforts
are taken to lower the plasma K+ concentration
99

HYPERCALCEMIA
Hypercalcemia (total serum calcium >10.5 mg/dL) NV=8.5 to 10.5
mg/dL. may be induced by a multitude of causes .
The most common causes of hypercalcemia are cancer and primary
hyperparathyroidism.
primary hyperparathyroidism accounts for the vast majority of
cases in the outpatient setting.
LABORATORY TESTS
Serum calcium concentrations of > 10.5 mg/dL are considered to
represent hypercalcemia.
Values up to 13 mg/Dl suggest mild or moderate hypercalcemia,
while
values greater than >13 mg/Dl indicate severe hypercalcemia.
101

Hypercalcemia: Ca++ > 10.5 mg/dl
Causes
• Hyperparathyroidism
• Malignancy
• Excessive vitamin D intake
• Paget’s disease of bone
• Granulomatous disorders (sarcoidosis, tuberculosis)
• prolonged immobilization
• Adrenal insufficiency
102

CLINICAL MANIFESTATIONS OF HYPERCALCEMIA
• CVS
– Hypertension
– Heart block
– Digitalis sensitivity
• Neuromuscular
– Skeletal muscle weakness
– Hyporeflexia
– Sedation to coma
• Renal
• Nephrolithiasis
• Polyuria (renal tubular dysfunction)
• Azotemia
• Gastrointestinal (PUD, Pancreatitis, Anorexia)
103

TREATMENT OF HYPERCALCEMIA
• Vigorous volume repletion with saline solutions &
Large doses of intravenous frusemide
• Oral or intravenous inorganic phosphates
• Corticosteroids decrease resorption of Ca++ from
bone & reduce the GI absorption of vitamin D.
• Surgery remains the definitive treatment of acute
hypercalcemic crisis (IVF volume depletion, renal
insufficiency & coma) in patients with
hyperparathyroidism.
• Treatment of hypercalcemia in a patient with
metastatic cancer is primarily that of prevention;
Place the patient on a low-calcium diet, and ensure
adequate hydration.
104

TREATMENT: Hypercalcemia
DESIRED OUTCOME
The indications for the treatment of acute hypercalcemia are dependent
on the degree of hypercalcemia, acuity of its development, and presence or absence of
symptoms.
The objectives of treatment are
reversal of signs and symptoms,
restoration of normocalcemia,
treatment of the underlying cause malignancies/ hyperparathyroidism / Medications
prevention of long-term consequences. complications
Chronic hypercalcemia is usually caused by an underlying medical condition or
prescribed therapies.
The treatment of malignancies may help mitigate acute hypercalcemic episodes.
The goals of treatment of hyperparathyroidism are to reduce serum calcium
concentrations as well as to reduce long-term complications such as vascular
complications, chronic renal insufficiency, and kidney stones.
Medications including thiazides, lithium, antacids, and vitamins D need to be
recognized as potential reversible causes of hypercalcemia.
105

For those patients with normal to moderately impaired renal function, the cornerstone
of initial treatment of hypercalcemia is volume expansion to increase urinary calcium
excretion.
Patients with severe renal insufficiency usually do not tolerate volume expansion; they
may be initiated on therapy with Calcitonin.
Patients with symptomatic hypercalcemia are often dehydrated secondary to vomiting
and polyuria; thus rehydration with saline containing fluids is necessary to interrupt the
stimulus for sodium and calcium reabsorption in the renal tubule.
Loop diuretics such as furosemide (40 to 80 mg IV every 1 to 4 hours) may also be
instituted to increase urinary calcium excretion and to minimize the development of
volume overload from the administration of saline
The importance of rehydration prior to loop diuretic use is Important because
dehydration may lead to increased serum calcium because of enhanced proximal tubule
calcium reabsorption.
106

Loop diuretics such as furosemide
MOA; Loop diuretics such as furosemide block calcium (and
sodium) reabsorption in the thick ascending limb of the loop of
Henle and augment the calciuric effect of saline alone
Calcitonin; MOA; decreases serum calcium concentrations,
primarily by inhibiting bone resorption. It may also reduce renal
tubular reabsorption of calcium, thus promoting calciuresis
short-term therapy with calcitonin is effective in reducing serum
calcium levels within hours
phosphate
MOA; intravenous phosphate may rapidly reduce ionized calcium
concentrations through the formation of insoluble calcium
phosphate salts.
The mechanisms of
109

Bisphosphonates [Pamidronate, etidronate, Zoldronate]
MOA; block bone resorption very efficiently, render the
hydroxyapatite crystal of bone mineral resistant to hydrolysis by
phosphatases, and also inhibit osteoclast precursors from attaching
to the mineralized matrix, thus blocking their transformation into
mature functioning osteoclasts
Glucocorticoid
MOA; glucocorticoid-induced reductions in serum calcium include
reduced gastrointestinal absorption, defective vitamin D
metabolism causing hypercalciuria, increased bone resorption,
Mithramycin
MOA; is a potent cytotoxic antibiotic that inhibits osteoclast-
mediated bone resorption and thereby reduces hypercalcemia.
Gallium nitrate MOA; inhibits bone resorption, 110

Exercise
• A patient with serum calcium 14.5 mg/dL, associated with severe
clinical symptoms & severe renal insufficiency. Recommend a drug
therapy Which is effective within hours to correct Ca level?
• Explain of drugs used in hypercalcemia Mechanism of action;
• Describe the Role of the kidney in Calcium Homeostasis
• The major causes of hypocalcemia in the adult are the following, :
• Therapeutic use of Calcitriol, are
• Which of the calcium preparations is the most preferable for IV
injection?
111

METABOLIC ACID-BASE DISORDERS
114

Diuretics
• Diuretic s are drugs which increase renal excretion of salt and
water: are principally used remove excessive extracellular fluid from
the body
• Three mechanism involved in urine formation
– Glomerular filteration
– Tubular reabsorption
– Tubular secretion
These processes maintain fluid volume, electrolyte
concentration & pH of body fluid
Diuretic Target these processes
120

Diuretics cont’d
Classification of diuretics
Most diuretics are therapeutically act by interfering
with sodium Reabsorption by tubule
1. Thiazide and related diuretics;e.g. hydrochlothiazide, etc
2. Loop diuretics: e.g. furosimide, etc
3. Potassium sparing diuretics: e.g. spironolactone, etc
4. Carbonic anhydrase inhibitors: e.g. acetazolamide
122

use
USES OF DIURETICS
• The aim of diuretic therapy is to enhance Na
excretion, thereby promoting negative Na
balance. This net Na (and fluid) loss leads to
contraction
Congestive Heart Failure
Hypertension
Increased Intracranial Pressure
Edema
Renal Edema Nephrotic Syndrome
Pulmonary Edema
Chronic Renal Failure
Acute Renal Failure
Premenstrual Edema and Edema of Pregnancy
123

Mechanism of Action of DIURETICS;
125

Diuretics cont’d
Classification of diuretics
Most diuretics are therapeutically act by interfering
with sodium Reabsorption by tubule
1. Thiazides diuretics;e.g. hydrochlorothiazide, etc
2. Loop diuretics: e.g. furosimide, etc
3. Potassium sparing diuretics: e.g. spironolactone, etc
4. Carbonic anhydrase inhibitors: e.g. Acetazolamide
126

Diuretics cont’d
1. Thiazides diuretics; hydrochlorothiazide,
• MOA; Inhibit Na+-Cl- Co transporter at distal convoluted
tubule (See next figure)
• Use; CHF, hypertension, edema of renal and cardiac origin.
• Use; Patients who have an adequate supply of ADH but whose
kidneys fail to respond to ADH excrete large volumes of very
dilute urine, not unlike those who have an ADH deficiency.
• Adverse effect: hypokalemia, hyperuricemia, hyperglycemia
and visual disturbance
127

Diuretics cont’d
2. Loop diuretics; furosimide,
• MOA; Inhibit Na+-k+-2Cl- Co transporter in ascending limb
• Mechanism of Action The site of action of loop diuretics is the thick
ascending limb of the loop of Henle, and diuresis is brought about by
inhibition of the Na–K–2Cl transporter. (See next figure)
• Therapeutic use:
– Sever Hypertension[ not for mild initial case ], CHF,
– Edema; Acute pulmonary edema, edema of cardiac, and
– Renal disease
• Because diuresis may be extensive, loop diuretics should be administered
initially in small doses; multiple doses, if needed, should be given in early
morning and early afternoon.
• These drugs should be restricted to patients who require greater diuretic
potential, SEVER CASES
• Adverse effect:
– Hypokalemia, hyperuricemia, diminished Ca and Mg absorption.
– fatigue, muscle cramp, drowsiness due to Hypokalemia,
– Dizziness, hearing impairment and deafness: reversible
129

Diuretics cont’d3. Potassium sparing diuretics ; spironolactone,
• MOA; Aldosterone Antagonists: block effect of aldosterone
• Mechanism of Action; Spironolactone (Aldactone) is structurally related to
aldosterone and acts as a competitive inhibitor to prevent the binding of
aldosterone to its specific cellular binding protein. Spironolactone thus
blocks the hormone-induced stimulation of protein synthesis necessary for
Na reabsorption and K secretion. Na+-k+ ATPase
• Mild diuretic causing diuresis by increasing the excretion of sodium, but
decrease excretion of potassium;
Therapeutic uses/Clinical Uses of Spironolactone:
1. Primary Hyperaldosteronism. Used as an aid in preparing patients with
adrenal cortical tumors for surgery.
2. Hypokalemia. in patients with low serum K resulting from diuretic therapy.
Its use should be restricted to patients who are unable to supplement their
dietary K intake or adequately restrict their salt intake or who cannot tolerate
orally available KCl preparations.
3. Hypertension and congestive heart failure. Although spironolactone may be
useful in combination with Thiazides, the latter remain drugs of first choice.
• Adverse effect: orthostatic hypotension, Hyperkalemia, Hyponatremia131

Control of Aldosterone Secretion
132

d
Nonsteroidal Potassium-sparing Drugs: Amiloride & Triamterene
MOA; Both diuretics specifically block the apical membrane
epithelial Na channel (ENaC) (Fig. 21-5). The reduced rate of Na
reabsorption diminishes the gradient that facilitates K secretion.
K secretion by the collecting duct principal cells is a passive
phenomenon that depends on and is secondary to the active
reabsorption of Na.
Clinical Uses
Triamterene can be used in the treatment of CHF, cirrhosis, and
the edema caused by secondary hyperaldosteronism.
It is frequently used in combination with other diuretics except
spironolactone.
Amiloride, but not triamterene, possesses antihypertensive
effects that can add to those of the thiazides.
These K-sparing diuretics have low efficacy when used alone,
since only a small amount of total Na reabsorption occurs at
more distal sites of the nephron.
133

Diuretics cont’d
4. Carbonic Anhydrase inhibitors: Acetazolamide
• MOA; Inhibit enzyme carbonic anhydrase in renal tubule cells and
lead to ↑ excretion of bicarbonate, Na+ , k+ ions in urine
• MOA; Inhibition of proximal tubule brush border carbonic anhydrase
decreases bicarbonate reabsorption, and this accounts for their diuretic
effect. In addition, carbonic anhydrase inhibitors affect both distal tubule
and collecting duct H+ secretion by inhibiting intracellular carbonic
anhydrase.
• Therapeutic use production of diuresis & tt of glaucoma.
Glaucoma; Because the formation of aqueous humor in the eye depends
on carbonic anhydrase, acetazolamide has proved to be a useful adjunct
to the usual therapy for lowering intraocular pressure
• . In eye it cause reduction in formation of aqueous humor
• Adverse effect:
hypokalemia, metabolic acidosis. b/c
Elevated urinary HCO3-excretion leads to the formation of alkaline urine and
to metabolic acidosis
as a result of both HCO3 loss and impaired Hsecretion
134

Diuretics cont’d
5. Osmotic diuretics: Mannitol
– Freely filtered at the glomerulus and relatively inert
pharmacologically and undergo limited reabsorption of
renal tubule
– MOA; The primary effect involves an increased fluid loss caused by the
osmotically active diuretic molecules; this results in reduced Na and
water reabsorption from the proximal tubule. They adminstered to
increase osmolality of plasma & tubular fluid.
• MOA; Osmotic diuresis
– They are used in cerebral edema and management
poisons,
137

cirrhosis
• Patients with cirrhosis should initially be
treated with spironolactone in the absence of
impaired glomerular filtration rate and
hyperkalemia. Thiazides may then be added
for patients with a creatinine clearance >50
mL/min. For those patients who remain
diuretic resistant, a loop diuretic may replace
the thiazide.
142

nephrotic syndrome
• Patients with nephrotic syndrome commonly
develop diuretic resistance. It is suggested
that the impaired natriuretic response may be
overcome by using higher doses to increase
the delivery of free drug to the secretory site
in the proximal nephron. Another approach is
to use the combination of a loop diuretic with
a distal diuretic.
144

Case study 1
• A 55-year-old male with kidney stones has
been placed on a diuretic to decrease calcium
excretion. However, after a few weeks, he
develops an attack of gout. Which diuretic was
he taking?
146

Case S t u d y 2
• A50-year-old woman is seen in the emergency
department complaining of a severe headache,
shortness of breath, and ankle edema. Her vision
is blurry and her blood pressure is 200/140 mm
Hg. A blood test reveals azotemia and
proteinuria. A chest radiograph reveals an
enlarged cardiac silhouette.
– What is your DX
– What are goal of tt
– pharmacological treatment might be considered?
147

Study questions
• Explain mechanism of action of 5 diuretics group
• Why some patients receiving diuretics develop hyperglycemia
• Larger Maximum effect dose for edema management with Furosemide is
require in w/c conditions?
• Which diuretics can be used to treat nephrogenic diabetes insipidus?
• What diuretics tharpy you recomened to treat nephrotic syndrome with
Albumin Value of 1gm/dL?
• A Patient with cirrhosis in the absence of impaired glomerular filtration
rate & creatinine clearance >50 mL/min, can be treated with
148

Case report 1
• 13. Chief Complaint “I’m preparing for a vacation but lack the energy to
plan. Besides, I look like I’ve been out in the sun already, Fever.” Carla
Stanley is a 43-year-old woman who presents to the clinic for her annual
visit. She has been busy at work and is excited to go on a planned and
“well-deserved” vacation on a Caribbean cruise. She reports feeling
continuously fatigued with bouts of nausea and anorexia for several
months. She is worried she will not be well enough to prepare for the trip.
Carla reports a recent craving for salty foods. PMH; Hypothyroidism × 15
years; Physical Examination; Gen; Tired-looking, Weight loss tanned
woman; VS; BP 94/70 sitting, 84/60 standing; P 79 sitting, 87 standing;
RR 22; T 96.8°F; Wt 60 kg, Ht 5'6''. Meds Levothyroxine 0.088 mg po
once daily Lab; , Na 120 mEq/L, K 7.0 mEq/L, BUN 15 mg/dL , TSH 4.8
mIU/L, Free T4 1.3 ng/dL Cortisol 1.4 mcg/dL, ACTH 2,096 pg/mL;
(Reference range for Cortisol: AM: 8–25 mcg/dL, PM 4–20 mcg/dL; ACTH
0–130 pg/mL )
Q questions
• What are the problems & the cause
• possible approaches?
149

Kus 10 ahmc

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