kus 10 ahmc

kidneys & urinary system

By Tatek

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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.

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Renal function

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Chronic kidney disease (CKD)

• Quantification of renal function,

• S/S (Lab parameters)

• CKD; Progression modifying therapies

• CKD; Management of complication

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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 or albumin8

CKD; Progression modifying therapies

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CKD; Progression modifying therapies

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CKD; Management of complication

• CKD(stage 4 & 5); S/S, Lab results

• Common complication

• Management of complication

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CKD; Management of complication

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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''

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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

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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

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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

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� 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

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� 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-inducednephrogenic.

� 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

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� 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.

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� 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

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plasma

volume is

reduced

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COMMON ELECTROLYTE DISORDERS

€ sodium sodium sodium sodium

€ PotassiumPotassiumPotassiumPotassium

€ calcium calcium calcium calcium

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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.

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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)

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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).

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hyperkalemia: K+ > 5.5 mmol/l[Mild 5.5-6, Moderate 6.1-7 & Severe >7 mmol/l]

CausesDecreased renal potassium excretion

Renal failureHypoaldosteronismPotassium sparing diuretics- Sprinolactone

Intercompartmental shiftsAcidosisMedications Severe injury or surgical stressCatabolic states

Increased potassium intakeSalt Substitutes

Causes; potassium supplements, Drugs[ACEI, ARB, PSD, BB], Acidosis, acute renal failure and CKD ; adrenal insufficiency , Addison’s disease, and hypoaldosteronism

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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,

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clinical manifestations of hyperkalemia

Cardiovascular Gastrointestinal Neuromuscular

Tall, peaked T wavesDecreased P wavesPR prolongationST-depressionQRS wideningHeart blockAsystole

NauseaVomitingDiarrheaIntestinal colic

ParesthesiasWeaknessParalysisConfusion

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Treatment of hyperkalemia

Involves three approaches:1. Measures to protect the myocardium• Calcium gluconate or calcium chloride reverses

membrane effects). Rapid onset2. 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 symptomsor 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

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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

DysrhythmiasECG changes

Digitalis toxicity potentiation

Postural hypotension

Impaired pressor responses

Muscle weaknessIleus

Respiratory failureHyporeflexiaConfusion

Depression

PolyuriaConcentrating defect

Glucose intolerancePotentiation of hypercalcemia,

hypomagnesaemia

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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

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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.

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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?

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SODIUM Role

• Physiologic functions of Na

– Osmolarity (Antidiuretic hormone (ADH)

– ECF volume; (Aldosterone)

– Action potential

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• 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

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Control of Aldosterone Secretion

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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

Etiology and diagnosis:

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CAUSES OF HYPONATREMIAI. Hyponatremia with normal or high plasma osmolality (pseudo

hyponatremia)

Hyponatremia with normal plasma osmolality Asymptomatic:severe hyperproteinemiaMarked 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.

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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

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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.

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CLINICAL MANIFESTATIONS

NEUROLOGIC MUSCULAR GASTROINTESTINAL

Altered consciousnessComaSeizuresCerebral edema

CrampsWeakness

Loss of appetiteNauseaVomiting

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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

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• 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.

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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. Rapidcorrection 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

84

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 increasesConversely, 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 reabsorptionof 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

CausesHypoparathyroidism (after thyroid surgery, burns

or sepsis)

Vitamin D deficiencyNutritional

MalabsorptionPostsurgical (gastrectomy, short bowel)Inflammatory bowel disease and SI fistulas

Chelation or Precipitation of calciumPancreatitisRhabdomyolysisMultiple 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

phosphateMOA; intravenous phosphate may rapidly reduce ionized calcium

concentrations through the formation of insoluble calcium

phosphate salts.

The mechanisms of109

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

ACID-BASE DISORDERS

113

METABOLIC ACID-BASE DISORDERS

114

X

116

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’d4. 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 anhydrasedecreases 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 Hsecretion134

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 poonce 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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