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Flashcards in Renal Week 2 Deck (199):
1

Hyponatremia

-low plasma concentration of sodium due to a deficit of sodium or a relative excess of water (Na less than 135)

*osmoregulation accomplished via changes in water balance (excretion or retention) and intake (thirst)

-Tonicity of ECF reflects tonicity of cells (because water freely moves between compartments)

-In patients with normal renal function, excessive water intake alone does not cause hyponatremia unless it exceeds 1 L per hour

2

Two questions when determining the type of hyponatremia?

What is serum osmolality?

If hypotonic --> what is volume status?

3

Hypertonic Hyponatremia

(>300mOsm/kg)

shift of water from cells into ECF in response to non-sodium solute (elevated serum osmolality)

Often due to hyperglycemia or mannitol/glycerol administration

“Water shift” hyponatremia

Treat underlying uncontrolled diabetes → osmolality goes back to normal

4

Isotonic Hyponatremia

(280-399 mOsm/kg)

Often due to lab artifact caused by hyperlipidemia or hyperproteinemia that reduce plasma water

-direct measurement of serum Na by ion-sensitive electrode will yield normal value

5

Hypotonic Hyponatremia

(less than 280 mOsm/kg) "True hyponatremia"

--> Check volume status

6

Hypovolemic Hypotonic Hyponatremia

-Causes?
-ADH response?
Treatment?

volume contraction, low total body sodium

1) Renal loss (UNa>20)
Salt losing nephritis, mineralocorticoid deficiency, osmotic diuresis, diuretics

2) Extrarenal loss (UNa less than 20)
Hemorrhage, GI loss, excessive sweating

ADH released appropriately → water retention

Treatment: normal saline

7

Euvolemic Hypotonic Hyponatremia

Causes?

normal total body sodium, normal ECF volume

-Usually due to inappropriate ADH secretion
-ADH secretion increased despite absence of physiologic stimuli (Posm or decreased EABV)

EX) SIADH (syndrome of inappropriate ADH secretion), primary polydipsia, hypothyroidism, adrenal insufficiency

8

Euvolemic Hypotonic Hyponatremia

Treatment

hypertonic saline (if seizure)

If asymptomatic → water restriction, correction of underlying disorder, stop offending drugs

9

Hypervolemic Hypotonic Hyponatremia

increased ECF volume, increased total body sodium

Sign = Edema, rales

Urinary concentration of sodium can be less than or greater than 20 --> indicative of different causes

10

Hypervolemic Hypotonic Hyponatremia

UNa less than 20 →

ADH response?

UNa less than 20 --> CHF, cirrhosis, nephrotic syndrome

Reduction in volume sensed despite an absolute increase in total body salt and water
Cirrhosis → vasodilation, CHF → low CO

ADH released because reduced effective blood volume is sensed

11

Hypervolemic Hypotonic Hyponatremia

UNa>20 →

ADH response?

UNa>20 → ARF, SKD

Diluting mechanism in distal tubule does not work or RBF and GFR are too low

Can also be caused by thiazide diuretics that prevent dilution of urine (block Na/Cl cotransporter)

ADH independent

12

Treatment of Hypervolemic Hypotonic Hyponatremia

Water and salt restriction (giving salt makes it worse!)
Loop diuretics (stop thiazides)
Inotropes for CHF

13

Hypernatremia

Disorders of concentrating ability

Na>145

Always associated with increased serum osmolality

Must ask what total body Na is (ECF volume)

14

Hypernatremia occurs due to...

1) ADH is decreased or ineffective
E.g Diabetes insipidus

2) Addition of hypertonic fluids (hypervolemic hypernatremia) - usually iatrogenic

3) Renal or extrarenal water losses exceed sodium loss (hypovolemic hypernatremia)

15

Hypernatremia with:

Decreased Total Body Na

total body water loss >> total body salt loss

UNa>20 → renal loss
UNa

16

Hypernatremia with:

Normal total body Na

Due to ADH deficiency or resistance

No response to ADH --> Nephrogenic Diabetes insipidus

No ADH --> Central diabetes insipidus

17

Nephrogenic Diabetes insipidus

ADH resistance (renal duct does not respond to ADH)

Can be congenital (rare), or acquired from CKD, hypercalcemia, hypokalemia, drugs

18

Central Diabetes insipidus

ADH deficiency

Mostly idiopathic, but can be caused by head trauma, surgery, neplasms

19

Treatment of nephrogenic vs. central diabetes insipidus

Nephrogenic DI:
-NOT ADH responsive --> treat with large fluid intake and thiazide diuretic

Central DI:
-ADH responsive, treat with DDAVP

20

Hypernatremia with increased total body Na

RARE

-usually due to receiving hypertonic fluid

21

Symptoms of Hypernatremia

Neuromuscular irritability, seizures, coma, death

Very severe and deadly - high mortality rate, serious marker of underlying disease

Extreme thirst

Failure to thrive in infants

22

Treatment of hypernatremia

restore tonicity to normal and correct sodium imbalances
SLOWLY restore water deficits to prevent cerebral edema
Must calculate water needed

23

Equation for water needed

Water needed (L) = 0.6 x body weight (kg) x [(actual Na/140) - 1]

24

ADH secretion stimulated by: (2)

osmoreceptors (hypothalamus) + baroreceptors (aortic arch, carotid sinus → emergency volume sensors)

Severe volume depletion can cause hyponatremia

25

Normal renal concentrating mechanisms allow excretion of urine 4x as concentrated as plasma. Requires: (4)

1) Ability to generate hypertonic interstitium
2) Secretion of ADH
3) Normal Collecting Duct Responsiveness to Vasopressin
4) ADH: release stimulated by serum osmolality AND intravascular blood volume

26

Basic facts about sodium (4)

1) Sodium is most abundant solute in ECF
2) Sodium is more important determinant of ECF volume
3) Disorders of sodium balance = disorders of ECF volume
4) Maintenance of ECF volume determines MAP and LV filling volume

27

Afferent limb of ECF volume sensors

1) Low pressure baroreceptors
2) High pressure baroreceptors
3) Intrarenal sensors (JGA)
4) Hepatic and CNS sensors

28

Low pressure baroreceptors

cardiac atria receptors + LV receptors + pulmonary vascular bed receptors

On VENOUS side of circulation

Protect body against ECF volume expansion and contraction

Volume expansion → increased venous return → low pressure baroreceptors change discharge rate → decrease SNS → alter natriuresis, diuresis, HR and peripheral vascular resistance

29

High pressure baroreceptors

carotid sinus body and aortic body

-On ARTERIAL side of circulation
-Assess pressure of arterial circulation
-Work to maintain MAP

Goal: normalize ECF volume in response to volume expansion or contraction

30

Intrarenal sensors (JGA)

Decrease in arterial pressure stretches membrane receptor → increase intracellular Ca2+ → increase renin secretion → increase sodium reabsorption

31

Physiological processes that serve to maintain GFR

1) Renal autoregulation
2) Tubuloglomerular feedback
3) Glomerulotubular balance

32

Renal autoregulation

ability of kidney to keep renal blood flow and GFR constant by contraction of vascular smooth muscle

33

Tubuloglomerular feedback

increased distal delivery of NaCl to macula densa → increases afferent arteriolar tone → return RBF and GFR towards normal

34

Glomerulotubular balance

property of kidney whereby changes in GFR automatically induce a proportional change in rate of proximal tubular sodium reabsorption

35

Humoral effectors that increase sodium reabsorption (antinatriuresis) (4)

Angiotensin II
Aldosterone
Catecholamines
Vasopressin

36

Humoral effectors that decrease sodium reabsorption (natriuresis) (4)

Natriuretic peptides
Prostaglandins
Bradykinin
Dopamine

37

Renal sympathetic nerves

SNS innervation of afferent and efferent arterioles of glomerulus

Activation → anti-natriuretic effect

Nerve stimulation enhances renin release from JGA

38

Causes of Extracellular volume contraction

Renal Causes
Non-renal causes: GI tract, dermal, third space fluid loss

39

Physiologic responses to extracellular volume contraction

preserve sodium and water

-cardiovascular and renal responses

40

Cardiovascular response to ECF volume contraction

Increased HR, increased cardiac inotropy, systemic vascular resistance, increased angiotensin II, increased ADH, increased endothelin

41

Renal response to ECF volume contraction

-Decreased GFR → smaller filtered load of Na+
-Activation of renal sympathetic nerves
-Decreased hydrostatic pressure, and increased oncotic pressure in peritubular capillaries
-Stimulation of renin-angiotensin-aldosterone system
-Increased secretion of arginine vasopressin (AVP)
-Inhibited secretion of ANP from atrial myocytes

42

Clinical Manifestations of ECF volume contraction

Thirst, postural dizziness
Weakness, palpitations
Decreased urinary output, confusion
Weight changes
Orthostatic BP, tachycardia, hypotension
Decreased elasticity or turgor of skin
Dry mucous membranes

43

When ECF volume is contracted what are your serum values?

BUN, acid/base balance, albumin, Hct?

Increased BUN - plasma creatinine ratio

Metabolic alkalosis during upper GI loss of fluid or metabolic acidosis during lower GI loss of fluid

Increased hematocrit/serum albumin because of hemoconcentration

44

When ECF volume is contracted what are your urine values?

UNa
FE Na
Specific gravity
Osmolality

Urine sodium > 20mEq/L = Renal losses Urinary sodium less than 20mEq/L = Extra-renal losses

FE Na less than 1%

Specific gravity > 1.010

Urine osmolality > 300mOsm/Kg

45

Treatment of ECF volume contraction

expand ECF volume

**Replacement fluid should resemble lost fluid

Blood, albumin, and dextran solutions contain large molecules that preferentially expand intravascular volume

Isotonic normal saline preferentially expands ECF volume

46

3 Causes of ECF volume expansion?

1) Disturbed starling forces: CHF, nephrotic syndrome, cirrhosis

2) Primary hormone excess: primary hyperaldosteronism, Cushing’s syndrome, syndrome of inappropriate secretion of ADH

3) Primary renal sodium retention: acute glomerulonephritis

47

Formation and persistence of edema with ECF volume expansion due to...(3)

1) Alteration in Starling forces
2) Arterial underfilling resulting in decreased effective arterial circulating volume
3) Excessive renal sodium and water retention

48

Clinical manifestations of ECF volume expansion

Weakness, exercise intolerance, DOE

Weight gain

Orthopnea, LE edema, distended neck veins

Increased urination at night

Basilar pulmonary rales
CXR with fluid overload and cardiomegaly

49

Treatment of ECF volume expansion (3)

Carbonic Anhydrase → acts at proximal tubule - weak diuretic to reduce Na+ reabsorption

K+ Sparing → distal segment Na/Cl cotransporter blocker

Loop diuretic → block Na/K/Cl cotransporter

50

K+ actions at proximal convoluted tuble

K+ reabsorption (reabsorb 80% of filtered load)

K+ reabsorption is paracellular (through tight junctions), passive reabsorption (driven by basolateral transport of Na+)

NOT regulatable, not a major player from clinical perspective unless GFR is significantly reduced

51

K+ actions at descending limb of loop of Henle

K+ secretion

ADDS K+ into tubule → back up to 100% of filtered load at base of loop

52

K+ actions at ascending limb of loop of Henle

3 channels that make this happen?

K+ reabsorption (reduces K from 100% to 10-15% of filtered load)

Transcellular
-Na/K/2Cl cotransporter at apical membrane → K+ into cell (secondary active transport) → some K+ leaks out of cell into tubule through K+ channel (apical membrane)
-K/Cl channel on basolateral side (allows reabsorption of K and Cl)
-Na/K ATPase on basolateral side → Na out/K in

53

K+ action at Cortical Collecting Tubule/Principal cells

K+ secretion --> K+ load back up to 100%

**KEY for regulating K+ excretion when GFR is relatively normal

-Most of K+ is obligatorily reabsorbed (only 10-15% remaining post distal convoluted tubule)

→ regulated K+ secretion in principal cells of fine tuning segments important in determining K+ excretion and ECF K+ balance

54

Regulators of K+ secretion in Cortical Collecting Tubule / Principal Cells

1) Mineralocorticoid receptors
2) Na+ delivery
3) WNK proteins

55

Effect of mineralocorticoid receptors in CCT

-regulates amount of activity of Na/K ATPase, Na and K channel

56

Why does Na+ delivery to CCT effect K+ secretion?

Can’t secrete potassium if there is no Na+ delivery to this distal nephron site - Na/K pump relies on high intracellular Na from Na entry via apical Na channel - without this, Na/K pump won't be as good at bringing K into cell (K can then be secreted)
→ Hyperkalemia

due to...Hypovolemia, CHF, cirrhosis, etc.

57

Mechanisms of Na+ reabsorption and K+ secretion at CCT (principal cells)

Na+ reabsorption via apical Na+ channel (ENAC) → extruded via Na/K ATPase

Basolateral entry of K+ into cell + Apical secretion into tubular lumen
1) K+ secretion - Enters tubule via K+ apical channel
2) Na/K pump on basolateral side, pumps K+ into cell → K+ flows down electrochemical gradient into lumen and excreted in urine

58

Intercalated cells and K+ action

what transporter is responsible for this?

K+ reabsorption - between collecting duct and urine 50% of K+ reabsorbed

50% of K+ reabsorbed→K+ added into tubule at descending limb

K/H transporter (K in, H+ out)

59

Complete path of K+ reabsorption/secretion

glomerulus
proximal tubule
descending loop
ascending loop
cortical collecting tubule/principal cells
Intercalated cells

K+ is filtered freely (glomerulus)
Reabsorbed (Proximal tubule),
Then secreted (descending loop of Henle)
Then reabsorbed (ascending loop of henle/distal convoluted tubule)
Then secreted (Cortical collecting tubule / principal cells)
Then finally reabsorbed post collecting tubule (intercalated cells)

60

What is the effect of GFR on K+ secretion/reabsorption

GFR is a minor player

-no real impact until GFR is VERY low

61

Mass action effect in regulation of K+ secretion

first-line regulator of K+ secretion

Increase K+ in ECF → basolateral ATPase Na/K pump runs faster (K+ is a cofactor for the pump, and rate limiting step needed for ATP splitting) → increase in intracellular [K+]

Best for large changes in K+ concentration

62

When you increase K+ what happens to aldosterone levels?

Increased K+ → stimulate adrenal zona glomerulosa cells to synthesize aldosterone → increase secretion of K+

63

How does aldosterone increase the secretion of K+? (3)

ACTS AT CCT (principal cells)

1) Increase # of Na/K/ATPase pumps on basolateral surface → increase rate of K+ entry and [K+] intracellularly

2) Increase # of apical Na+ channels → increase apical K+ secretion, and movement of Na+ in

3) Increase # of K+ channels → easier for K+ to flow into lumen

64

What happens to K+ levels when you have:

1) no aldosterone or renin
2) ACEI
3) Spironolactone/eplerenon
4) Ameloride

1) No aldosterone or renin → can’t secrete K+ at cortical collecting tubule → hyperkalemic

2) ACEI → decrease K+ secretion → hyperkalemia

3) Spironolactone, eplerenone → Block aldosterone binding to mineralocorticoid receptor → hyperkalemia

4) Ameloride → blocks epithelial Na+ channel → hyperkalemia

65

Effect of loop diuretics on K+ levels

-selectively inhibit ascending limb Na/K/Cl cotransporter

-Causes massive increase in K+ secretion

Inhibition of Na/K/Cl cotransporter → make interstitium less hypertonic at descending limb and fine tuning segments → more water remains in tubule → increased tubular flow --> more K+ secretion

66

Effects of tubular flow on K+ secretion

Slow Tubular Flow → reduce K+ secretion

Fast Tubular Flow → increase K+ secretion

67

Why does slow tubular flow decrease K+ secretion

Buildup of K+ in tubular fluid before it is “washed away” by flow of tubular fluid downstream

As K+ lumen concentration rises, electrochemical gradient decreases → reduced secretion

68

Why does fast tubular flow increase K+ secretion?

K+ washed away really fast from apical side of membrane, so there is greater electrochemical gradient

69

How does alkalosis (increased pH) effect K+ balance

Increases K+ secretion → HYPOKALEMIA

Shift K+ into cells → reduce ECF [K+] and increase [K+] intracellular
→ increase driving force for apical K+ secretion into lumen → increase K+ secretion and increase K+ excretion → HYPOKALEMIA

70

How does acidosis (decreased pH) effect K+ balance

Shift K+ out of cells → inhibit apical K+ channels by lowered pH → decrease in K+ secretion

-can "depend", unpredictable sometimes

71

Major determinants of urinary K+ excretion (4)

1) Normal distal tubule function (adequate Na+ delivery also)
2) Aldosterone activity (stimulate distal nephron K+ secretion - *most important)
3) Urine flow rate (increased flow rate, increase K+ excretion)
4) Delivery of non-reabsorbed anions to distal nephron

72

Factors that influence potassium shifts between intracellular and extracellular fluid spaces (6)

1) pH

2) Insulin

3) Adrenergic activity

4) Physical conditioning and exercise (leak K+ into ECF)

5) Cell membrane Na/K ATPase (Na out, K+ in)

6) Hyperosmolality (shift K+ out of cells)

73

plasma K+ _____ with acidemia (usually), and _____ with alkalemia

rises
falls

74

Effect of insulin on K+

first line defense against hyperkalemia, major regulatory of internal K+ balance

Increase plasma K+ → stimulate insulin release (K+ moves into cells even without glucose)

Insulin deficiency can cause rise in plasma K+ chronically (hyperkalemia)

75

Effect of adrenergic activity on K+ levels

B2 agonists (catecholamines) → stimulate entry of K+ into cells, major regulator of internal K+ balance

B-Blockers may potentiate hyperkalemia
A-agonists impair K+ entry into cells --> hyperkalemia

76

Potassium Adaptation

Relatively slow process that allows adaptation to gradually increasing amounts of K+ in diet

-Rapid increase in K+ could be fatal

-Involves aldosterone, insulin, and induction of Na/K ATPase in the renal tubular cells

Can be impaired in acute renal failure or in chronic renal failure when GFR is extremely depressed

77

Treatment of hypokalemia

Harder to treat than hyperkalemia

-restore plasma and total body K+ to normal

-Preferable to give K+ as oral supplements

-Diuretics that reduce renal K+ excretion (spironolactone, triamterene, amiloride)

78

Consequences that hypokalemia

cardio and neuro?

worse than hyperkalemia

1) Neuro = weakness, paralysis

2) Cardio = atrial/ventricular arrhythmias (worse with digitalis), U waves on ECG

79

Acute causes of hypokalemia

CELL SHIFT

1) Catecholamine Excess - B2AR
-Medications - B2AR agonists
-Physiology - Stress
-Chest pain, asthma, alcohol or drug withdrawal

2) Insulin excess (Rare)

80

Causes of hypokalemia without K+ deficit (4)

1) alkalosis
2) familial hypokalemic periodic paralysis
3) B-adrenergic drugs
4) too much insulin

81

Causes of hypokalemia with K+ deficit

1) Poor dietary intake
2) Cellular incorporation
3) *GI loss
4) Urinary loss
5) Excessive mineralocorticoid effect (too much aldosterone)
6) Renal tubular acidosis

82

Causes of chronic hypokalemia

renal or extrarenal

differentiate with Urine K

-Low (less than 20 Meq/L) → extrarenal
-High (>20 Meq/L) → renal

83

Hyperkalemia defined as serum K+ > ______

Serum K+ > 7.0, above 10 is often fatal

84

Consequences of Hyperkalemia

Cardiac effects:
-Push cell potential toward threshold →
1) Tall T wave
2) Wide QRS complex, flat P waves
3) Sine wave QRST pattern with vfib or cardiac arrest

Neuromuscular effects: weakness, paralysis

85

Pseudohyperkalemia

Caused by:
hemolysis of drawn blood, increased WBC or platelet count, tourniquet applied too tightly

Hyperkalemia in the test tube but not in the patient

Assess with ECG

86

Causes of acute hyperkalemia (7)

CELL SHIFT

1) Digitalis intoxication
2) Acidosis
3) B-adrenergic block
4) A2 adrenergic agonists
5) Hyperosmolality
6) Inadequate insulin response (diabetes)
7) Ischemic/dead body part (rhabdomyolysis, intestinal or peripheral vascular arterial insufficiency)

87

Chronic hyperkalemia - differentiate between the different types how?

Differentiate based on GFR

GFR less than 20 --> chronic or acute renal failure

GFR > 20 --> CHECK ALDOSTERONE LEVEL

88

If GFR is > 20 how do you differentiate etiology based on aldosterone levels

Low aldosterone → check renin
-renin Low → DM
-renin High → adrenal insufficiency

High aldosterone → check urine Na
-Low UNa → decreased Na delivery
-High UNa → drugs, PHA

89

Treatment of hyperkalemia (3)

K > 6.0 → medical emergency

1) Reverse depolarization with calcium infusion

2) Shift K+ into cells
-Glucose/insulin, B2 Agonists (albuterol, catecholamine), NaHCO3- infusion (move K into cells)
-K exchange resin (effective chronically)

3) Remove K+ from body:
Diuretics, hemodialysis

90

Prevalence of HTN in the US and lifetime risk of developing HTN

80 million people in US and 1 billion people worldwide with HTN

90% lifetime risk of developing HTN if you are normotensive at age 55
-Systolic BP more important that DBP as a CVD risk factor

Only 35% of persons with HTN have their BP under control (below 140/90)

91

Essential hypertension

single reversible cause of elevated BP CANNOT be identified - (90-95%) of HTN cases

92

Causes of essential HTN

Environmental factors: high dietary NA, LOW GFR, excess caloric intake (obesity), alcohol, stress, sedentary lifestyle, smoking, low K+ or Ca2+ intake

Genetic factors (higher incidence in African Americans)

93

Why does HTN occur due to an increase in SVR?

two hypotheses for explaining this

1) Guyton hypothesis
2) VSMC hypothesis

94

Guyton Hypothesis (5 steps)

1) Primary defect in renal sodium excretion
2) Increase in plasma volume
3) Increase in CO → overperfusion of vital/nonvital organs
4) Autoregulatory increase in systemic vascular resistance (to maintain normal organ perfusion)
5) Increase in BP (afterload mediated normalization of CO)

95

“Unwillingness to Excrete Na” Theory

humans with essential HTN possess a genetically determined impairment of kidney’s ability to excrete excess Na

96

Vascular Smooth Muscle Cellular Hypothesis (5 steps)

1) Inhibit Na/K ATPase
2) Increase in vascular cell Na
3) Decrease in cell Na in/Ca out exchange
4) Increase in cell Ca → increase VSMC contraction
5) → Increase in systemic vascular resistance and increase in BP

97

Salt and HTN

Modern diet is much higher in Na than we evolved to have

Excessive Na intake alone not sufficient to cause HTN

All Na absorbed in GI tract → kidney must excrete excess Na to prevent ECF volume expansion and maintain Na balance

Natriuresis = renal Na excretion

98

Mechanisms of impaired natriuresis

1) Loss of nephron mass or impaired GFR

2) Activation of SNS and neurohormonal axis (increases renin, AgII --> Na and water reabsorption)

3) Abnormal blood vessel response to vasoconstrictors (increase afferent constriction --> decrease GFR)

99

Secondary HTN

HTN caused by an identifiable mechanism (5-10%)

100

Causes of secondary HTN

1) Renal causes:
-Parynchymal disease
-Renal artery stenosis

2) Other causes:
-Cushing’s, coarctation of aorta, sleep apnea, drug induced, thyroid or parathyroid disease
-Primary hyperaldosteronism
-Pheochromocytoma

101

Stimuli for renin release (3)

1) Activation of B-sympathetic nerves

2) Stimulation of renal baroreceptors by decreased arteriolar pressure (due to renal artery stenosis)

3) Activation of macula densa chemoreceptor by reduced delivery of NaCl to distal tubule

102

How does renal artery stenosis cause HTN?

1) decreased EABV sensed by kidney → abnormal activation of renin release by kidney

2) Renin: → AgI → AgII → bind AT1 and AT2 receptors

3) Raise arteriolar pressure by: direct arteriolar constriction and Na/water retention

103

How to diagnose renal artery stenosis (4 steps/tests)

1) Elevated renin levels in blood

2) Doppler study of renal vasculature to visualize stenosis

3) CTA (contrasted study to visualize stenosis)

4) Angiogram - looking for pressure drop across the lesion (no pressure drop= not functional, pressure drop = functional)

104

Treatment of renal artery stenosis

Due to atherosclerosis > 70% in renal artery → HTN

High BP with time causes damage to contralateral kidney which will maintain HTN even if original renal artery stenosis removed → TIMELY REPAIR IS CRITICAL

Percutaneous balloon dilation of renal arteries + anti-hypertensive medication

105

Primary hyperaldosteronism

excess aldosterone secretion due to pathological defect in adrenal cortex → high aldosterone, low renin → expansion of ECF volume, suppression of plasma renin

106

Two causes of primary hyperaldosteronism

1) Aldosterone producing adenoma

2) Idiopathic adrenal hyperplasia

107

Aldosterone producing adenoma presentation and treatment

(UNILATERAL)

-TX with unilateral adrenalectomy

-NaCl administration will decrease aldosterone

-Fludrocortisone → salt retention, decrease aldosterone

108

Idiopathic adrenal hyperplasia presentation and treatment

(BILATERAL)

NaCl administration no change in aldosterone

Fludrocortisone → may or may not do anything, competes with aldosterone for receptor

TX with spironolactone (gynecomastia side effects)

109

Pheochromocytoma

benign tumor of adrenal medulla → excess catecholamines → increase vascular resistance

110

Target Organ Damage with HTN (5 main organ systems)

Heart: LVH, angina or prior MI, prior coronary revascularization, HF
Brain: stroke, TIA
Chronic Kidney Disease
Peripheral arterial disease
Retinopathy

111

Non-Pharmacologic Treatment of Essential HTN

STOP SMOKING, weight reduction, DASH eating plan, dietary sodium reduction, physical activity, moderation of alcohol consumption

112

How do you treat a patient with prehypertension

(120-139) → no pharm, only lifestyle modification

Still associated with increased risk of CV events

113

How do you treat a patient with Stage 1 HTN

140-159/90-99

Lifestyle + one or two drugs

Thiazide diuretic + may consider…
ACEI/ARB
Beta-Blocker
Calcium Channel Blocker

114

How do you treat a patient with Stage 2 HTN

>160/>100

Lifestyle + Two drug combination:

Thiazide diuretic + ACEI/ARB or BB or CCB

115

Goals of HTN treatment

Treat BP to less than 140/90 or BP less than 130/80 with diabetes or chronic kidney disease

116

2 medications that work on the proximal tubule

1) Mannitol
2) Acetazolamide

117

Mannitol

mechanism of action

non metabolized, non-reabsorbed osmotic diuretic

Mechanism of action: elevates osmolarity of glomerular filtrate → hinder tubular water reabsorption, excess water excreted by kidneys

118

Mannitol

uses (2)
adverse effects (1)

Use: management of intracranial pressure, glaucoma

Adverse effects: acute increase in ECF volume (because increases ECF osmolarity)

119

Acetazolamide

mechanism of action

Carbonic Anhydrase Inhibitor

Inhibits regeneration of bicarb in proximal tubule → Na and bicarbonate loss
Induces metabolic acidosis (due to loss of HCO3-)

120

Acetazolamide

uses (3)

glaucoma, prevention/treatment of high altitude sickness, metabolic alkalosis

121

Loop diuretics

Names of drugs (3)

Mechanism of action

furosemide, torsemide, ethacrynic acid (non-sulfa)

Mechanism of action: inhibit Na/K/2Cl cotransporter in thick ascending loop of Henle → decrease tonicity of medullary interstitium → inhibit water reabsorption in collecting duct

122

Loop diuretics

Uses (4)

volume overload -->
heart failure
BP reduction
pulmonary edema

Hypercalcemia

123

Loop diuretics

Adverse effects

lowers what 4 ions?
increases what?
causes what acid/base problem?

Hypokalemia
Hypocalcemia
Hypomagnesemia
Hyponatremia

Uric acid retention → Precipitate gout attack

Metabolic alkalosis

124

Thiazides

names (4)
Mechanism of action

hydrochlorothiazide, chlorthalidone, metolazone, indapamide

Mechanism of action: inhibit Na/Cl cotransport in distal convoluted tubule (less efficacious than loops because smaller portion of filtrate Na+ reabsorption remains)

-Less efficacious than loop diuretics
-Need more efficacious loop diuretic at GFR

125

Thiazides

uses (2)

1) Antihypertensive effect secondary to decreased plasma volume and decreased CO

2) Secondary mild vasodilation

126

Thiazides

Adverse effects
-increases 3 things
-decreases 3 things
-and a problem with acid/base balance

Metabolic alkalosis

Hypokalemia
Hypomagnesaemia
Hyponatremia

Hyperuricemia → gout
Hyperglycemia
Hypercalcemia

127

K+ sparing diuretics

names (2)
mechanism of action

Spironolactone, Eplerenone

Mechanism of action: aldosterone antagonist
Competitively inhibit mineralocorticoid receptor in collecting tubule → reduce Na reabsorption and K+ secretion

Eplerenone more specific (less gynecomastia)

128

Uses of K+ sparing diuretics (4)

Hypokalemia
Heart failure
Hyperaldosteronism
Resistant Hypertension

129

Adverse effects of K+ sparing diuretics (3)

Hyperkalemia
Gynecomastia
Amenorrhea

130

Hydralazine and minoxidil do what?

mechanism of action

vasodilators (arterial)

increase intracellular cGMP → relaxation of arterial smooth muscle → decrease systemic pressure and contractility

Preferential dilation of arteries → increased renin secretion → reflex sympathetic discharge and sodium reabsorption

131

Hydralazine and minoxidil

adverse effects (5)
uses (2)

Adverse Effects:
Edema, tachycardia, neuropathy
Lupus rash (hydralazine)
Hair growth (minoxidil)

Uses:
HTN, heart failure

132

ACE inhibitors

names?
Mechanism of action

Lisinopril, enalapril, “-pril”

Mechanism of action: inhibit ACE enzyme, prevent conversion of AgI → AgII
-Prevent AgII vasoconstriction and stimulation of aldosterone release
-No effect on non-ACE controlled pathways
-Reduce aldosterone levels, reduce breakdown of bradykinin

133

ACE inhibitors

use

1st line therapy for HTN, CKD, HF, DM nephropathy

134

ACE inhibitors

adverse effects (5)

Cough (Secondary to increase in bradykinin and substance P)

Hyperkalemia

Rise in serum creatinine (transient, due to dilation of efferent arteriole)

Contraindicated with bilateral renal artery stenosis

Angioedema (allergic rxn)

135

ARBs

Mechanism of action

Mechanism of action: block AngII at AT1 receptor → prevent AgII mediated vasoconstriction and aldosterone release

-Reduce aldosterone levels
-No effect on Bradykinin

136

ARBs use

1st line therapy for HTN, CKD, HF, DM nephropathy

137

ARBs adverse effects (3)

Adverse Effects:

-Hyperkalemia
-Rise in serum creatinine (transient, dilation of efferent arteriole)
-Angioedema

138

Terazosin, doxazosin, prazosin do what?

alpha-1 receptor antagonists

139

Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)

mechanism of action

Peripheral postsynaptic blockade → decrease in arterial tone
Relaxes smooth muscle of bladder neck

140

Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)

use (1)

primarily for BPH

141

Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)

Adverse effects (5)

Postural hypotension, dizziness, somnolence, impotence, nasal congestion/rhinitis

142

Clonidine and methyldopa do what?

central alpha-2 receptor agonists

143

Alpha-2 Receptor Agonists: Clonidine, Methyldopa

Mechanism of action

Mechanism of action: centrally acting agent, stimulate alpha-2 receptors in CNS and periphery→ decreases sympathetic tone, decreases PVR and CO, inhibit peripheral NE release

-Methyldopa safe in pregnancy

144

Alpha-2 Receptor Agonists: Clonidine, Methyldopa

Adverse effects (5)

dry mouth, depression, lipid abnormalities, sedation, orthostatic hypotension

145

Alpha-2 Receptor Agonists: Clonidine, Methyldopa

Uses (4)

HTN, ADHD, smoking cessation, ETOH withdrawal

146

Sodium Nitroprusside

Mechanism of action
onset, duration

Mechanism of action: nitric oxide donor which activates endovascular guanyl cyclase causing myosin dephosphorylation and vascular smooth muscle relaxation

→ arterial and venous dilation

Onset in seconds
Lasts only 1-2 minutes

147

DHP calcium channel blockers

names?
effect?

amlodipine, felodipine, -dipine

Block L-type calcium channels (selective for vascular LTCC) --> potent vasodilators with no effect on cardiac contractility or conduction

148

Adverse effects of DHP (4)

Reflex tachycardia
Headache
Peripheral edema (due to vasodilation)
Gingival hyperplasia

149

Uses of DHPs (2)

1) HTN - Good 2nd line agents for BP reduction especially in African Americans, elderly

2) Migraine prophylaxis

150

Non-DHPs

names?
effect?

verapamil, diltiazem

Block LTCC, more cardioselective, less potent vasodilators

Verapamil efficacy > diltiazem

Cardiac effects: decrease cardiac contractility, decrease SA node automaticity, decrease AV node conduction

151

Adverse effects of non-DHPs (5)

Constipation
Bradycardia
Nausea
Conduction defects

-inhibits CYP450 --> drug interactions

152

Uses of non-DHPs (4)

primarily reserved for negative inotropic activity

Angina
Rate control for AFIB
Migraine prophylaxis
HTN

153

atenolol, metoprolol, bisoprolol, and nebivolol are beta blockers with what selectivity?

cardio selective - B1 receptors
-no alpha blockade

154

propanolol and timolol are beta blockers with what selectivity?

non-selective B1 (cardiac) and B2 (bronchial/vascular)

155

Labetolol and carvedilol are beta blockers with what selectivity

beta and alpha blocker

Provides extra antihypertensive effect - no cardioselectivity, has a-blockade

156

Adverse effects of B-blockers (5)

Decrease libido, bradycardia, bronchospasm, glucose/lipid changes, fatigue

157

Normal pH range

7.35-7.45

158

60 kg person → add __ mEq of H+ to ECF every day

60

159

Total bicarb in ECF = ___ mmol → only a ___ day supply of ECF bicarb available (60-70 mmol destroyed every day)

360 mmol
5-6

160

Carbon dioxide

“volatile” gaseous acid

1.Eliminated by lungs effectively under normal conditions

161

Organic acids

(e.g. Lactic and citric acid)

1.Metabolized to neutral products (glucose, water, CO2)q

162

Metabolism and acids

generates “nonvolatile acid” from proteins and nucleic acids

1.Proteins (sulfur containing amino acids) → Sulfuric acid (H2SO4)

2.Nucleic acids → Phosphaturic acid (H3PO4)

3.Must be eliminated by the kidneys

163

Buffering of nonvolatile acid

buffers bind H+ but H+ is NOT ELIMINATED - goal is to prevent H+ from binding to vital proteins in heart/brain

164

Bone as a buffer

Bone (acidosis → suppress osteoblasts, stimulates osteoclasts → release Na, K, CO3 2- and HPO3- from bone)

165

Bicarb buffering system

buffers and eliminates H+ from the body

1.H+ + HCO3- → H2CO3 → CO2 + H2O (removed by lungs)
- Low CO2 required to drive rxn to right (high CO2 stimulates hyperventilation → blow down CO2)

2. Convert nonvolatile acid to a gaseous volatile form that can be eliminated rather than simply buffered

3. Elimination of each H+ requires the “suicide” destruction of a bicarbonate anion → bicarbonate lost in elimination of acid must be continually replaced

166

CO2 can build up at the tissue level if: (2)

1) Rise in metabolic rate without proportional increase in blood flow

2) Decrease in blood flow without a change/decrease in metabolic rate
→ impairs function of BBS → less H+ removed → H+ binds proteins and disrupts function

167

Role of kidney in maintenance of bicarb levels (3)

1. eliminate acid ions
2. Reabsorption of filtered bicarb
3. Synthesis of bicarb

168

Kidney role in elimination of acid anions

Acid anions that produce hydrogen ions (HSO4-, H2PO4, etc.) must be eliminated → filtered at glomerulus and excreted in urine

169

Reabsorption of filtered bicarb in kidney


Bicarb anion freely filtered (small solute) → needs to be avidly reabsorbed

85-90% of filtered load of bicarb reabsorbed in proximal tubule

170

Two pumps involved in reabsorption of bicarb and how they function

1. Sodium-Hydrogen Exchanger (NHE): in apical membrane
- H+ secreted from inside cell → lumen of tubule
- Once in lumen, combines with bicarb → H2CO3 → CO2 and H2O
-CO2 then diffuses into cell
- CO2 + H2O in cell → (via carbonic anhydrase) H2CO3 → H+ + HCO3-
- H+ excreted into tubule via NHE
- HCO3- into blood via NBC

2. Sodium-Bicarb Cotransporter (NBC): on basolateral angle transports Na and HCO3- into blood

171

End result of bicarb reabsorption

**No net gain/loss of ECF H+ or HCO3-

i.DOES NOT change ECF acid/base balance

ii.Filtered bicarb is simply reabsorbed to ECF while H+ is secreted into urine

iii.BUT impaired proximal bicarb reabsorption will result in a proximal renal tubular acidosis (RTA) due to net loss in bicarb

172

Bicarb synthesis

1. Kidneys synthesize bicarb to replace exactly what is lost in acid elimination process (every H+ excreted/secreted, HCO3- generated)

2.Done by epithelial alpha intercalated cells of collecting duct
a.Generates NET increase in H+ → acidifies urine

173

After new bicarb is synthesized, which results in H+ increase in tubule, what happens?

MUST buffer urine because H+ pumped into urine in collecting duct

174

How is the H+ buffered in bicarb synthesis? (2)

1. Titratable acid
2. Ammonia trapping

175

Titrateable acid and H+ trapping

complexing hydrogen ion to a filtered acid anion (HPO4 2-) or other buffers (creatinine, urate)

i.Only 30-40 mmol H+ titrated this way (half)

ii.Constant

176

Ammonia trapping

1. NH3 diffuses easily through apical membrane → binds H+ in tubule → NH4+ that is “trapped”

i.Ammoniagenesis: in proximal tubule cells
- Glutamine metabolized to NH3 and bicarbonate
- NH3 binds H+
- Bicarb added to peritubular capillary

2.Process augmented by high intracellular [H+] in proximal cells (chronic acidosis or hypokalemia)

3.Can be increased up to 200 mmol of H+ buffering per day

177

Daily bicarb reabsorption > ____ mmol, daily bicarb synthesis = ____ mmol →

>4000 mmol
60-70

no bicarbonate synthesis can take place until bicarbonate reabsorption is complete upstream
- As long as there is HCO3- in tubular lumen, bicarb will be reabsorbed but will not be synthesized

178

Net acid excretion (NAE):

balances nonvolatile acid production

i.NAE = NH4+ excretion + titratable acid excretion - HCO3- excretion

1.Normal conditions:

a.40-50% of NAE is titratable acid (constant), 50-60% of NAE is NH4+ excretion (can increase), and bicarb excretion is zero

179

Renal response to metabolic acidosis


a. Increases number of apical H+ transporters and basolateral HCO3- transporters → increase H+ secretion capacity available for HCO3- synthesis

b.Increase buffering with HCO3- →
1) Increased CO2 production → elimination of CO2 by lungs
2) Increased destruction of HCO3-
→ decrease filtered load of HCO3- → decreases H+ secretion required for HCO3- reabsorption → increase H+ secretion capacity available for HCO3- synthesis

c.→ Increased HCO3- synthesis, replenishment of lost HCO3-

180

NAE: metabolic acidosis

a. NH4+ excretion increases

b.Titratable acid excretion unchanged

c.Bicarb excretion remains zero

181

Renal response to respiratory acidosis

Refer to Mady Lion's notes: search renal response to respiratory acidosis (complicated chart)

182

Renal response to chronic metabolic acidosis

1. Bicarb excretion increases (up to 80 mmol/day)

a.Decreased reabsorption

2.NH4+ and titratable acid excretion decreases

183

Respiratory alkalosis

Decreased ECF CO2 → decreased H+ → decreases number of apical H+ transporters and basolateral HCO3- transporters

184

Hypokalemia and plasma pH


in response, K+ shifts out of cells into ECF, and exchanges with H+ which shifts into cells

1.More intracellular H+ available in renal tubules for secretion

2.Increased ammoniagenesis → more H+ trapping and excretion

3.Intercalated cells will preferentially reabsorb K+ and secrete H+

a.Via H+/K+ ATPase on apical membrane

4.More H+ secretion/excretion = more HCO3- synthesis

5.PREDISPOSES TO METABOLIC ALKALOSIS

a.Alkalosis → hypokalemia and hypokalemia → alkalosis

185

Hyperkalemia and plasma pH

in response K+ shifts into cells from ECF, and exchanges with H+ out of cells

1.Less intracellular H+ available in renal tubules for secretion

2.Decreased ammoniagenesis → less H+ trapping and secretion

3.Less H+ secretion/Excretion = Less HCO3- synthesis

4.PREDISPOSES TO METABOLIC ACIDOSIS

a.But hyperkalemia stimulates aldosterone → increases H+ secretion and HCO3- synthesis

i.Counteractive

186

Metabolic acidosis compensation assesment

expected CO2 = 1.5x[HCO3-] + 8 +/- 2

1.Compensation adequate → “SIMPLE”

2.Compensation inadequate → “MIXED”

3.COMPENSATION IS ALWAYS THE SAME DIRECTION AS PRIMARY CHANGE

187

Respiratory alkalosis (including compensation assessment)

always due to hyperventilation

1.Anxiety, fever, pain, lung disease, liver disease, sepsis, brain disease, pregnancy

2.Acute or chronic (before or after renal compensation)

a.Acute = Change in HCO3- = decrease 2:10 PCO2

b.Chronic = change in HCO3- = decrease 4:10 PCO2

188

Respiratory acidosis (including compensation rules)

breathing too little

1.Neuro problem, muscle fatigue, aspiration, pneumonia, COPD, ILD, hypokalemia, hypothyroidism

2.Acute or chronic (before or after renal compensation)

a.Acute = Change in HCO3- = decrease 1:10 PCO2

b.Chronic = change in HCO3- = decrease 4:10 PCO2

189

Metabolic alkalosis

increased pH, increased HCO3-

190

Causes of metabolic alkalosis (5)


1) Addition of bicarbonate (antacids)

2) Contraction alkalosis (loss of chloride rich fluids)
- Vomiting, ng suctioning, diuretics
-Lose water, which essentially increases [HCO3-]

3) Loss of hydrogen (GI, renal)
- Renal losses due to diuretics or mineralocorticoid excess
- H+ excretion causes HCO3- resorption

4) Post hypercapnia
- Development of metabolic alkalosis in a patient with chronic respiratory acidosis who is being mechanically ventilated → rapid lowering of CO2 with high bicarb

5) Hypokalemia

191

Maintenance of metabolic alkalosis

always the kidney’s fault - unable to excrete excess bicarb

a.Chloride depletion → resorption of bicarb

b.Increased mineralocorticoid activity
- Mineralocorticoids stimulate H+-ATPase pump of intercalated cell in distal tubule → more H+ secretion and bicarb reabsorption → maintains alkalosis

c.Hypovolemia - commonly accompanies metabolic alkalosis
→ aldosterone release

192

Chloride responsiveness vs unresponsiveness in metabolic alkalosis

UCl less than 20mEq --> chloride responsive
-Due to loss of intravascular volume (diuretics, vomiting, CF, congenital chloride losing diarrhea)

UCl > 20 mEq → chloride resistant
-Due to excess mineralocorticoids (hyperaldosteronism, Cushing’s, Licorice ingestion)

193

Metabolic acidosis

reduction in bicarb and pH

1.Kidney must handle daily acid load of 60mEq H+, which consumes 60 mEq of HCO3-

194

What happens in the proximal and distal tubule in metabolic acidosis

Proximal tubule → reabsorb HCO3-

i.Carbonic anhydrase inhibitors (acetazolamide, topiramate) → excretion of bicarb

Distal tubule (Collecting duct)

i.Principal Cell:

1.ENaC brings Na into cell

2.RomK allows K+ to flow out into tubule

3.Na pumped into blood via Na/K ATPase on basolateral membrane

ii.Intercalated Cell:

1.Secretes H+ (H+ ATP pump)
2.Makes HCO3-
3.Acidifies urine
4.Excretes daily acid load

195

Non anion gap metabolic acidosis

loss of bicarb causing metabolic acidosis

a.Loss of bicarb typically from GI or kidney
- Renal loss of bicarb = + urine anion gap
- GI loss of bicarb = negative urine anion gap

b.Can result in renal tubular acidosis

196

Renal tubular acidosis

Proximal → problem with reabsorption of bicarb at proximal tubule

- + urine anion gap

Distal → unable to excrete H+ → can’t produce HCO3-
- + urine anion gap

Hyperkalemic → increased K+ inhibits NH3 production
- + urine anion gap

197

Anion gap metabolic acidosis

caused by addition of acid (not CO2) that uses up HCO3-

a.Anion gap “increased” when it is > 18

b.MUDPILES

i.Methanol
ii.Urate (renal failure)
iii.DKA (ketones)
iv.Propylene glycol
v.Isoniazid
vi.Lactate (hypoxia)vii.Ethylene glycol, Ethanol
viii.Salicylate (ASA)

198

Utility of serum and urine anion gap

can be used to determine if renal acid excretion (new bicarbonate generation) is appropriate

199

Urine anion gap

If metabolic acidosis present, NH4+ production should increase

1.Urine anion gap = Na+ + K+ - Cl-

a.NH4+ production increased → urine Cl- should also increase to maintain electroneutrality

2.Negative urine anion gap suggests NH4+ production is occurring in kidney → non-anion gap metabolic acidosis due to GI loss

3.Positive urine anion gap → renal NH4+ production impaired, RTA present