Renal Week 2 Flashcards
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
Two questions when determining the type of hyponatremia?
What is serum osmolality?
If hypotonic –> what is volume status?
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
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
Hypotonic Hyponatremia
(less than 280 mOsm/kg) “True hyponatremia”
–> Check volume status
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
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
Euvolemic Hypotonic Hyponatremia
Treatment
hypertonic saline (if seizure)
If asymptomatic → water restriction, correction of underlying disorder, stop offending drugs
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
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
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
Treatment of Hypervolemic Hypotonic Hyponatremia
Water and salt restriction (giving salt makes it worse!) Loop diuretics (stop thiazides) Inotropes for CHF
Hypernatremia
Disorders of concentrating ability
Na>145
Always associated with increased serum osmolality
Must ask what total body Na is (ECF volume)
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)
Hypernatremia with:
Decreased Total Body Na
total body water loss»_space; total body salt loss
UNa>20 → renal loss
UNa
Hypernatremia with:
Normal total body Na
Due to ADH deficiency or resistance
No response to ADH –> Nephrogenic Diabetes insipidus
No ADH –> Central diabetes insipidus
Nephrogenic Diabetes insipidus
ADH resistance (renal duct does not respond to ADH)
Can be congenital (rare), or acquired from CKD, hypercalcemia, hypokalemia, drugs
Central Diabetes insipidus
ADH deficiency
Mostly idiopathic, but can be caused by head trauma, surgery, neplasms
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
Hypernatremia with increased total body Na
RARE
-usually due to receiving hypertonic fluid
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
Treatment of hypernatremia
restore tonicity to normal and correct sodium imbalances
SLOWLY restore water deficits to prevent cerebral edema
Must calculate water needed
Equation for water needed
Water needed (L) = 0.6 x body weight (kg) x [(actual Na/140) - 1]
ADH secretion stimulated by: (2)
osmoreceptors (hypothalamus) + baroreceptors (aortic arch, carotid sinus → emergency volume sensors)
Severe volume depletion can cause hyponatremia
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
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
Afferent limb of ECF volume sensors
1) Low pressure baroreceptors
2) High pressure baroreceptors
3) Intrarenal sensors (JGA)
4) Hepatic and CNS sensors
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
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
Intrarenal sensors (JGA)
Decrease in arterial pressure stretches membrane receptor → increase intracellular Ca2+ → increase renin secretion → increase sodium reabsorption
Physiological processes that serve to maintain GFR
1) Renal autoregulation
2) Tubuloglomerular feedback
3) Glomerulotubular balance
Renal autoregulation
ability of kidney to keep renal blood flow and GFR constant by contraction of vascular smooth muscle
Tubuloglomerular feedback
increased distal delivery of NaCl to macula densa → increases afferent arteriolar tone → return RBF and GFR towards normal
Glomerulotubular balance
property of kidney whereby changes in GFR automatically induce a proportional change in rate of proximal tubular sodium reabsorption
Humoral effectors that increase sodium reabsorption (antinatriuresis) (4)
Angiotensin II
Aldosterone
Catecholamines
Vasopressin
Humoral effectors that decrease sodium reabsorption (natriuresis) (4)
Natriuretic peptides
Prostaglandins
Bradykinin
Dopamine
Renal sympathetic nerves
SNS innervation of afferent and efferent arterioles of glomerulus
Activation → anti-natriuretic effect
Nerve stimulation enhances renin release from JGA
Causes of Extracellular volume contraction
Renal Causes
Non-renal causes: GI tract, dermal, third space fluid loss
Physiologic responses to extracellular volume contraction
preserve sodium and water
-cardiovascular and renal responses
Cardiovascular response to ECF volume contraction
Increased HR, increased cardiac inotropy, systemic vascular resistance, increased angiotensin II, increased ADH, increased endothelin
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
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
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
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
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
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
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
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
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
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
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
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
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
Regulators of K+ secretion in Cortical Collecting Tubule / Principal Cells
1) Mineralocorticoid receptors
2) Na+ delivery
3) WNK proteins
Effect of mineralocorticoid receptors in CCT
-regulates amount of activity of Na/K ATPase, Na and K channel
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.
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
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)
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)
What is the effect of GFR on K+ secretion/reabsorption
GFR is a minor player
-no real impact until GFR is VERY low
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
When you increase K+ what happens to aldosterone levels?
Increased K+ → stimulate adrenal zona glomerulosa cells to synthesize aldosterone → increase secretion of K+
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
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
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
Effects of tubular flow on K+ secretion
Slow Tubular Flow → reduce K+ secretion
Fast Tubular Flow → increase K+ secretion
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
Why does fast tubular flow increase K+ secretion?
K+ washed away really fast from apical side of membrane, so there is greater electrochemical gradient
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
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
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
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)
plasma K+ _____ with acidemia (usually), and _____ with alkalemia
rises
falls
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)
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
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
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)
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
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)
Causes of hypokalemia without K+ deficit (4)
1) alkalosis
2) familial hypokalemic periodic paralysis
3) B-adrenergic drugs
4) too much insulin
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
Causes of chronic hypokalemia
renal or extrarenal
differentiate with Urine K
- Low (less than 20 Meq/L) → extrarenal
- High (>20 Meq/L) → renal
Hyperkalemia defined as serum K+ > ______
Serum K+ > 7.0, above 10 is often fatal
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
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
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)
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
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
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
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)
Essential hypertension
single reversible cause of elevated BP CANNOT be identified - (90-95%) of HTN cases
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)
Why does HTN occur due to an increase in SVR?
two hypotheses for explaining this
1) Guyton hypothesis
2) VSMC hypothesis
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)
“Unwillingness to Excrete Na” Theory
humans with essential HTN possess a genetically determined impairment of kidney’s ability to excrete excess Na
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
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
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)
Secondary HTN
HTN caused by an identifiable mechanism (5-10%)
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
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
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
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)
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
Primary hyperaldosteronism
excess aldosterone secretion due to pathological defect in adrenal cortex → high aldosterone, low renin → expansion of ECF volume, suppression of plasma renin
Two causes of primary hyperaldosteronism
1) Aldosterone producing adenoma
2) Idiopathic adrenal hyperplasia
Aldosterone producing adenoma presentation and treatment
(UNILATERAL)
- TX with unilateral adrenalectomy
- NaCl administration will decrease aldosterone
- Fludrocortisone → salt retention, decrease aldosterone
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)
Pheochromocytoma
benign tumor of adrenal medulla → excess catecholamines → increase vascular resistance
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
Non-Pharmacologic Treatment of Essential HTN
STOP SMOKING, weight reduction, DASH eating plan, dietary sodium reduction, physical activity, moderation of alcohol consumption
How do you treat a patient with prehypertension
(120-139) → no pharm, only lifestyle modification
Still associated with increased risk of CV events
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
How do you treat a patient with Stage 2 HTN
> 160/>100
Lifestyle + Two drug combination:
Thiazide diuretic + ACEI/ARB or BB or CCB
Goals of HTN treatment
Treat BP to less than 140/90 or BP less than 130/80 with diabetes or chronic kidney disease
2 medications that work on the proximal tubule
1) Mannitol
2) Acetazolamide
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
Mannitol
uses (2) adverse effects (1)
Use: management of intracranial pressure, glaucoma
Adverse effects: acute increase in ECF volume (because increases ECF osmolarity)
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-)
Acetazolamide
uses (3)
glaucoma, prevention/treatment of high altitude sickness, metabolic alkalosis
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
Loop diuretics
Uses (4)
volume overload –>
heart failure
BP reduction
pulmonary edema
Hypercalcemia
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
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
Thiazides
uses (2)
1) Antihypertensive effect secondary to decreased plasma volume and decreased CO
2) Secondary mild vasodilation
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
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)
Uses of K+ sparing diuretics (4)
Hypokalemia
Heart failure
Hyperaldosteronism
Resistant Hypertension
Adverse effects of K+ sparing diuretics (3)
Hyperkalemia
Gynecomastia
Amenorrhea
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
Hydralazine and minoxidil
adverse effects (5) uses (2)
Adverse Effects:
Edema, tachycardia, neuropathy
Lupus rash (hydralazine)
Hair growth (minoxidil)
Uses:
HTN, heart failure
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
ACE inhibitors
use
1st line therapy for HTN, CKD, HF, DM nephropathy
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)
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
ARBs use
1st line therapy for HTN, CKD, HF, DM nephropathy
ARBs adverse effects (3)
Adverse Effects:
- Hyperkalemia
- Rise in serum creatinine (transient, dilation of efferent arteriole)
- Angioedema
Terazosin, doxazosin, prazosin do what?
alpha-1 receptor antagonists
Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)
mechanism of action
Peripheral postsynaptic blockade → decrease in arterial tone
Relaxes smooth muscle of bladder neck
Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)
use (1)
primarily for BPH
Alpha-1 Receptor Antagonists: (terazosin, doxazosin, prazosin)
Adverse effects (5)
Postural hypotension, dizziness, somnolence, impotence, nasal congestion/rhinitis
Clonidine and methyldopa do what?
central alpha-2 receptor agonists
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
Alpha-2 Receptor Agonists: Clonidine, Methyldopa
Adverse effects (5)
dry mouth, depression, lipid abnormalities, sedation, orthostatic hypotension
Alpha-2 Receptor Agonists: Clonidine, Methyldopa
Uses (4)
HTN, ADHD, smoking cessation, ETOH withdrawal
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
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
Adverse effects of DHP (4)
Reflex tachycardia
Headache
Peripheral edema (due to vasodilation)
Gingival hyperplasia
Uses of DHPs (2)
1) HTN - Good 2nd line agents for BP reduction especially in African Americans, elderly
2) Migraine prophylaxis
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
Adverse effects of non-DHPs (5)
Constipation
Bradycardia
Nausea
Conduction defects
-inhibits CYP450 –> drug interactions
Uses of non-DHPs (4)
primarily reserved for negative inotropic activity
Angina
Rate control for AFIB
Migraine prophylaxis
HTN
atenolol, metoprolol, bisoprolol, and nebivolol are beta blockers with what selectivity?
cardio selective - B1 receptors
-no alpha blockade
propanolol and timolol are beta blockers with what selectivity?
non-selective B1 (cardiac) and B2 (bronchial/vascular)
Labetolol and carvedilol are beta blockers with what selectivity
beta and alpha blocker
Provides extra antihypertensive effect - no cardioselectivity, has a-blockade
Adverse effects of B-blockers (5)
Decrease libido, bradycardia, bronchospasm, glucose/lipid changes, fatigue
Normal pH range
7.35-7.45
60 kg person → add __ mEq of H+ to ECF every day
60
Total bicarb in ECF = ___ mmol → only a ___ day supply of ECF bicarb available (60-70 mmol destroyed every day)
360 mmol
5-6
Carbon dioxide
“volatile” gaseous acid
1.Eliminated by lungs effectively under normal conditions
Organic acids
(e. g. Lactic and citric acid)
1. Metabolized to neutral products (glucose, water, CO2)q
Metabolism and acids
generates “nonvolatile acid” from proteins and nucleic acids
- Proteins (sulfur containing amino acids) → Sulfuric acid (H2SO4)
- Nucleic acids → Phosphaturic acid (H3PO4)
- Must be eliminated by the kidneys
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
Bone as a buffer
Bone (acidosis → suppress osteoblasts, stimulates osteoclasts → release Na, K, CO3 2- and HPO3- from bone)
Bicarb buffering system
buffers and eliminates H+ from the body
- H+ + HCO3- → H2CO3 → CO2 + H2O (removed by lungs)
- Low CO2 required to drive rxn to right (high CO2 stimulates hyperventilation → blow down CO2) - Convert nonvolatile acid to a gaseous volatile form that can be eliminated rather than simply buffered
- Elimination of each H+ requires the “suicide” destruction of a bicarbonate anion → bicarbonate lost in elimination of acid must be continually replaced
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
Role of kidney in maintenance of bicarb levels (3)
- eliminate acid ions
- Reabsorption of filtered bicarb
- Synthesis of bicarb
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
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
Two pumps involved in reabsorption of bicarb and how they function
- 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 - Sodium-Bicarb Cotransporter (NBC): on basolateral angle transports Na and HCO3- into blood
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
Bicarb synthesis
- Kidneys synthesize bicarb to replace exactly what is lost in acid elimination process (every H+ excreted/secreted, HCO3- generated)
- Done by epithelial alpha intercalated cells of collecting duct
a. Generates NET increase in H+ → acidifies urine
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
How is the H+ buffered in bicarb synthesis? (2)
- Titratable acid
2. Ammonia trapping
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
Ammonia trapping
- 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
- Process augmented by high intracellular [H+] in proximal cells (chronic acidosis or hypokalemia)
- Can be increased up to 200 mmol of H+ buffering per day
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
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
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-
NAE: metabolic acidosis
a. NH4+ excretion increases
b. Titratable acid excretion unchanged
c. Bicarb excretion remains zero
Renal response to respiratory acidosis
Refer to Mady Lion’s notes: search renal response to respiratory acidosis (complicated chart)
Renal response to chronic metabolic acidosis
- Bicarb excretion increases (up to 80 mmol/day)
a. Decreased reabsorption - NH4+ and titratable acid excretion decreases
Respiratory alkalosis
Decreased ECF CO2 → decreased H+ → decreases number of apical H+ transporters and basolateral HCO3- transporters
Hypokalemia and plasma pH
in response, K+ shifts out of cells into ECF, and exchanges with H+ which shifts into cells
- More intracellular H+ available in renal tubules for secretion
- Increased ammoniagenesis → more H+ trapping and excretion
- Intercalated cells will preferentially reabsorb K+ and secrete H+
a. Via H+/K+ ATPase on apical membrane - More H+ secretion/excretion = more HCO3- synthesis
- PREDISPOSES TO METABOLIC ALKALOSIS
a. Alkalosis → hypokalemia and hypokalemia → alkalosis
Hyperkalemia and plasma pH
in response K+ shifts into cells from ECF, and exchanges with H+ out of cells
- Less intracellular H+ available in renal tubules for secretion
- Decreased ammoniagenesis → less H+ trapping and secretion
- Less H+ secretion/Excretion = Less HCO3- synthesis
- PREDISPOSES TO METABOLIC ACIDOSIS
a. But hyperkalemia stimulates aldosterone → increases H+ secretion and HCO3- synthesis
i. Counteractive
Metabolic acidosis compensation assesment
expected CO2 = 1.5x[HCO3-] + 8 +/- 2
- Compensation adequate → “SIMPLE”
- Compensation inadequate → “MIXED”
- COMPENSATION IS ALWAYS THE SAME DIRECTION AS PRIMARY CHANGE
Respiratory alkalosis (including compensation assessment)
always due to hyperventilation
- Anxiety, fever, pain, lung disease, liver disease, sepsis, brain disease, pregnancy
- 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
Respiratory acidosis (including compensation rules)
breathing too little
- Neuro problem, muscle fatigue, aspiration, pneumonia, COPD, ILD, hypokalemia, hypothyroidism
- 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
Metabolic alkalosis
increased pH, increased HCO3-
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
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
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)
Metabolic acidosis
reduction in bicarb and pH
1.Kidney must handle daily acid load of 60mEq H+, which consumes 60 mEq of HCO3-
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:
- Secretes H+ (H+ ATP pump)
- Makes HCO3-
- Acidifies urine
- Excretes daily acid load
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
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
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)
Utility of serum and urine anion gap
can be used to determine if renal acid excretion (new bicarbonate generation) is appropriate
Urine anion gap
If metabolic acidosis present, NH4+ production should increase
- Urine anion gap = Na+ + K+ - Cl-
a. NH4+ production increased → urine Cl- should also increase to maintain electroneutrality - Negative urine anion gap suggests NH4+ production is occurring in kidney → non-anion gap metabolic acidosis due to GI loss
- Positive urine anion gap → renal NH4+ production impaired, RTA present
