Tuesday, 9/19/2000 9 a.m. Dr. Carroll
Pharmacology Kavita & Laura
ANTIDIURETIC HORMONES:
RENAL PHYSIOLOGY
I. Kidney has three basic functions
A. Filtration
1. Excretes unwanted end products of metabolism (eg. uric acid, urea, creatinine)
2. Reabsorbs wanted products (e.g. Na+, H2O, K+, Cl-, HCO3-)
B. Maintains extracellular fluid at a constant volume
1. Resists changes in body fluid osmolality
2. Examples
a. Drinking 8 glasses of water in an hour no ADH excrete large volumes of hypoosmotic urine
b. Person in the desert release of ADH excrete low volume of hyperosmotic urine
C. Maintains acid/base balnce
1. H+ secreted into the urine making it acidic
2. HCO3reabsorbed from glomerular filtrate
II. Anatomy of the kidney
A. 1,000,000 nephrons
1. 5/6 are cortical nephrons
2. 1/6 are juxtamedullary
B. Cortical Nephrons
1. Short loops of Henle
2. Do not descend into the hyperosmotic gradient area
3. Rapid blood flow through the cortex
C. Juxtamedullay Nephrons
1. Long loops of Henle
2. Involved in maintaining a hyperosmotic gradient
3. Slow blood flow through the medulla via vasa recta
4. Loop diuretics increase blood flow through the vasa recta and get rid of the hyperosmotic gradient
III. Glomerular Filtration
A. Kidney filters approx. 180 L per day
B. Approx. 20% of the blood enters the kidney via the afferent arteriole
C. 99% of glomerular filtrate is reabsorbed in 1 pass thru the kidney
D. 1% leaves as urine
E. Little protein enters the filtrate
F. Inulin used to determine GFR (= 125 ml/min)
1. Inulin is filtered, not secreted, and not reabsorbed
G. If GFR is increased, efficiency of reabsorption is reduced due to fluid moving in the proximal convulated
tubule( PCT) at a faster rate (seen in hypertension)
H. If GFR is decreased, efficiency of reabsorption is increased due to fluid moving in the proximal
convulated tubule at a slower rate (seen in CHF)
IV. Renal Blood Flow
A. Use PAH to determine renal blood flow
B. PAH cleared in 1 passage, this is done in 2 ways
1. Glomerular filtration
2. Organic acid transport system
a. Non-specific transport, transports weak acids
b. Thiazide and loop diuretics use this system to get into the PCT
c. Uric acid
i. Waste product which may aggravate gout
ii. Uses this system to get into the PCT
d. Thiazide and loop diuretics compete with uric acid for transport
C. Another type of transport system
1. Organic base transport system
a. Histamine and Choline
b. K+ sparing diuretics, triamtrene and amiloride use this route
V. Proximal Convulated Tubule
A. Majority of glomerular filtrate reabsorbed in the PCT (55-70%)
B. Permeable to H2O and Na+
C. No change is osmolality (300 mOsm)
D. Reabsorption of Na+, Cl-, H2O, glucose, HCO3-, K+
E. Na+
1. Actively transported out of tubular cell
a. These causes a gradient from lumen into tubular cell
b. H2O passively follows
2. Cation exchange
a. Minor route
b. Na+ exchanged for H+ (Na+ reabsorbed and H+ secreted into lumen)
c. Uses Carbonic Anhydrase (CA)
i. In the tubular cell, H+ formed from dissociation of H2CO3 to H+ and HCO3-
ii. CA used to make H2CO3 from CO2 and H2O
iii. If use a CA Inhibitor, H+ will not be able to be secreted into lumen thus Na + will not reabsorbed
to the same extent leading to more Na + in the urine, H2O will follow
3. Low Sodium Diets affects the PCT
a. Less salt in the diet leads to less Na+ to be transported out of the PCT
b. Initially, low Na+ diet will increase efficiency of reabsorption
c. At the thin descending limb of the Loop of Henle and the medullary collecting duct,
less Na+ will arrive there, therefore not able to create hyperosmotic gradient and in turn
less H2O is reabsorbed. All of this leads to diuresis.
F. HCO3-
1. HCO3- in the lumen can not enter the tubular cell as is
2. Using CA, it is converted into CO2 and H2O, which can diffuse into tubular cell
i. HCO3- combines with the secreted H+ and then is converted
+
G. K
1. Normally almost all of it is reabsorbed
2. If use a diuretic that inhibits CA, H + not formed
3. So, HCO3- in the lumen will combine with K +, therefore less is reabsorbed which leads to
hypokalemia this is a major side effect of diuretics
H. Glucose
1. Actively transported
2. H2O passively follows
I. GFR influences filtration and reabsorption
1. See III. G and H
VI. Thin Descending Loop of Henle
A. Membrane permeable to H2O but not permeable to Na+
VII. Thin Ascending Loop of Henle
A. Membrane is not permeable to H20 and is permeable to Na+
B. Na+ diffuses into the interstitium which helps to maintain the hyperosmotic gradient
VIII. Thick Ascending Loop of Henle
A. Membrane not permeable to H2O
B. Active transport of Na+, K+, Cl-, and Ca2+ into the interstitium
C. Cl- most important ion because 2 Cl- for every Na+
D. K+ that is not reabsorbed from PCT while be reabsorbed here
E. Loop Diuretics work here by blocking reabsorption of these ions therefore eliminating the hyperosmotic
gradient. The loss of the hyperosmotic gradient increases the loss of the ions (stay in the urine)
IX. Distal Convoluted Tubule (DCT)
A. Na+ actively reabsorbed
1. Thiazide blocks this reabsorption
B. Membrane impermeable to H2O
1. So urine becomes hypoosmotic
C. Macula Densa
1. Association of the afferent and the DCT
2. Pressure sensing
3. Senses the flow rate of urine
a. If flow is too fast, chemical message goes to glomerulus which leads to a decrease in GFR
4. Senses Na+
a. Low Na+ stimulates renin release of angiotensin I release of angiotensin II Aldosterone
release.
b. Aldosterone in Na+ reabsorption affects cortical collecting tubule
X. Cortical Collecting Duct (CCD)
A. Na+ actively reabsorbed, enhanced by aldosterone
B. When ADH is not present
1. Person is well hydrated
2. Membrane not permeable to H2O
3. Decrease in fluid osmolality due to Na+ reabsorption
C. When ADH is present
1. Person is dehydrated or blood volume drops
2. Amount of ADH released is proportional to the degree of dehydration
3. Membrane is permeable to H2O
4. H2O moves into interstitial fluid
D. Aldosterone
1. Stimulates Na+ reabsorption into the tubular cell
2. K+ and H+ move into the lumen
3. At high levels, it enhances loss of K+ or H+
E. CA Inhibitors
1. At the cortical collecting duct, H+ competes with K+ for exchange with Na+
2. When CA is blocked, there is less H+ therefore more K+ will be exchanged for Na+
F. ADH
1. Made by the hypothalamus
2. Makes the collecting duct permeable to H2O
3. Typically, ADH is present in some amount and is functioning except if
a. Person very hydrated or
b. If there is a problem with the hypothalamus
XI. Medullary Collecting Duct
A. If ADH is absent,
1. Membrane not permeable to H2O or urea
2. No fluid reabsorption occurs
3. No change in osmolality
4. Leads to excretion of large volume of hypoosmotic urine
B. If ADH is present
1. Membrane permeable to H2O and urea
2. Reabsorption of H2O from the lumen
3. Excrete a low volume of hyperosmotic urine
C. Low Protein Diet
1. Do not produce enough urea to aid in the reabsorption of H 2O
2. Leads to more rapid urination
XII. Syndrome of Inappropriate ADH secretion (SIADH)
A. Massive amount of ADH released
B. Maximal H2O reabsorption from both parts of the collecting duct
C. Person will excrete a hyperosmotic urine (may be greater than 1200 mOsm)
D. Body osmolality may decrease as a result
E. Treatment
1. Demeclocycline
a. Drug of choice
b. Blocks the action of ADH
2. Lithium
a. May also be used
b. Too much leads to a decrease in sensitivity of the CCD
c. This can lead to Nephrogenic Diabetes Insipidus
XIII. Diabetes Insipidus: 2 Types
A. Hypothalamic
1. Not enough ADH made
2. Treatment
a. Desmopressin Acetate
i. Deaminated form of ADH
b. Why not give ADH?
i. It has suppressor activity
ii. Has effects on blood pressure (scribe note: did not specify how)
B. Nephrogenic
1. Collecting duct does not respond to ADH
2. Frequent urination leads to uncomfortable feeling for affected person
3. Excreting a very hypoosmotic urine (almost like distilled H 2O)
4. Retain Na+
5. Treatment
a. Thiazide Diuretics
i. Drug of choice
ii. Blocks Na+ reabsorption in the DCT
1. Leads to excessive amount of Na+ arriving at collecting duct
2. This overwhelms the Na+ pump
3. Leads to an increase in Na+ excretion (in the urine)
4. Brings the urine osmolality close to (but not equal to) 300 mOsm
iii. Decresases the rate of urination by decreasing GFR
iv. In non suffers of this type of diabetes, thiazide diuretics act to increase the rate of urination
and urine osmolality will reach 300 mOsm
b. Loop Diuretics
i. Brings the urine osmolality to 300 mOsm
ii. But increases the rate of urination