Renal Flashcards
Formula for clearance
C=(UxV)/P
Clearance
Using concentration
Urine flow rate
Plasma concentration
GFR
Clearance PAH
Filtration fraction
GFR/eRPF
Effective renal blood flow=effective plasma flow/fraction of blood that is plasma
Usually FF
.17-.21
Early stages of DM are associated with what
Glomerular hypertension/hyperfiltration. Give ACE inhibitors or angiotensin receptor blockers
What is the clearance of a solute
Ml/min plasma from which all of solute x has been removed
To calculate GFR we use 24 hour infusion of insulin. Why
Freely filtered
Not reabsorbed
Not secreted
Not endogenous molecule satisfies those conditions
How calculate true GFR
Insulin clearance
What must happen for clearance to exceed GFR
Tubular secretion
What endogenous chemical clearance equals the effective renal plasma flow
PAH (p-aminohippurate)
How calculate effective renal blood flow (RBF)
ERPF/fraction of blood that is plasma
?????
Fraction of blood that is plasma=1-hematocrit
Filtration fraction
True GFR(inulin clearance)/EPRF (PAH clearance)
T1/2
(.693 Vd)/clearance
Vd =apparent volume of distribution for the solute (I-iothalamate) freely filtered and not reabsorbed but has tubular secretion
Vd and T1/2 then allows the clearance rate to be calculated
Creatinine
Freely filtered, not reabsorbed but some secretion
Error in GFR from creatine
Creatinine clearance-inulin/inulin clearance ???
Why does error increase as GFR increases
As DFR falls the fraction of the total mass of creatinine ending in the urine decreases and more Plasma Cr
Creatine can be used to calculate GFR, but what’s thie issue with old people
Produce less creatine due to a decline in muscle mass—-so can remain normal despite significant decline in renal function
Cockcroft galt forma for creatine clearance (ml/min)
((140-age)x(wt(kg))/ serum creatinine (mg/dL)x72) (x.85 for females)
MDRD formula for GFR
Takes into account race,surface area
Fraction of filtered solute that ends up in the urine
(VxU)/GFRxP
If inulin concentration in infusion is doubled. What happens to
Clearance
U V
FE
Idk
How does glucose clearance change
Doesn’t
Clearance is always 0
If above issue osmotic retention and polyuria and polydipsia
Clearance H20
V-Cosm
=-.88?????
Free water clearance 0
Free water clearance positive
Free water clearance negative
Plasma osmolality=urine osmolality
Urine dilute
Urine is concentrated
How calculate daily sodium intake
Daily input=output
TBW white male
23-(.03age)+(.5weight)-(.62xBMI)
TBW black male
-18.37-(.09age)+(.34weight)+(.25height)
TBW white female
-10.5-(.01age)+(.2weight)+(.18height)
TBW black female
-16.71-(.05age)+(.22weight)+.24height
Height cm and weight kg
Na requirement
TBWx(desired Na-serum Na)
Wish to raise the resum Na from 120 to 135 when TBW is 35.8. How many ml of 3% NaCl solution (513mmol/L0 would need to be infused to meet the Na requirement
1046.78
Fractional Excretion Na
Usually near 1%
Na excreted/Na filtered= UxV/PxGFR=Cna/Ccr
BUN:Cr normal
10-15:1
Low BUN:Cr
Acute tubular necrosis (damage to kidney parenchyma so urine is more of an extracelular fluid ooze-cant concentrate)specific granite <1.01
Low protein intake
Starvation
Severe liver disease
High BUN:Cr
Pre renal acute kidney injury (small amount of concentrated urine, specific gravity >1.02)
High protein intak e
After GI bleed
Post renal AKI
Small amount of normal uring
Imaging will show accumulation upstream from block
Relief of obstruction can lead to post obstructive diuresis, can be life threatening
Blood uring
24 hour protein excretion (mg/day)
UproxV
Uprox(24hrUcr/Ucr)
Calculate 24 hour creatine. Excretion
UcrxV
V=24 hr U Cr/UCr
Upro/Ucr
Grams/day of protein excreted
Microalbumin
Detect small amounts in urine (trace amounts)
Name thiazide diuretics (hypertension, edema)
Hydrochlorothiazide
Metolazone
Chlorthilidone
Name loop diuretics (edema, hypertension)
Furosemide
Torsemide
Bumetanide
Ethacrynic acid
K sparing diuretics
Na channel blocker
- amigo ride
- triamterene
Aldosterone antagonist
- spironolactone
- eplerenone
Aquaretics (hyponatremia
Conivaptan
Tolvaptan
Carbonic anhydrase inhibitor (urinary alkalinization, mountain sickness, glaucoma)
Acetazolamide
Osmotic diuretic (maintain uring flow, pull water from cells for excretion)
Mannitol
Natriuretic
Substance that promotes the renal excretion of sodium
Aquaretic
Substance that produces free water clearance
CH2O
V-Cosm
V-(UosmxV/Posm)
Damage to any vessel branch or renal arterial vessels is a HUGE problem. Why
No arterial anastomoses
Ischemia and death downstream
What diuretics work at the proximal tubule
Osmotic diuretics
Carbonic anhydrase inhibitors
What diuretics work on thin descending loop of Henley
Osmotic diuretics
What diuretics work on thick ascending limb of henle
Loop diuretics
What diuretics work on distal convoluted tube
Thiazide diuretics
What diuretics work on cortical collecting duct
Na channel blockers spironolactone
What diuretics work on collecting duct
Vaptans
Why give diuretics
Essential hypertension
Edema associatedwith
- congestive heart failure
- liver failure
- kidney failure
What are K sparing diuretics and how do they work
Triamtrene, amiloride…Na channel blockers
Spironolactone-aldosterone antagonist
Name K losing diuretics and how they work
Thiazides-Na Cl cotransporter blockers
Loop diuretics-Na K 2Cl cotransporter blockers
Carbonic anhydrase inhibitors (seldom used)
Osmotic diuretics-non reabsorbable solutes
Where does mannitol work
PCT
Where does furosemide work
Thick segment
Where do thiazides work
EarlyDT
Where do K losing diuretics work
Early DT
Where do K sparing work
Late DT
Where do spironolactone and triamterene work
Late DCT
Effect of hypokalemia and hyperkalemia
Hypo-neurons don’t fire hyperpolarized
Hyper-depolarizes maybe lethal since Na channels cant reactivation
Why are K losing diuretics and digitalis often given together to patients with CHF
Hypokalemia increases the toxicity of the digitalis
Heart and hyperkalemia
Tall T wave
Prolonged PR interval
Wide QRS interval
Flattened P waves
Arrhythmias including bradycardia, ventricular tachycardia or fibrillation
Sinus arrest or nodal rhythm with possibl easystole
Hypokalemia heart
Flattened T waves
ST segment depression
Prolonged QT interval
Tall U waves*
Atrial arrhythmias
Ventricular tachycardia or ventricular fibrillation
What diuretics have greatest amount of diuresis
Loop
Where do loop diuretics act
TAL
MOA furosemide
Inhibits reabsorption of sodium and chloride in the thick ascending limb of the loop by blocking Na K 2Cl cotransporter
Inhibits paracellular reabsorption of Ca and Mg by the TAL due to loss of K backleak responsible for lumen+transepithelial potential
Effects furosemide
Causes increased excretion of water, sodium, K, Cl, Mg, and Ca
What use furosemide for
Edema, heart fail, hepatic disease, renal disease, acute pulmonary edema by decreasing preload (decrease EC vol, rapid dyspnea relief), HTN(works with low GFR)
SE furosemide
Hypokalemia, hyponatremia, hypocalcemia, hypomagnesia, hypochloremic metabolic alkalosis, hyperglycemia, hyperureicemia, hyperuricemia, ototoxicity (vertigo), hypersensitivity BC IT IS A SULFONAMIDE
Torsemide MOA
Similar to furosemide with longer T1/2 better oral absorption and some evidence that is works better in heart failure
Bumetadine
Sulfonamide similar to furosemide,but more predictable oral absorption ethacrynic acid: non sulfonamide loop diuretic reserved for those with sulfa allergy
Clinical effect of furosemide
Max doses_>profound diuresis! From dissatisfaction of the medullary interstitial gradient —irrespective of whether urine was dilute or concentrated, get large volume of isotonic urine
How give furosemide
PO, IV, IM
IV 5 min last 2 hours
PO 30-60 min lasts 8 hours
When prescribe furosemide
When rapid and massive fluid removal is needed (edema, cardiac, renal origin), acute pulmonary edema, HTN that is unresponsive to other diuretics (still works with RBF and GFR are low)
Furosemide and acute pulmonary edema
Rapid effects <5min that are though to be due to prostagladin mediated venodilaion that reduces preload
SE furosemide
HypoNa, hypoCl, hypoK, which lead to hypovolemia and hypotension
HypoMg
HypoCa
Furosemide as a K losing diuretic causing hypoCl metabolic acidosis
K H exchange at cells try to maintain plasma K
Also Na K exchange
Risk of hypoCa and furosemide
Kidney stones (OPPOSITE OF THIAZides
Ototoxicity of furosemide
Hyperglycemia
Hyperuricemia (gout)
Decrease HDL, increase LDL, increase TG (atherosclerosis
Preg and furosemide
NO
Digoxin and loop diuretics
Frequent interactions since both drugs are often used to treat heart failure and the risk of digoxin toxicity is increased by low K due to the diuretic
Ototoxicity drugs and loop diuretics
Increased chance of hearing loss if combined with drugs having similar toxicity
Potassium sparing diuretics and loop diuretics
Can counterbalance potassium wasting effects
Loop diuretics other drug interactions
Lithium toxicity, potentialte effects of other antihypertensive agents and have diuretic effects antagonized by NSAIDS
Bumetanide
More predictable absorption
Toresimide
Long T1/2 better for absorption, may work better in heart failure
Ethacrynic acid*
Among the few diuretics that can be used by people who are allergic to sulfa drugs
Loop diuretics cause the largest Na loss, are K losing, and cause similar __ loss than either loop of K sparing diuretics
HCO3
Thiazide diuretics most used
Hydrochlorothiazide-sulfa drug
12 others often ending in thiazide
Where do thiazides work
early DCT
MOA hydrochlorothiazide
Inhibitors Na reabsorption in the DT via blockade of NaCl cotransporter
Effects of hydrochlorothiazide
Increases urinary excretion of Na and H2O
Increases urinary excretion of K and Mg
K losing
Clinical use of hydrochlorothiazide
HTN (not effective in patients with low GFR)
Edema
Calcium nephorlithiasis
SE hydrochlorothiazide
Orthostatis hypotension
Hypo k, mg, na, cl, metabolic alkalosis
Hyper ca, hyperglycemia, hyperuricemia
Sulfa-hypersensitivity
Chlorothiazide
Similar to HCTZ but poor oral absorption
Chlorthaliodne
Similar to HCTZ but half life of f40-60 hrs..prolonged/stable response with proven benefits is reason it is preferred by some hypertension specialists
Metolazone
Another long acting thiazide diuretic, this’s is a favorite of cardiologists for use as an adjunct diuretic in the treatment of CHF
MOA thiazide
Block Na Cl cotransporter
More Ca reabsorption in PT bc of volume contraction
Mg only reabsorbed in TALH.distal nephron …loss greater with thiazides than loop diuretics
Location of thiazide diuretics means its diuresis _ with loop diuretics, _ downstream acting K sparing diuretics
<
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THIAZides and low GFR and RBF
Don’t work
THIAZides cause the greater __ loss. Implications?
HCO3
Impairs distal nephron H secretion
Pharmacokinetics thiazide
Diuresis begins < 2 hours after oral ingestion with peak at 406 hours and effects lasting 12 hours.. in other works shouldn’t take this one at bedtime
Drug is exceed unchanged in uring
Uses of thiazide diuretics
primary HTN and edema
Nephrotoxicity diabetes insipidus
Decreases Ca excretion, day decraese risk of kidney stones (opposite of loop diuretics(
Can be added to loop diuretics to increase diuresis
Adverse effects thiazides
Hypovolemia
K losing (downstream Na K exchanger tried to salvage Na at hte expense of K)
Hypochloremic metabolic alkalosis
Hypomagnesia
Drug interactions thiazide
Combined with antiHTN meds
K loss can be offset by combining K sparing diuretics
Increase risk of digoxin and lithium toxicity
Chlorthalidone
1-2 x more potent
Different structure
Longer HL
Larger volume of distribution than HCTX, prescribed much less commonly in the US
Doses of thiazide 12.5-25
Reduce CVD mortality and morbidity
THIAZides are intermediate with _ loss, are _ losing, and cause larger _ lossdue to inhibtion of distal H secretion
Na K HCO3
Where does spironolactone act
Cortical collecting duct
K sparing diuretics
Triamterene, amiloride..Na channel block
Spironolactone..aldosterone antagonist
MOA amiloride
Blocks the luminal Na channels in CT
MOA spironolactone
Blocks aldosterone receptor in CD
Effects amiloride
Small increase in Na excretion
Blocks major pathway for K elimination so K is retained
H Mg Ca excretion also decreased
Clinical applications amiloride
Counteracts K loss induced by other diuretics in the treatment of HTN or heart failure
Ascites, pediatric HTN
SE amiloride
Hyper K Hypo Na Hypo vol HyperCl metabolic acidosis Dizzy, fatigue, headache
Nauseas vom
Triamterene
Similar to amiloride for edema and off label HTN rapidly absorbed, duration of 6-9 hrs, eliminated as drug metabolites
Spironolactone MOA
Competitive antagonist of aldosterone receptors
Partial agonist at androgen receptors
Effects of spironolactone
K sparing
Clinical applications spironolactone
Counteracts K loss induced by other diuretics in the treat of HTN, heart failure, ascites
Hyperaldosteronism
Reduce fibrosis post MI
Hirsutism
SE spironolactone
HyperK
Amenorrhea, hirsutism, gynecomastia, impotence
Eplerenone
More selective aldosterone antagonist, approved for use in post MI heart failure and alone or in combination for HTN
Amiloride and triamterene _ urinary Na excretion and _ unitary K excretion
Increase
Decrease
If Na cant get into the cell, K cant get out of the cell into the tubular lumen
Pharmacokinetics amiloride triamterene
Channel is blocked directly, effects are seen more rapidly than with spironolactone but smaller and therefore harder to detects lasts 12-16 hours
Uses of triamtene
HTN, edema, often in combo with loop of thiazide diuretic
Adverse effects K sparing
Hyperkalemia
Nausea, vom, leg cramps, dizzy, bloody dyscrasias rare
MOA spironolactone
Blocks ability of aldosterone to bind to its receptor and increase Nareabsorption int he CCD
Leads to increased Na accretion
Pharmacokinetics spironolactone
Can take 48 hours to work
Steroid hormones produce effects with a slow onset
Uses spironolactone
HTN and edema, often in combination with a loop or thiazide diuretic
Primary hyperaldosteronism
Reduce mortality rate in patients with severe heart failure
SE spironolactone
HyperK, endocrine effects include gynecomastia, importance’s, menstrual irregularities, hirsutism and deepening voice
Drug interactions spironolactone
Often combined with thiazide and loop diuretics to counteract their K loss
Should NEVER be given with drugs that increase plasma potassium levels, but used cautiously with ACE inhibtiors
Amiloride/triamtere and spironolactone are _ sparing and cause the smallest _ loss while causing _ excretion to fall below normal. They also cause significant __ loss by interfering with distal H secretion
K Na HCO3
Where do vaptans work
CD
MOA vaptans
Block antidiuretic hormone receptor in the CD
MOA conivaptan
Non peptide arginine vasopressin receptor antagonist
V1A and V2
Effects conivaptan
Promotes excretion of free water
Decreasing Uosm
Increasing Posm
Clinical applications conivaptan
Euvolemic and hypervolemic hyponatremia in patients that are hospitalized, symptomatic, not responsive to fluid restriction
Why monitor plasma sodium and nuerological status in conivaptan
Too rapid serum sodium correction can lead to seizures, osmotic demyelination, coma, or death
SE conivaptan
Orthostatic hypotension, fatigue, thirst
Polyuria, bedwetting
Tolvaptan
Selective V2 receptor antagonist given ORALLY
Initiate and reinitiate tolvaptan in patients ONLY IN A HOSPITAL where plasma sodium can be closely monitored
Must use <30 days for hyponatremia, longer use can kill by hepatoxicity
MOA conivaptan and tolvaptan
Prevents ADH mediated insertion of the aquaporin water channels into luminal membrane of principle cells in collecting duct
Prevents the reabsorption of water, therefore increases water excretion
Decrease plasma volume and increase plasma osmolality primarily due to an increase in plasma sodium
Pharmacokinetics conivaptan and tolvaptan
Conivaptan-t1/2 5.3-8.1 hours
Tolvaptan effects increase to peak at 4 hrs, lasts 4-8hours
Uses of vaptans
Hypervolemic or euvolemic hyponatremia
AD polycystic kidney disease
SE vaptans
Orthostatic hypotension
Fatugue
Thirst
Polyuria, bedwetting
Drug interactions vaptans
Metabolized by CYP3A4, so inhibitors and inducers of this enzyme can alter its half life and potential for toxicity
Selective water loss means
- possibility of hypovolemia
- other electrolytes and drugs can become concentrated..hyperNa, K uricemia
Toxic levels
Where do carbonic anhydrase inhibitors act
PT
Where do osmotic diuretics act
Tin descending limb
Main carbonic anhydrase inhibitor
Acetazolamide-sulfa drug
Causes metabolic acidosis and alkaline urine
MOA carbonic anhydrase inhibitors
Na bicarbonate diuresis
Bicarbonate remains in early proximal tubule
H cyclone lose, inhibiting Na/H exchange
Hyperchloremic acidossi
Uses of carbonic anhydrase inhibtiors
Urinary alkalinization
Metabolic alkalosis
Glaucoma:acetazolamide, dorzalamide
Acut mountain sickness
Adverse effects carbonic anhydrase inhibitors
Hyperchloremic metabolic acidosis
Nephrolithiasis: renal stones
Potassium wasting
Main osmotic diuretic
Mannitol
Also use urea, glycerin and isosorbide
MOA mannitol
Non metabolized 6 carbon sugar, freely filtered with minimal reabsorption
The inability to reabsorbed. This keeps water water in the proximal tubular lumen; this water is delivered to the distal portions of the nephron where much of it is excreted
Pull water out of cells
Excrete TBW in excess of plasma electrolytes
Pharmacokinetics mannitol
Distributes in ECF, must give IV large amounts 50-2000 g
Effects are noticeable within 30-60 minutes and mannitol is eliminated unchanged in the urin over a period of 6-8 hours
SE mannitol
EC volume is acutely increased bc mannitol sucks water out of the cells which can exacerbate heart failure
Headache, nausea, vomiting and fluid electrolyte imbalances also occur
Uses of mannitol
Prophylaxis of renal failure
Reduction of intracranial pressure
Reduction of intraocular pressure
Carbonic anhydrase causes _ Na excretion _ K and _ Hco3
Some more MOST
Osmotic diuretics cause _ Na, _ K _ KCO3 excretion
More, smoke,some
Herbal diuretics
Many souls ith claims that they are effective
Some can
Probably OK by themselves BUT DO NOT MIC WITH CONVENTIONAL DIURETICS bc of potential for adverse effects
Licorice
Contains sweet glycyrrhizic acid , potentials aldosterone effects in kidney and dose-dependently increases systolic blood pressure
Treat renal insufficiency or nephrotic syndrome
Loop diuretic
Add thiazide according to ClCr
Add distal diuretic
Treat cirrhosis
Spironolactone
ClCr >50 add HCTZ
ClCr<50 do to loop diuretic and treat like renal insuff or nephrotic syndrome
Treat CHF
Treat like renal insufficiency or nephrotic syndrome if not mild
Mild and ClCr <50 treat like “”
Mild and ClCr>50 add HCTZ then treat like rest
Causes of diuretic resistance
Incorrect diagnosis (venous or lymphatic edema)
Inappropriate NaCl or fluid intake
)
Inadequate drug reaching tubule lumen in active form
-poor absorption (uncompensated HF)
-decreased RBF (HF, cirrhosis, old)
Decreased functional renal mass (AKI, CKD, old
Inadequate renal response
-low GFR (AKI, CKD)
, decreased effective arterial volume (edema)
-activation RAAS (edema
-nephron adaptation (prolonged diuretic therapy
-NSAIDS(indomethacin, asprin
How lower bp
Thiazide diuretics, furosemide, K sparring diuretics
Treat HTN
ACE I or ARB or CCB not black
Black thiazide
Diuretics for heart failure
Stage C-HF
Diuretics to relieve congestion
Aldosterone antagonists
Diabetes insipidus
Excesssice passing of urine , tasteless
Central-lack of ADH
Can treat with ADH agonist
Nephrogenic-unresonveness to ADH
Treat with thiazide diuretic
Treat diabetes insipidus
Desmopressin, a synthetic V2 agonist if central
If lack of ADH response frominterstitial fibrosis, Li, antagonism of ADH in principal cells
Thiazide diuretics
___ is the most common cause of nephrogenic DI
Appearance of DI symptoms in this case coincides with use of Li to treat bipolar disorder
Thiazide diuretics are contraindicated in ___
Li induced DI bc Li reabsorption-like Na reabsorption is increased in the proximal tubule and can cause Li toxicity
How treat Li induced diabetes insipidus
Amiloride..blocks influx of Li into CCD cells
Very dilute urine->urine of appropriate concentration to maintain water homeostasis bc amiloride blocks Li influx into principal cells, allowing ADH to work
THIAZides treat nephrogenic diabetes insipidus IF
It is NOT caused by lithium
If Li causes nephrogenic DI (from bipolar treatment), _____ is the treatment
Amiloride
Describe the distribution of calcium in the body
Plasma least, more intracellularly, most IN THE BONE
Why is it important to control Ca within a narrow range
Muscle contraction
Intracellular signaling
Bone formation
Neuronal excitation
Effects of hyper and hypocalcemia
Hyper-raise threshold
Hypo-lowers threshold
How does hypoalbuminia effect calcium. What are the implications
Decreases total serum calcium without affecting ionized.
If serum albumin is abnormal, clinical decisions should be based on ionized calcium levels
Corrected calcium
Measured total Ca (mg/dL)+.8 (4-serum albumin )
Hormones that control calcium
Calcitrion (1,25 OH vitamin D3)
PTH
Calcitonin
Sites of regulation—-kidney, bone, intestine
Effects of calcitonin
Lowers blood Ca levels in three ways:
-inhibits Ca absorption by the intestines
-inhibits osteoclast activity in bones
-inhibits renal tubular reabsorption of Ca (increase Ca excretion)
Like PTH it inhibits tubular phosphate reabsorption
Effects of PTH
Increase plasma Ca, decrease plasma PO4–>increased ionized plasma Ca
- acts in distal nephron to increase Ca reabsorption
- inhibits PO4 reabsorption int he proximal tubule
- enhances bone release of Ca
What controls secretion of PTH
Serum Ca acting on calcium sensing receptors on Parathyroid cells in a negative feedback manner
Activated by low Ca
Calcitrion (1,25-OH D3)
Renal synthesis from 25-OH vitamin D3 is stimulated by PTH
Acts through calcitrion receptor
Increases blood Ca levels
How does calcitrion (VD3) increase Ca levels
Promotes absorption of dietary calcium from GI tract
Increases renal tubular reabsorption of filtered Ca
Stimulates release of Ca from bones…acts on osteoblasts to activate osteoclasts
__ of filtered calcium is reabsorbed in the PT. How
65
Paracellular, but some active transport
The thick ascending limb of loop henle has lumen positive voltage that drives ____ Ca reabsorption of __%
Paracellular
20
Distal tubule is site of _% of calcium reabsorption but major site of regulation. How
8
Active transport along electrical and chemical gradients
Renal epithelial Ca channel(TRPV5)-along with calbindin, regulated by calcitriol
Calcium reabsorption is _ in CD
5%
Klotho
Enzyme that can break down complex carbs, disruption leads to premature aging…has a direct stimulators effect on TRPV5
How is conductance of TRPV5 regulated
PTH and locally synthesized tissue kallikrein
Calbindin-D28K and TRPV5 expression is regulated by __
Vitamin D
What is the response to hypercalcemia
Decreased Ca absorption
Increased Caexcretion
Decrease bone resorption
NORMOCALCEMIA
Causes of hypercalcemia
*entry of calcium into ECF by bone resorption and intestinal absorption
Primary hyperparathyroidism, thiazide diuretics, milk alkali syndrome, familial hypocalciuric hypercalcemia, malignancy, immobilization syndrome, granulomatous disease, VD intoxication
Clinical features of hypercalcemia
Mild-asymptomatic
Severe-neurologic (weak, fatigue, confusion, stupor, coma) and GI (anorexia, nausea, vomiting and constipation)
NV cause hypovolemia —impaired calcium excretion—worsening
How manage acute hypercalcemia
Increasing calcium excretion
Decreasing resorption
Decreasing absorption
—-ECF volume replacement with .9% saline
——furosemide
—-calcitonin
What give if hypercalcemia not responding to saline diuresis, and espicially if secondary to malignancy
Bisphosponates
Causes of hypocalcemia
Decreased calcium absorption from GI or decreased resorption
Hypoparatyroidism, chronic kidney disease,familial hypocalcemia, rhabdomyolysis, septic shock, VD defiency, parathyroidectomy, acute pancreatitis (Ca soaps)
What is true hypocalcemia
When ionized calcium concentration is reduced
Hypocalcemia clinical feature
Neuromuscular irritability (fatigue, paresthesia, circumpolar, twitching, tetany, chvostek, trousseau, laryngeal and bronchial spasm)
Altered central nervous system function (emotional disturbances, depression, coma, seizures, papilledema, cerebral calcifications)
CVD (lengthen QT, dysrhythmias, hypotension, CHF)
Derm(dry skin, coarse hair, brittle nails, cataracts)
How manage hypocalcemia (seizures, tetany, hypotension or cardiac arrhythmias)
IV calcium
How manage chronic mild hypocalcemia
Oral calcium supplements +/- VD
How treat hypocalcemia with hypoparathyroidism
Calcium and VD supplements
Why need phosphorus
Bone formation, cellular energy metabolism, regulation of protein/enzyme function
Describe body distribution of phosphorus
85% bone rest in cells
1% ECF
2/3 organic phosphate
1/3 inorganic
What increases serum phosphate
Decrease by carbohydrate or glucose infusion
Increase by high phosphate meal
Effect of PTH on PO43
Decreases serum by increases renal excretion
FGF-23 effect on PO43
Decreases serum PO4 by increases renal excretion
1,25 (OH)2D3 effect on phosphorus
Increase serum PO4s..increases intestinal phosphate absorption
Insulin effect on phosphate
Decrease serum PO43..shirt phosphate into cells
What is FGF-23
Phosphatonin released by bone that promote PO43 excretion by the kidney…familial problems also can be secreted by tumor to cause phosphate wasting
The dietary intake is 900 mg/day
70kg man filters 200 molecules PO42 per day with 12.5 excreted int he urine
- contrast with 1% of filtered Na excreted in urine
- corresponds to 900 mg/day or 64% of dietary intake/day that needs to be laminated by kidneys
Becomes problematic when GFR falls
PhosphorusReabsorption..55-85% is reabsorbed in PCT
3 Na dependent PO43 transporters
NaPi2 is responsible for 85% transport, highly regulated
FGF-23 and PTH regulate
In the kidney phosphorus is regulated by what
PTH and FGF-23
Causes of hyperphosphatemia: decreases renal excretion of phosphorus
Chronic kidney disease stages 3-5
Acute renal failure/acute kidney injury
Hypoparathyroidism, pseudohypoparathyroidism
Acromegaly
Tumoral calcinosis
FGF-23 inactivating gene mutation
GALNT3 mutation with aberrant FGF-23 glycosylation
KLOTHO inactivating mutation with FGF-23 resistance
Bisphosphonatesc
Causes of hypophosphatemia:exogenous phosphorus administration
Ingestion of phosphate, phosphate-containing enemas
IV phosphate delivery
Redistribution of phosphorus : causes of hyperphosphatemia
Respiratoy acidosis/metabolism acidosis Tumor lysis syndrome Rhabdomylosis Hemolytic anemia Catabolic state
Causes of hyperphosphatemia: pseudohperphosphatemia
Hyperglobulinemia, hyperlipidemia, hemolysis, hyperbilirubinemia
Clinical features of hyperphosphatemia
Deposition of Calvclium in soft tissues and resultant fall in ECF ionized calcium
Calciphylaxis
Chronic hyperphosphatemia causes what
Renal osteodystrophy
How manage hyperphosphatemia
Acute-saline diuresis
End stage kidney disease-reduce dietary intake/intestinal absorption (phosphate binder)
Describe secondary hyperparathyroidism in CKD
CKD causes decreased 1,25 (OH)2D3 and increased phosphorus causing decreased calcium and increased FGF-23…increases PTH
Both FGF-23 and PTH are phosphatic
Renal osteodystrophy
Bone demineralization due to chronic kidney disease
Can cause bonejoint pain, bone deformation or fracture
What causes renal osteodystrophy
Hyperparathyroidism secondary to hyperphosphatemia…kidney is unable to excrete phosphate
Renal osteodystrophy combined with hypocalcemia
Kidney unable to activate vitamin D to calcitrion needed for Ca absorption from diet
Treat renal osteodystrophy
Ca/VD supplement
Restriction of dietary phosphate, use of phosphate binders
Hemodialysis/renal transplantation
China cal et (calcium sensitized drug, lowers PTH)
What may cause hypophosphatemia
Redistribution of extracellular phosphate into the intracellular space
Decrease in intestinal absorption of phosphate
Decrease in renal reabsorption of phosphate
Re-feeding hypophosphatemia
Can be cause of death in starving people/anorexics as hexokinase phosphorylation glucose taken into cells
Alcohol related hypophosphatemia
Tend to be malnourished so re feeding syndrome partially responsible
Diabetes mellitus hypophosphatemia
When treated with large doses of insulin
Urinary loss causing hypophosphatemia
Faccini
Oncogene osteomalacia causing hypophosphatemia
Tumor makin FGF23
Clinical signs of hypophosphatemia (occur only if total body phosphate depletion is present)
Muscular abnormalities-weak, rhabdomyolysis, impaired diaphragmatic function, respiratory failure, heart failure
Neurologic abnosmalities-paresthesia, confusion, stupor, dysarthria, seizures, and coma
Hemolysis and platelet dysfunction
Chronic hypophosphatemia-rickets, in kids, stromal Asia in adults
Manage moderate hyphosphatemia
Asymptomatic and requires no therapy except treatment of the underlying cause
Manage persistent hypophosphatemia
Oral phosphate
Manage severe hypophosphatemia
IV phosphate therapy espicially when associated with serious clinical manifestations
Hypophosphatemia patients frequently are also hypo____ and hypo__ and these disorders must also be corrected
Kalemic
Magnesemic
Describe distribution of Mg
50% mineralized in bone
49% intracellularly
10% ionized but has crucial role as cofactors in many biological processes such as ATPases, regulation of ion channels and translational processes
1% extracellular with 60% of that ionized , 30% bound albumin, 10% complexed with phosphatase
15% of Mg is reabsorbed in the PCT> how
Paracellular and follows Na
70% of Mg is reabsorbed in the TAL. How
Driven by the transepithelial gradient generated by Na K 2Cl cotransporter
10% of Mg is reabsorbed in DCT. How
Via TRPM6 channels
Why is Mg absorption unique
PCT not major site of reabsorption
Describe Mg reabsorption in DCT
Mg concentration same inside and outside, so electrical potential is primary driver of cellular Mg influx, intracellular shuttling is not well understood
Hormonal regulation is uncertain and thought to be indirect, EGF is only hormone identified thus far
_% of ICU patients have hypomagnesemia
60
What causes hypomagnesia in ICU patients
Decreased nutrition, diuretics, decreased albumin, aminoglycosides, decreased reabsorption (PPI)
Common causes of Mg defiency
Alcoholism, malabsorption, parenteral nutrition, PPI, familial hypomagnesia with secondary hypocalcemia
Increased losses
Redistribution -hungry bone syndrome
Clinical signs of hypomagnesia
Neuromuscular manifestations(weak, tremor, seizures, tetany, positive chvostek and trousseau (but think Ca first), nystagmus
CVD-T wave changes, U waves, prolonged QT and QU, repolarized alternans, premature ventricular contractions, v fib, monomorphic ventricular tachycardia, enhanced digitalis toxicity)
Metabolic-hypoK and Ca
Treat hypomagnesia
Oral or IV Mg
When is hypermagnesia seen
End stage renal disease
Massive intake..epsom salt
Magnesium infusion..administration to limit neuromuscular excitability in pregnant women with pre-ecclampsia/ecclampsia
Clinical signs of hypermagnesemia
<3.6 asymptomatic
- 8-7.2-nauseas flushing headache
- 2 to 12 somnolence, hypoca, absent DTR, hypotension, bradycardia
> 12 -muscle paralysis-flaccid
Treat hypermagnesemia
Normal renal function-stop administration and wait and/or add loop or thiazide diuretic
Reduced renal function -stop administration and wait and/or add loop thiazide diuretic then ADD SALINE
End stage kidney disease-dialysis
With hypertension why do expel feel better when not taking meds
Side effects
Risk of HTN
Family history Age Males Black Diabetes
Primary HTN
92%, no cause found, chronic and progressice, use drugs that lower BP but DONT treat underlying cause
Low renin
Normal renin
High renin
Secondary HTN
Primary cause identified, less, can be cured by treating cause
Causes of secondary HTN
Chronic kidney disease Renovascular OC Coarctation Primary aldosteronism Cushing
Calculate arterial pressure
COxperipheral resistance
Resistance formula
8nl/pir^4
N-viscosity
L length
R radius
Sympathetic baroreceptor reflex
Reflex circuit keeps arterial pressure at present level on a second by second basis
How does the sympathetic baroreceptor reflex “sense”
Stretch receptors located in the carotid sinus and aortic arch
What happens when sympathic baroreceptor reflex is opposed
Attempts to reduce arterial reassure with drugs
Innervated the heart and travel along the blood vessels, forming multiple synapses such that the nerves resemble a string of beads
A1 adrenergic receptor
On bc to cause vasoconstriction to maintain venous return with changes in posture
A2 adrenergic receptors
Act both in the brain and in the periphery in a presynaptic receptors act in both the brain and in their periphery in a presympathetic tone
B1 adrenergic receptors
Increase heart rate and contractility, and stimulate renin secretions by the kidneys
B2 adrenergic receptors
Dilate skeletal muscle vasculature
-important during fight or flight response with concomitant a1 receptor vasoconstriction blood shunted to msucles
What is the ultimate regulator of blood pressure
Renal blood volume, it is slow!
But keep in mine, high salt intake causes hormonal changes that shift the intrinsic renal relationship between arterial pressure and urinary output of Na to the left, low salt to the right
In HTN, the blood pressure set point is resent to a higher level, but can be either salt resistant or salt sensitive
Salt resistant, not changes in slope but increases
Salt sensitive, bo up in dose response
Drugs for lowering bp
Vascular smooth muscle
Vascular a1 receptors
Renal tubules (B1 juxtagloerular cells, angiotensin converting enzyme, angiotensin II receptors, aldosterone receptors)
Brainstem
Sympathetic ganglia
Adrenergic terminals
Cardiac B1 receptors
Hypertension drugs
Thiazide diuretics, ACEI or ARB, and CCB
Why are B blockersnow generally limited to other compelling indications
Do not prevent MI, heart failure, or death as well as other therapies
Associated with a significantly higher incidence of stroke than other therapies
Describe RAAS
Angiotensin I cleaved from angiotensinogen by renin is cleaved by angiotensin converting enzyme to form angiotensin II.
Effects and angiotensin II
Vasoconstrictor, increases total peripheral resistance
Acts to increase extracelllular fluid volume
- stimulating thirst
- stimulating aldosterone secretion
- stimulating ADH secretion
Why get increase in TPR in chronic hypertension
Follow an initial increase in cardiac output
In some cases TPR increase is initiating event
Why is hypertensive vascular remodeling reduced by ACEI or ARB and CCB
Idk
Lifestyle modifications for essential hypertension
Weight reduction
Na restriction
Alcohol restriction
Exercise
Smoking cessation
Maintence of K and Ca intake
Stress management
What drugs affect the angiotensin II formation or action
Aliskirin
ARBS
ACEI
How does RAAS inhibition effect kidney
Serum creatinine increases (preserves kidney function in hyperfiltering diabetics, can also alarm. Physicians)
Ang II tone helps maintain resistance in efferent arterioles
MOA captopril
Competitive inhibitor of ACE
Effects of captopril
Prevents conversion of angiotensin I to II
Lowers levels of angiotensin II
Increase renin and decrease aldosterone
Lowers bp
Clinical application captopril
Hypertension, add thiazide or loop diuretic if additional lowering is needed at max recommended dose
Acute HTN
HF with reduced ejection fraction
LV dysfunction following MI
Diabetic nephropathy
SE captopril
Cough
Angioedema
Hypotension
Headache
Enalapril
Another early ACEI, a prodrug with active form available for IV
Benzapril
ACE inhibitor, longer half life permitting 1 dose a day
Lisonopril
Now widely used ACE inhibitor, longer half life permitting 1 dose a day
What is the main reason to stop taking ACE inhibitor
Cough
Deadly side effect of ACE inhibitor
Angioedema can be deadly
CHOKE AND SWALLOW ON OWN TONGUE
Losartan MOA
Competitive nonpeptide angiotensin II receptor antagonist for AT1
Effects of losartan
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II
Induces a more complete inhibition of the renin angiotensin system than ACE inhibitors
Does not affect the response to bradykinin
Clinical applications of losartan
Treatment of diabetic nephropathy with increased Scr and proteinuria in type 2 diabetes and HT
HT, Akon or in combination with other antihypertensives
Hypertension with left ventricular hypertrophy to reduce risk of stroke
CKD and HT regardless of race or diabetes status, to improve kidney outcomes
Heart failure if intolerant of ACE inhibtiors
Off label Marian
SE losartan
More common in diabetic nephropathy
Hypotension, first dose hypotension, orthostatic hypotension
Fatigue, dizzy
Hypoglycemia, hyperkalemia
Diarrhea, gastritis, nausea, weight gain
Anemia
Weakness, back/knee
Cough
Valsartan
T1/2 6-10 hrs, noteworthy in that not a prodrug requiring activation, excreted primarily in feces as unchanged drug
Candesartal
T1/2 is 5-9 hrs, noteworthy for its relatively irreversible binding
Aliskiren MOA
Direct renin inhibitor, resulting in black of the conversion of angiotensinogen to angiotensin I
Effects aliskiren
Decreases the formation fo angiotensin II, a potent blood pressure elevating peptide elevating peptide viavasoconstriction, aldosterone release and Na retention
ACE inhibitor and ARB therapy can be offset by increases in plasma renin activity (PRA), which is blocked by direct renin inhibitors
Clinical applications aliskiren
Treatment of HTN alone or in combination with other antihypertensive agents
SE aliskiren
Few
Rash
Cough
Diarrhea
Rout of aliskiren
2 weeks see effects
T1/2=24hrs
What should new drug for HTN be based on
Age, race, Conor I’d conditions
Asthwhen should you not use a drug like B blocker like propranolol
Asthma B2 agonists are used for bronchodilator
Diabetes..B2 receptor effects offset hypoglycemia and alert patient via palpitations
When should you not use calcium channel blockers for HTN
Heart failure
Blacks health problems
HTN at earlier age
Average bp higher
Worse disease severity
More stroke, heart disease, and stage KIDNEY disease, heart failure
__, ___ and ___ are less effective as monotherapy than in whites but __ and ___ work well
B blockers, ACE inhibitors and ARBS
Diuretics , calcium channel blockers
B blockers, ace inhibitors and ARBS work well when added with a
Diuretic
Should be used first line combinations herapy if SBP>15 and DBP>10
Secondary HTN is more common in kids, what do
Identify cause and treat
Do not give _ or _ to sexually active girls
ACE inhibitors
ARBS
What can angII decrease cause
Efferent tone
Precipitate renal failure in patients with bilateral renal stenosis
Can help preserve renal function in diabetic patients
ACEI contraindication
Pregnancy
All trimesters
Manifestations of renal artery stenosis
Asymptomatic incidental RAS
Renovascular hypertension
Accelerated CV disease CHF, stroke, scndoary aldosteronism
Ischemic nephropathy
Appearance of what suggests bilateral renovascular hypertension rather than primary hypertension
Flash pulmonary edema, progressive renal failure, refractory congestive cardiac failure
Essential HTN vs renovascular HTN
Renovascular has more abdominal bruit, blood urea, potassium, duration, urinary casts and proteinuriia
Effect of bilateral renal stenosis
Reduced renal perfusion
Increase RAAS, impaired
Na and water excretion ->volume exmpasion inhibitors RAAS
Overall-reduced arterial pressure only after volume depletion may lower GFR
Detect with renin plasma
Unilateral renal artery stenosis block of RAS
Reduced arterial pressures
Enhanced lateralization of diagnostic tests
GFR fallelevated plasma renin
Systemic effects of increased renin due to stenosis
Vasoconstriction, Na retention, aldosterone secretion, vascular, sympathetic nervous system, Myocardial effects
How treat renal stenosis
Not surgery it fails to materially recover kidney function
Use drugs to block the RAAS and statin therapy
Red urine
Hematuria
Cloudy urine
Pyuria +/- bacteria
Beeturia
Rhubarb and blueberries
Green urine
Asparagus
Blue urine
Methylene blue in viagara
Yellow urine
Riboflavin (BIRGHT yellow)-can be used to turn it yellow if drinking a lot of water to pass a drug test
Defiency branched chain alpha keto acid dehydrogenase (BCKDC)
AR maple syrup I urine disease
Buildup of branched chain aa (leucine, isoleucine, valine) and their toxicity by products (ketoacidosis) in the blood and the urine unless dietary intake is carefully managed
Everyone has smelly pee after asparagus due to breakdown of sulfurous aa into volatile/odorous compounds
Only a fraction can smell
Woah
Sweet smell and taste or urine or see if it attract ants
DM
Smell of urine with UTI and/or kidney stones
Fishy
Specific gravity low urine (normal 1.01-1.025)
What does 1.025 mean
DI
Glomerulonephritis
Pyelonephritis
Can’t concentrate urine
Highly concentrated
Normal pH of urine
6 ——fixed acid is being excreted as ammonium
What does a negative reading for urine dipstick leukocytes indicate
A high power field likely has 3-5 neutrophils
Brown urine, dipstick positive for blood, no RBC visible by microscopy
MYOGLOBINURIA Intravascular hemolysis Nephrotic syndrome Urine contains a dye Nephrotic syndrome Analgesi nephropathy
Positive nitrate urine test?
Gram negative organism?
50 for urine ketones
Diabetic ketoacidosis
Bilirubin in urine
Liver disease
Urobilinogen in urine
Hemolytic disease
Protein over 1000 in urine
Nephrotic
Foamy urine suggesting protein but protein negative and sulfasalicylic acid test indicates presence of protein
Bcence Johnson protein in multiple myeloma
Urine over 100 mg/dL glucose
Filtered load of glucose is greater than PCT reabsorption capacity
Triple phosphate crystals (struvite) in either common form (coffin lid) or rapidly precipitated form, ammonium urate crystals
Calcium phosphate crystals
Amorphous phosphates
Urine infected with ammonia producing organisms
ALKALINE
System needs, tyrosine, and leucine in urine
Cystine crystals (hexagon) tyrosine cryastals (fine delicate needles), calcium oxalate crystals (enveloped), uric acid footballs), sodium irate, sulfonamide crystals (antibiotics), amorphous-specs(urate)
Acidic urine
Metabolic origin
Urine casts
Damage to the glomerular endothelial cells
Form when the tubule cells die and slough off
WBC casts form HTN there is tubulointerstitla nephritis
Tamm horsfall protein
Encase/lubricate junk in the tubular lumen to facilitate elimination
Keep distal tubules from collapsing if GFR ceases
Sop up waste products secreted by the proximal tubule that bind to protein so that my protein transporters and channels continue to function properly
The __ __ is the first fluid barrier found between the extracellular subcompartments with a one way lymphatic shunt returning interstitial fluid to the plasma
Capillary membrane
The __ __ is the seconda barrier to fluids, separating intracellular from extracellular fluids
Cell membrane
Fluid distribution between plasma, interstitial fluid and intracellular
IC>IS>plasma
Extracellular Iona
Na Cl HCO3
Intracellular ions
K, PO43 protein
The kidneys maintain the extracellular __ ion concentrations from which the cells of the body extract their needs
Small
Major sources of ions
Liver, lymphocytes
Gibbs-donnan equilibrium
Maintains cell volume constant
With protein inside the cell and na outside
Causes of extracellular edema:increased capillary hydrostatic pressure
Increased capillary hydrostatic pressure
Excess kidney retention of salt and water (acute or chronic kidney fail, mineralocorticoid excess)
High venous pressure (heart failure, venous obstruction , failure of venous pumps)
Decreased arteriolar resistance (excessive body heat, insuffiency of the sympathetic nervous system, vasodilator drugs)
Causes of extracellular edema : decreased plasma proteins
Loss of protein (nephrotic syndrome)
Loss of protein from denuded skin areas (burns, wounds)
Failure to produce proteins (liver disease, severe protein or caloric malnutrition)
Causes of extracellular edema : increased capillary permeability
Immune reactions that cause release of histamine, toxins, bacterial infections, vitamin defiency, espicially vitamin C, prolonged ischemia, burns
Causes of extracellular edema: blockage of lymph return
Cancer, infections(filariasis, nematodes), surgery, congenital absence or abnormality of lymphatic vessels
What prevents extracellular edema
Interstitial normally has low compliance
Lymph flow can increase 10-50 fold
Increased amounts of protein poor capillary fluid flow wash protein out from the interstitial space, decreasing net capillary filtration pressure
What are the two main causes of intracellular edema
Depression of metabolic systems of tissues
Lack of adequate nutrition to the cells
*cells lack the resources to drive the NaKATPase pump, so Na accumulates in cells and they expand and water follows sodium into the cells
Other causes of intracellular edema
Too little extracellular Na or too much water
What does high extracellular edema cause
Brain cell swell
Are water and Na regulated separately
Yup
Na content and concentration are not the same thing
Na content
Sensed by effective vascular volume, stretch receptors
AngII Aldo SNS ANF
H2O
Plasma osmolality
Osmoreceptors
ADH
RBF and GFR are ______ but urinary output of Na and H2) increases as __ increases
Autoregulated
MAP
Tubuloglomerular feedback of increased GFR and RBF
Increased delivery of solute to juxtaglomerular apparatus
Increased resistance of afferent arterioles
Decreased RBF and GFR
What happens to creatinine when GFR falls due to ACEI
Creatinine increases
This presernves kidney function in hyperfiltering diabetics can also alarm physicians
Glomerulotubular balance
Small increase in GFR dueto increased MAP, get increase Pc, ensuring that there is proportional reabsorption of filtrate. More is reabsorbed but more is also delivered to the thin limbs and more reaches the distal portions
With volume expansion, dilution of plasma proteins+ increased RBF leads to these changes in the peritubular capillary
Countercurrent multiplier
Create gradient of 2 across the transported is multiplied along the length of the transporter array due to countercurrent flow
In TAL to provide solute for the hypertonic renal medullary interstitial while simultaneously diluting the tubular fluid
Concentrated outflow
Generated hypertonic renal medullary interstitial
Dilute outflow
Neededfor the possible excretion of excess water
Vascular sensory for circulating volume
Vascular
Low pressure-cardiac atria, pulmonary vasculature
High pressure-carotid sinus, aortic arch, juxtaglomerular apparatus of kidneys
Hormones that effect PT where 67% of reabsorption occurs through NaH exchange, Na cotransport and organic solute, NaH CL anion exchange
Angiotensin II
NE
E
Hormones that regulate the late distal tubules and collecting duct which reabsorbed 3% of load with Na channels
Aldosterone
ANP
Low Na intake, hormones
Ability to retain na will become maxed out and arterial pressure then falls to a level where intake=output on the curve
High Na intakehoromones
Hormones minimal values and Na dumping hormones are a maximal values, and further increases in Na intake will cause arterial pressure to increase to a value where intake=output
What happens with increased ECF volume from increased Na intake
Decreased sympathetic activity, increased ANP, decreased pi, decreased RAAS
All leading to increased excretion of Na
What does decreased sympathic activity do
Dilation of afferent arterioles
Decreased Na reabsorption
What does increased ANP do
Constriction of efferent arterioles
Decreased Na reabsorption
What does decreased pi cause
Decreased Na reabsorption
What does decreased RAAS cause
Decreased reabsorption
Signs of hypovolemia
Decreased skin tumor Thirst Dry mucous membranes Sunken eyes Oliguria As worsens get tachycardia, hypotension, tachypnea, confusion
Signs of hypervolemic
Edema, bounding pulse
Relative hypovolemia
Decrease ECFV and increase in total body sodium
Renal causes of relative hypovolemia
Severe nephrotic syndrome
Renal causes of renal absolute hypovolemia
Diuretics, Na wasting tululopathies, genetic or acquired tubulointerstitila disease, Obstructive uropathy/postobstructive diuresis, hormone defiency, hypoaldosteronism, adrenal insuffiency
Causes of volume excess
Oliguric acute renal failure, acute glomerulonephritis, severe chronic renal failure, nephrotic, nephrotic syndrome, primary hyperaldosteronism, Cushing, liver disease, conn, gordon, Liddell
Hypernatremia levels
Plasma >145
Hyponatremia values
<135
Calculate plasma osmolality
2xNa in plasma
More accurate
2plasma Na+glucose in plasma/18+ BUN plasma/2,8
Normal plasma osmolality
285-295
Effect of vasopressin
Plasma osmolality up and blood pressure or volume decrease
What increased ADH
Increase plasma osmolality
Decrease blood volume
Decrease blood pressure
Nausea, hypoxia
Morphine, nicotine, cyclophosphamide
What Decreases ADH
Decreased plasma osmolality
Increased blood volume
Increased blood pressure
Alcohol, clonidine, haloperidol
What increases thirst
Increased osmolality
Decreased blood volume
Decreased blood pressure
Increased angiotensin II
Dry mouth
Decrease thirst
Decreased osmolality
Increased blood volume
Increased blood pressure
Decreased angiotensin II
Gastric distention
Response to drinking water and decrease in plasma osmolality
Inhibits osmoreceptors in anterior hypothalamus—THIRST decreased
Decrease ADH
Decrease H2O permeability in late distal tubule and CD
Decrease H2O reabsorption
Decrease urine osmolarity and increase volume
Increase plasma osmolarity toward normal
Response to water deprivation and increase in plasma osmolarity
Stimulates osmoreceptors in anterior hypo->increase thirst
Increase ADH from PP
Increase H2O permeability in late DT and CD
Increase H2O reabsorption
Increase urine osmolarity
Decrease urine vol
Decrease plasma osmolarity toward normal
Volume compartment lose na and H2O
Diarrhea
Lose volume from ECF
Body compartment: lost H2O
Water deprived
Lose volume os ICF and ECF
Increase osmolarity in ICF and ECF
Body compartment
Lost Na
Adrenal insuffiency
Lose volume ECF gain volume ECF lost osmolarity in ICF and ECF
Body comparemtn gain na and H2O
Infusion of isotonic NaCl
Gain volume in ECF
Body compartment gain Na
High NaCl intake
Increase volume ECF lose volume ICF
Gain osmolarity in ICF and ECF
Body compartment gain H20
SIADH
Gain volume ECF, ICF, lose osmolarity ICF and ECF
What is the most common electrolyte abnormality encountered in clinical practice
Hyponatremia
<135 mEq/L
In 15-20% of hospitalized patients!!!
What causes hyponatremia
CHF
Liver disease sepsis
Nephrotic syndrome
Prego
Drugs for euvolemic
SIADH
SALT LOSS hyponatremia symptoms
Stupor/coma Anorexia, nausea, vom Tendon reflexes decreased Limp muscles (weak Orthostatic hypotension Seizures/headache Stomach cramping
Treat minimal hyponatremia
Fluid restriction
Treat moderate symptoms of hyponatremia
Vaptans or hypertonic NaCl
Treat severe hyponatremia
Hypertonic NaCl
Normonatremia brain
NaKCli and H2O
Acute hyponatremia brain
NaKCl and INCREASED H2O
Chronic hyponatremia brain
NaKCL and H2O decrease
Osmotic demyelination
Increase na and decrease H2O
Calculate infusion rate for NaCl 3%
Ptweightxdesired correction rate
Overly rapid correction of hyponatremiacan cause what
Osmotic demyelination syndrome
Can do 2.5 mEq/L/hr in acute
In chonic .5?
Causes of SIADH
Desmopressin, oxytocin, NSAIDS, MDMA, tumors producing vasopressin , brain tumors, HIV, traumatic brain injury
Hypernatremia common in hospitalized?
1% associated with high mortality and morbidity in the elderly
See in people that live alone and fall
Indicator of neglect in nursing home
Ppl in desert
Causes of hypovolemia hypernatremia
Administration of hypertonic saline, hypertonic sodium bicarbonate
Hypertonic dialysis
Hypertonic feedings
Primary hyperaldosteronism
Cushing
Causes of euvolemic hypernatremia
Diabetes insipidus
Hypodipsia
Insensible dermal and skin loses
Causes if hypovolemia hypernatremia
Lack of access to water broken thirst MOA
Mnemonic for hypernatremia symptoms
TRIP
Twitching tremors, hyperreflexia
Restlessness, irritable, confusion
I intense thirst, dry mouth, decreased urine output
Pulmonary and peripheral and peripheral edema
Treat hypovolemia hypernatremia
Isotonic saline
Treat hypernatremia
Hypotonic IV solutions
Calculate water deficit
.6% body weightx (1-140/Na)
Why correct hypernatremia slowly
Will cause brain edema
Correct over 48 hours at .5mEq/L/hr
What keeps ion distribution between ICF and ECF
NaKATPase
Define hyperkalemia
> 5.3
Define hypokalemia
<3.7 mEq/L
High K
Cells stay refractory since Na channels are not deactivated
High T wave, prolonged PR interval, v fib
Low K effect
Hyperpolarized
Low T wave
High U wave low ST
What is the normal K range
3.5-5
Academia ICF and H and K
ICF takes in H
Low ECF pH<7,35
High H buffered by raising ECFK
Alkalemia ICF K and H
ICF donates H so ECF has ph>7.45
Low H, bufferented by lowering ECF K
How can too much K cause death
K into ECF could lead to fatal hyperkalemia if not for its rapid redistribution into the ICF; insulin is most important
K into ICF hormones
Enhance cell uptake
Insulin!!!!! B2 agonist Aldosterone defiency A blockers Alkalosis Hypoosmolarity
K into cell hormones
A agonist (NE, EPI) Insulin defiency Aldosterone B2 blockers Acidosis Hyperosmolarity Exercise Lysis
Aldosterone does what
Increase Na in
K out at principal cells of collecting duct
What enhances K secretion if normal or excess potassium
Plasma K Aldosterone ADH Acid base balance Tubular fluid flow rate
DISTAL NEPHRONNNN
Low levels of aldosterone
Limit Na permeability in distal nephron, and without Na influx, do not have K secretion/excretion
Increased Na delivery and increased flow rate
Combine to promote increased K secretion/excretion
Hypokalemia with what K levels
<3.5
Acid base balance normal with hypokalemia
Due to redistribution or extrearenal k losses
Acid base metabolic acidosis hypokalemia
With renal or extrarenal K loss
Hypokalemia metabolic alkalosis
Love K excretion
High Cl excretion
-BP normal diuretics
-BP high hyperaldosteronism
Hyperkalemia with what K level
> 5.5
Pseudohyperkalemia with hyperkalemia
Due to RBC cell lysis
Causes of hypokalemis
GRAPHIC IDEA
GI losses (vomit, diarrhea)
Renal tubular acidosis (types I and II)
Aldosterone
Paralysis
Hypothermia
Insulin excess
Cushing
Insufficient intake
Diuretics
Elevated beta adrenergic activity
Alkalosis
Signs and symptoms of hypokalemia
CNS-drowsi
Neuromuscular-weak skeletal and weak smooth (ileus and constipation)
CV-ventricular arrhythmias, hypotension, cardiac arrest
Renal-impaired concentrating ability causes polyuria and nocturnal
Metabolic?
Goals of treating hypokalemis
Prevent life threatening conditions
Replace K
Diagnose/correct underlying cause
Hyperkalemia causes RED FETS
Renal disease: ARF, CKD, type iV RTA
Excessive intake: food, K+IV fluids, blood transfusion
Drugs: K sparing diuretics, K salts of penicillin
Fictitious: prolonged use of tourniquet, hemolysis
Endocrine: Addison’s
Tissue release: rhabdomysis, burns, hemolysis, cytotoxic therapy
Shift out of cell: acidosis, B antagonist, insulin defiency, tissue damage
Cardiac signs of hyperkalemia
Abnormal heart rhythm, bradycardia, v fib, peaked T wave
Neuromuscular signs of hyperkalemia signs and symptoms
Numbnesss, weakness
Common causes of hyperkalemia: meds targeting RAAS
NSAIDS, COX2 inhibitors , aliskiren beta blockers
ACEI
ARBS
Spironolactone
Amiloride
Treat hyperkalemia
Antagonize cardiac effects (IV Calcium)
Redistribute K into cells (give insulin and glucose, B2 agonist such as albuterol)
Facilitate K elimination (administer K losing diuretic consider mineralocorticoid (if have hypoaldosteronsm , cation exchange resin, dialysis)
Pseudohyperkalemia
Hemolysis
Thrombocytopenia
Leukocytosis
Redistribution hyperkalemia
Acidosis. Decreased insulin B block Arginine infusion Digitalis overdose Periodic paralysis
Impaired renal K excretion
GFR<5 mL/mim oliganuria
> 20 impaired K secretion
-low or normal aldosterone
Low aldosterone
Addison disease
Hyporeniinemic
Drugs
High aldosterone
Primary tubular disorders
Drugs-spironolactone, amiloride, triamterene
UTI can result in what
Cystitis Prostatis Pyelonephritis Renal damage in young children Pre term birth Complications from frequent antibiotic use -antibiotic resistance, C diff
Asymptomatic UTI
Asymptomatic bacteriuria
UTI pathophysiology
Contamination of the periurethral area with a uropathogen from the gut
Colonization of the urethra and migration to the bladder
Colonization and invasion of the bladder, mediated by pili and adhesins
Neutrophil invasion
Bacterial multiplication and immune system subversion
Biofilm formation
Epithelial damage by bacterial toxins and proteases
Ascension to the kidneys
Colonization o the kidneys
Host tissue damage by bacterial toxins
Bacteraemia
Uncomplicated UTI
Acute cystitis or pyelonephritis
-likely in nonpregnant outpatient women without an atomic abnormalities or instrumentation of the urinary tract
Cystitis
Pyelonephritis
Complicated UTI
Compromised urinary tract or host defense
- urinary obstruction
- urinary retention caused by neurological disease
- immunosuppression
- renal failure
- renal transplantation
- pregnancy
- foreign bodies (calculi, indwelling catheters)
Inflammatory response in the bladder and __ accumulation int he catheter
Fibrinogen
Most common uncomplicated and complicated uTI pathogens
EPUC
Uropathogenic E. coli
UPEC
Biofilm like intracellular bacterial communities
Type 1 pili*, antigen 43, curli
P. Mirabilis
Produce urease
Calcium crystals and magnesium ammonium phosphate precipitates
Crystalline biofilm
P aeruginosa
Microcolony formation by changing hydrophobicity of P aeruginosa surface
Lectins, rhamnolipids
E faecalis
Fibrinogen
What are the types of UTI
Asymptomatic bacteriuria
Cystitis
Pyelonephritis
Complicated UTIprostatis
Symptoms ASB
None
Clinical presentation ASB
Urine screen unrelated to GU tract symptoms
Bacteriuria
Treat ASB
None
Cystitis symptoms
Dysuria, urinary frequency, urgency
Nocturia, hesitancy, suprapubic discomfort, gross hematuria
Clinical presentation cystitis
Likely a young, non pregnant female with above symptoms
Treat cystitis
Nitrofurantoin, TMP-SMX, fosfomycin
Oral beta lactam (amoxicillin, cefpodoxime, cefdinir, cefadroxil)
Fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin)
First line cystitis for gram + and - bacteria (P aeruginosa and proteus)
Nitrofurnation
MOA nitrofurnation
Not fully understood
Conversion of nitrofurantoin into highly reactive intermediates by bacterial reductase
Toxic intermediates react nonspecifically with many ribosomal proteins and disrupt synthesis of proteins, RNA, DNA, and metabolic processes
Pharmacokinetics nitrofurantoin
Metabolized and excreted so quickly that no systemic antibacterial action is acheived
Adverse reactions nitrofurnation
Anorexia, nausea, vomiting
Antagonizes nalidixic acid (synthetic quinolone antibiotic)
Contraindications nitrofurnation
Glucose 6 phosphate DH defiency
Antagonizes nalidixic acid (synthetic quinolone antibiotic)
Cystitis first line fosomycin for gram positive and negative bacteria MOA
CELl wall synthesis inhibitor
Inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine
Resistance for fosofomycin
Due to inadequate transport of drug into the cell
Pharmacokinetics fosfomycin
Only oral form approved in USA, oral bioavailability is 40%
AE fosfomycin
Limited (headache and diarrhea)
CE fosfomycin
Safe in pregnancy!
First line for cystitis
Nitrofurnation and fosfomycin
TMP-SMX
Can you take nitrofurantoin and fosfomycin is suspect early pyelonephritis
No doesn’t achieve adequate renal tissue levels
Why should TMP-SMX be avoided
If prevalence of resistance is known to exceed 20%
Second line cystitis oral beta lactam
Amoxicillin-aminopenicillin
Cefpodoxime-3rd generation cephalosporin
Cefdinir-3rd generation ceph
Cefadroxil-1st gen cephalosporin
Less effective than fluoroquinolones (more side effects) and TMP-SMX
Why are fluoroquinolones third line for cystitis
SE
Name fluoroquinolones
Ciprofloxacin
Levofloxacin
Ofloxacin
Moxifloxacin is NOT RECOMMENDED bc attains lower urinary levels than other fluoroquinolones
FDA warning fluoroquinolones
Disabling and potentially irreversible adverse effects of systemic fluoroquinolones outweighs their benefits in treating uncomplicated cystic
Tendinitis and tendon rupture
Peripheral neuropathy
CNS effects
Why not use ampicillin and amoxicillin to empirically treat cystitis
Resistance
Resistance to oral antibiotics is rare
Espicially among outpatients with uropathogenic E. coli
How treat cystitis if resistance is identified
Ertapenem (a car ape EM)
Ertapenem
As a class carbapenems have a wide spectrum with good activity against gram negatives (including p aeruginosa), gram positive, and anaerobes
Ertapenem specifically is insufficiently active against P aeruginosa
Symptoms of pyelonephritis
Unilateral back or flank pain, fever
Mild-low grade fever with or without lower back pain or costovertebral angle pain
Severe-high fever, rigors, nausea, vomiting, and flank andor loin pain
Development of bacteremia
Clinical presentation pyelonephritis
Fever (not present in cystitis), low back pain
May or may not have symptoms of cystitis
Treat pyelonephritis
Fluoroquinolones (ciprofloxacin, levofloxacin)
TMP-SMX, oral beta lactam, aztreonam
Fluoroquinolones for first line pyelonephritis
Ciprofloxacin or levofloxacin
Give for severe pyelonephritis or risk factors for resistance
-administered with parenteral broad spectrum antibiotic until susceptibility data is available
Aminoglycosides used are gentamicin and tobramycin
What are aminoglycosides gentamicin and tobramycin active against
Gram negative and P aeruginosa
MOA aminoglycosides gentamicin and tibramycin
Irreversible protein synthesis inhibitos, binds to 30s ribosomal subunit
Interference with the initiation complex of peptide formation
Misreading of mRNA leading to production of non functional proteins
Pharmacokinetics amioglycosides gentamicin and tobramycin
Cleared by kidneys
Adverse effects of aminoglycosides gentamicin and tibramycin
8th CN toxicity: vertigo, hearing loss
Renal toxicity
Neuromuscular blockade
Second line for pyelonephritis
TMP SMX, oral beta lactams, aztreonam
When use TMP SMX , oral beta lactams, or aztreonam for pyelonephritis
Fluoroquinolone patient hypersensitivity or fluoroquinolone resistance
Name oral beta lactams
Amoxicillin cefpodoxime
Cefdinir
Cefadroxil
What give to pyelonephritis if patient cant tolerate TMP SMX or oral beta lactams
Aztreonam
Aztrenonam second line pyelonephritis
Monobactam, monocyclic beta lactam ring
What does aztreonam work against
Activity against aerobic gram negatives (P aeruginosa)
Why can aztreonam be used in patients with penicillin hypersensitivity
Little cross reactivity with bicycling beta lactams
MOA aztreonam
Cell wall synthesis inhibitor, transpeptidase inhibitor
Pharmacokinetics aztreonam
IV formulation, 1-2 hour half life, prolonged in renal failure
Adverse effects aztreonam
Limited, neutropenia (children 3-11%) , pain at injection (children 12%)
Complicated UTI symptoms
Similar to uncomplicated cystitis and pyelonephritis
Can by cystic, pyelonephritis or both
Clinical presentation complicated UTI
Severe dysuria
70-80% of all complicated UTI are due to an indwelling catheter
Treat complicated UTI
Organisms causing complicated UTIs are more likely to be resistant to commonly used oral agents recommended for empiric treatment of uncomplicated cystitis
Cystitis
Ciprofloxacin or levofloxacin
Pyelonephritis (mild)
Ceftriaxone, ciprofloxacin, levofloxacin or azteronam
Pyelonephritis severe
Beta lactam and beta lactamase inhibitor or a carabapenem
First line for complicated cystitis fluoroquinolones
Ciprofloxacin or levofloxacin
Covers p aeruginosa
MOXIFLOXACIN is not recommended
-attains lower urinary levels than other fluoroquinolones
How treat complicated cystitis with presence of gram + cocci on gram stain suggests enterococci UTI (E faecalis, E faecium)
Mpicillin or amoxicillin
Poor empiric choices due to high precenalnce of resistance
Nitrofurantoin
TMP SMX
Fosfomycin
Oral beta lactams (amoxicillin, cefpodoxime, cefdinir, cefadroxil)
Use these drugs only is uropathogenic is known to be susceptible
Phenazopyridine
Urinary analgesic with unknown mechanism, can cause significant nausea
Colors urine orange/red
First line for complicated (mild ) pyelonephritis
Ceftriaxone,
ciprofloxacin or levofloxacin
- covers P aeruginosa
- moxifloxacin is NOT recommended
- attains lower urinary levels than other fluoroquinolones
Aztreonam
Ascomplicated pyelonephritis first line severe
Cefepime
Piperacillin+ tazobactam
-if P aeruginosa suspected a higher dose can be used
Ceftolozane+tazobactam
Ceftazidime+avibactam
Meropenem
-if p aeruginosa suspected a higher dose can be used
Imipenem
Doripenem
Tazobactam and avibactam
B lactamase inhibtiors
How are b lactamase inhibitors given
Piperacillin+tazobactam
Ceftolozane+tazobactam
Ceftazidime+avibactam
What determines tha antibacterial spectrum of b lactamase inhibtiors : tazobactam and avibactam
By companion beta lactam
MOA tazobactam and avibactam
Resemble B lactam molecules, very weak antibacterial action
Protect hydrolysable B lactams from inactivation by these enzymes
Good inhibtors of amber class A B-lactamase -these b lactamase are produced by staphylococci, H influenzae, N gonorrhea, salmonella, shigella, E. coli* and K pneumoniae*
Poor inhibtiors of class C b lactamase -these B lactamase are produced by enterobacter app, citrobacter spp, S marcescens, and P aeruginosa
Adverse effects tazobactam and avibactam
Limited (<10%), diarrhea, constipation, vomiting, skin rash
Bacteria that can cause complicated UTI
E. coli, K pneumoniae, enterobacter, P aeruginosa
Name carbapenems for complicated pyelonephritis first line
Imipenem, doripenem, meropenem, ertapenem (resistant cystitis)
What are carbapenems good against
Wide spectrum with good activity against gram negatives (including p aeruginosa), gram positives, and anaerobes
- doripenem and meropenem have greater activity against gram negatives and slightly less activity against gram positives
- ertapenem insufficiently active against P aeruginosa
Carbapenems are resistant to ___
B lactamases
MOA carbapenems
Inhibit transpeptidase, similar to penicillins and cephalosporins
Imipenem pharmacokinetics
Metabolized by dihydropeptiase in kidney
Doripenem, meropenem, ertapenem
Not metabolized by dihydropeptidase
of the carbapenems, ___has the longest half life ( 4 hours), administered with lidocaine to reduce irritation after intramuscular injection
Ertapenem
Adverse effects imipenem (more common)
Nausea, vomiting, diarrhea, skin rashes, infusion site reactions, seizures
Doripenem, meropenem, ertapenem AE
Less likely to cause seizures
Complicated pyelonephritis (severe) first line b lactams
Piperacillin-anti-pseudomonas penicillin
Ceftazidime-3rd gen cephalosporincefepime-4th gen cephalosporin
Ceftolozane-5th gen ceph
Which b lactams are given in combo with a b lactamase inhibtor to extend the spectrum
Piperacillin
Ceftazidime
Ceftolozane
MOA b lactams
Cell wall synthesis inhibitors, bind and inhibit transpeptidase
AE complicated pyelonephritis b lactams
B lactam hypersensitivity
Prostatic pathogen
E. coli (most), proteus, P aeruginosa
Enterobacteriaceae including klebsiella, enterobacter, and seratia spp
Symptoms prostatis
Fever, chills, malaise, myalgia, dysuria, lower urinary tract symptoms (frequency, urgency, urge incontinence), pelvic of perineal pain and cloudy urine
Clinical presentation prostatis
Patient is acutely ill with spiking fever, possible complaint of pain
During the exam, a prostate will be warm, firm, edematous and tender
Treat prostatis
TMP SMX
Ciprofloxacin
Levofloxacin
Post streptococcal glomerulonephritis
Most common cause of acute nephritis in kids
-97% of cases occur in regions with poor ppl
Caused by prior infection with group A beta hemolytic strep(gram+)
Clinical presentation post strep glomerulonephritis
Asymptomatic, microscopic hematuria
Acute nephritic syndrome (red/brown urine, proteinuria, edema, HTN, elevation in serum creatinine)
Treat post strep glomerulonephritis
Management-loop diuretic, anti HTN agent, dialysis
Recurrent group A beta hemolytic strep infection
-antibiotics
Treat recurrent strep
With agents greater B lactamase stability
Penicillin G
-IM injection if adherence to previous antibiotic uncertain
Cephalexin or cefadroxil
-1st gen cephalosporins
Cefpodoxime or cefdinir
-3rd gen cephalosporins
Amoxicillin or clindamycin
What is clindamycin effective against
Streptococci, staphylococci, and pneumococci
- enterococci and gram negative aerobes resistant
- very effective against anaerobes
MOA clindamycin
Protein synthesis inhibitor, binds 50S ribosomal subunit
Pharmacokinetics clindamycin
Penetrates most tissue (not brain and CSF)
Metabolized in the liver and excreted int he urine
AE clindamycin
Diarrhea, nausea, skin rashes
Risk factor for C diff induced diarrhea and colitis
-GI filled with anaerobes
Case questions
Ok
Benign prostatic hyperplasia causes bladder outlet ___
Obstruction
Lower urinary tract symptoms
Interrupted stream, frequency, hesitation, fullness, dribbling, urgency, weak stream
Moxafloxacin
Don’t pick it-doesn’t go into urine
A1 adrenergic receptor antagonists for BPH
Terazosin, doxazosin, tamsulosin, silodosin, alfuzosin
What do a1 adrenergic receptors do
Relax muscle tone
Rapid relief of symptoms
A1>a1 for blood vessels vascular resistance
B
A
What does prostate smooth muscle contraction
A1A
Detruser receptor for instability
A1D>a1A
Spinal cord
Control of urinary function
A1D
Stimulation of __ receptors mediates lower urinary tract symptoms
A1
A1 receptors +NE
Muscle contraction
Bladder outlet obstruction
A1D receptors and NE
Detruser instability
A1 antagonists compete with NE
Reduce spasm
Promote muscle relaxation
Improve urine flow
Terazosin and doxasin specificity
A1»a2
Take 1 hours prior
Terazosin and doxazosin uroselective
No
AE terazosin and doxazosin
Postural hypotension, dizziness fatigue
Terazosin and doxazosin drug interactions
PDE-5 inhibitors (sildenafil, vardenafil)
Tamulosin and silodosin specificity
A1a=a1D>a1B
Tamsulosin and silodosin uroselective
Yes
A1a-a1D
AE tamsulosin and silodosin
Reduced ejactulation, IFIS
Drug interactions tamulosin and silodosin
PDE inhibitors (sildenafil, vardenafil)
Increase concentration of CYP3A4
Alfuzosin specificity
Non specific
A1 selective
Alfuzosin uroselective
Yes (functional)
AE alfuzosin AE
QT prolongation
Drug interactions alfuzosin
PDE-5 inhibitors (sildenafil, vardenafil)
Increase concentration of CYP 3A4 substrates
Clinical summary of a1 adrenergic receptor antagonists
- best monotherapy for prompt relief of symptoms (days)
- all have comparable clinicalefficacy
- alfuzosin has functional uroselectivity
- distributes into the prostate>serum
- avoid in hepatic impairment
- take immediately after the same meal every day
Tamsulosin-FDA approved as generic
Steroid 5a reductase inhibitors
Finasteride, dutasteride
Prevents enlargement and shrinks prostate
Delayed action
-shrinkage takes 3-6 months
Why does the prostate enlarge
Aging+dihydrotestosterone
Steroid 5a reductase inhibitors blunt prostate enlargement
Ok
What enables prostate epithelium survival and growth
Androgenic steroids, testosterone, and DHT
__ is 10times more potent than its precursor
DHT
_____ coverts serum T to DHT in cells
Steroid 5a reductase type 1 and type 2
A hyperplastic prostate has excess ___
SAR-2
DHT starvation causes what
Epithelial atrophy, shrinkage, and gradual relief of LUTS
Direct effects of steroid 5a reductase inhibitors
T accumulation
DHT depletion
Indirect effects of steroid 5a reductase inhibitors
Androgen receptor less occupied
No gene transcription
Finasteride
Specific inhibitors SAR2
Dunasteride
Dual inhibitorSAR1 and 2
Finasteride
Selectivity, SAR in BPH, prostate DHT, PSA, serum T, serum DHT
SAR2
SAR2»1
90% decreased
PSA 50% decreased
15-20% increased
70% decreased
Dutasteride
Selectivity, SAR in BPH, prostate DHT, PSA, serum T, serum DHT
SAR 1 and 2
SAR2»1
90% decreased
50% decreased
15-20% increased
90% decreased
Clinical summary of finasteride and dutasteride
Take 3 months for measurable effect to be observed
Have similar efficacy
- improved LUTS
- reduced prostate volume and reduced serum PSA
- reduced need for surgery
Have similar AE
- erectile dysfunction
- gynecomastia
- depressed libido
- ejaculation disturbance
No dosage adjustment necessary for:
Age, renal insuffiency
No established clinically significant drug interactions
Use caution with liver abnormalities
-metabolized by hepatic CYP3A
Combination therapy:
A1 adrenergic antagonist+5a reductase inhibitor.
For severe symptoms of BPH, known to have large prostate, no response from monotherapy
Long term combination therapy significant improves patient symptoms versus either drug alone
BPH treat
PDE-5 inhibtors tadalafil
-for patients with both BPH and ED
ED
Consistent or recurrent inability to acquire or sustain an erection of sufficient regidity and duration for sexual intercourse
Risk factors for ED
Obesity, smoking, stress, CVD, adverse drug effect (diuretics, antidepressants SSRI)
Physiology of penile erection
Blood flows into corpora cavernous and corpus spongiosum (glans penis)
NO facilitates smooth msucle relaxation
- maximize blood flow
- penile engorgement
Relaxed smooth muscle leads to blood in sinusoids and a rigid organ
What does NO lead to
Increase in cGMP, decreases in iCa, smooth muscle relaxation and erection
What do PDE-5 inhibitors do
Competitive inhibitors of the PDE-5 enzyme
Sildenafil onset, duration, stomach contents, t1/2, clearance
Take 1 hour prior, 4 hours, empty, 4, hepatic CYP3A4
Vardenafil onset, duration, stomach contents, t1/2, clearance
Take 1 hour prior, 4-5 hours, empty, 4, hepatic CYP3A4
Tadalafil onset, duration, stomach contents, t1/2, clearance
Take 1 hour prior, 36 hours(1 weekend), doesn’t matter, 18, hepatic CYP3A4
Avanafil onset , duration, stomach contents, t1/2, clearance
Take 15 min prior (high dose)**
Take 30 min prior (normal dose)
4 hours, doesn’t matter, 4 hours, hepatic CYP3A4
PDE-5 inhibtors have high specificity for the
PDE-5 enzymes
Adverse effects of sildenafil, vardenafil, and avanafil
Blue vision and blurred vision
PDE-5 1 fold in corpus cavernosum
PDE-6 10 fold in retina
PDE-1 80 fold
Vasculature, heart, brain
But little significance
PDE-11 800 fold pituitary, testes, heart
Negligible
Side effects PDE-5 inhibitors
Reasonably well tolerated
PDE-5
SE PDE-5 inhibitors
Well tolerated
PDE-5 related
-headache, dyspepsia, nasal congestion
PDE-6 related (sildenafil, vardenafil, and avanafil)
-blurred blue vision
Specific to tadalafil
-back pain, myalgia, limb pain
Contraindications PDE-5 inhibitors
- organic nitrates
- extreme and dangerous
Specific to vardenafil
-patient needs to be hemodynamically stable
Specific to tadalafil
-when used for BPH, concurrent a1 blockers not recommended
Specific to sildenafil
-concurrent a blockers initiated at lowest recommended dose
Second line ED theapies
Vacuum erection devices
-try first, l,ess expensive and non invasive
Penile injections with alprostadil
-prostagladin E1
MOA alprostadil
Leads to increase in cAMP, decreases in iCa, smooth muscle relaxation, and erection
Adverse effects alprostadil
Prolonged erection (priapism)-medical emergency, need to evacuate clogged blood
- can result in permanent corporal fibrosis and ED
- 6% of men using intrapenile alprostadil injection (can also occur with PDE-5 inhibitors )
Treat priapism from alprostadil
Sympathomimetic (phenylephrine)+aspiration
Nephrin thick wall vs thin wall transport
Thick active
Thin passive
Faconi
PCT
Filtered glucose, aa, uric acid, phosphate, and bicarbonate are passed into the urine instead of being absorbed
Not considered to be a defect in a specific channel, but a more general defect in the function of the proximal tubules
Clinical features faconi
Polyuria, polydipsia, hypovolemia Hypophosphatemia rickets Growth failure Type 2 renal tubular acidosis Hypokalemia Hyperchloremia Hypophosphatemia/phosphaturia Glycosuria -recall this also can be caused by the sodium glucose co transporter 2 SGlT2 inhibtors (the gliflozins such as canaglofloxin) -proteinuria/aminoaciduria -hyperuricosuria
Treat faconi
Treat underlying causes
Replace substances water in the urine
- HCO3 (can use citrate), phosphate+vitamin D to promote bone growth
- if genetic causes, minimize intake of substance that is not handled properly (cysteine, tyrosine, galactose, copper)
Inherited salt losing renal tubulopathies
Bartter syndrome type I
Bartter syndrome type II
Barter syndrome III
Bartter syndrome type IV
Bartter syndrome IVB
Bartter syndrome type V
Gitelman Syndrome
Bartter
Concentrating capacity reduced and diluting capacity reduced
Gitelman
Concentrating capacity normal.near normal and diluting capacity reduced
Barter syndrome
Dysfunction inNKCC2 , ROMK, CLC-kB ,CLC-Ka
Classic bartter type 3
CLCNKB gene
Defect in Cl channel
Inheritance bartter
AR
Rare
Presents in childhood
Neonatal bartter
Seen 24-30 weeksof gestation as polyhydramnios;polyuria/polydipsia with hypercalcuria after birth
Classic bartter
No noticeable symptoms until school agi
- polyuria/polydipsia
- vomiting, growth retardation
Symptoms of bartter are identical to those taking what
Loop diuretics
Treat barrett
Life long increases in dietary Na and K and K sparing diuretics to limit K loss
-also PGE2 directly stimulates renin release from juxtaglomerular cells and contributes to the electrolyte abnormalities that are seen in bartter syndrome..NSAIDS can help correct this
Symptoms of bartter (like loop diuretics)
Normal to low BP
Polyuria/polydipsia
Elevated plasma renin and aldosterone
Hypokalemia
Hyponatremia
Hypocalcemia
Hypomagnesia
Hypochloremic alkalosis
Hyperglycemia
Hyperuricemia
Increased cholesterol and triglycerides
ISOTONIC URINE
Gitelman syndrome
Defect in. NaCl symporter-defective in gitelman syndrome
Inheritance Gitelman
AR less rare than bartter
Mutations in the gene coding for the thiazide sensitive NaCl cotransporter in distal tube
Presentation gitelman
Late childhood or adulthood, may be more severe in females
Mimics chronic use of thiazide diuretics
May get htn at later stage
Symptoms gitelman
Polyuria/polydipsia Hypokalemia Hyponatremia Hypercalcemia Hypomagnesemia Hypochloremic metabolic alkalosis Hyperglycemia Hyperuricemia Increased cholesterol and triglycerides
And can DILUTE OR CONCENTRATE URINE
Treat gitelman syndrome
Life long
Cornerstone is taking NaCL to avoid sodium depletion (which would increase Aldo) and providing supplementation of K and Mg
-but supplementation->side effects
Aim for asymptomatic stable hypokalemia and borderline hypomagnesemia
-an aldosterone antagonist can stabilize the hypokalemia, but it competes with compensatory secondary hyperaldosteronism
NSAIDS are ineffective in gitelman syndrome (defect is downstream from macula densa)
Gitelman is more __ than bartter
Benign
Diagnosis bartter or gitelman
Exclusion
Made in someone who presented with unexplained hypokalemia and metabolic alkalosis with a moral or low bp
Urine in bartter and gitelman
Gitelman-dilute
Bartter-isotonic
Calcemia/calciuria in bartter and gitelman
Bartter-hypocalcemia/hypercalciuria, opposite of gitelman
In bartter/gitelman urine __ concentration is typically greater than 25 mEq/L despite volume contraction
Chloride
Patients who secretively take diuretics have a variable urine chloride concentration correlations with or without diuretic effect..so a urine diuretic screen should be obtained
Failure to respond to loop or thiazide diuretics appropriately can aid in diagnosis of _ and _, respectively
Bartter
Gitelman
Liddle syndrome
ENaC channel doesn’t degrade properly
Inheritance liddle (pseudoaldosteronism)
Rare AD
Mutation changes ENaC Chen also so that they are not degraded correctly by ubiquitin proteasome system->increased Na reabsorption with K loss
—early and often severe hypertension associated with
-low plasma renin activity, low aldosterone
-metabolic alkalosis
-hypokalemia
Treat liddle
Low Na diet and K sparing diuretics
Pseudohypoaldosteronism
Caused by a failure of response to aldosterone, leading to renal tubular acidosis and hyperkalemialevevls of aldosterone are actually elevated due to a lack of feedback inhibition
Therapy pseudohypoaldosteronism
Large amounts of Na
Renal tubular acidosis
Due to unmeasured anions (anion gap)
Normal 8-16 mEq/L
Type 2 renal tubular acidosis
Renal loss of HCO3(cant reabsorbed)
Normal anion gap
Hyperchloremia
Type 1 renal tubular acidosis
Decrease excretion of H as titratable acid and HN4
Decrease ability to acidity urine
Normal anion gap
Type 4 renal tubular acidosis
Hypoaldosteronism
Decreased excretion of NH4
Hyperkalemia inhibits NH3 synthesis
Normal anion gap
Renal tubular acidosis
Acidemia, normal anion gap, normal serum creatinine, no diarrhea
Type 1 renal tubular acidosis
Distal
Impaired H secretion
<15 HCO3
Urine pH>5.5
Low K
Autoimmune disorder related
Severe
Renal tubular acidosis 2
Proximal tubule
Impaired proximal HCO3 reabsorption
Plasma HCO3 12-20
Ph urine under 5.5, over 7 when give alkali therapy
Los plasma K
Related to faconi, multiple myeloma, drugs
RTA3
Combo of 1 and 2, very rare genetic form (carbonic anhydrase II defiency)
RTA4
ADRENAL
Hyperkalemia
Lack of Aldo or failure of kidney to respond to it
Plasma HCO3>17
Urine pH <5.5
High plasma K
Related to diabetic nephropathy, drugs (ACEI, ARB, heparin, NSAIDS)
Normal anion
Renal tubular acidosis
Accumulation of acid in the body due to a failure if the kidneys to properly acidity the urine
Type 1 RTA
H secretion by a intercalated cells is somehow impaired
Recall this is how new HCO3 is generated to maintain acid base homeostasis
Phosphate and ammonia buffer this H
Treat renal tubular acidosis type 1 (major consequence is low blood K, leading to extreme weakness, irregular heartbeat, paralysis)
Untreated->growth retardation in kids, progressive kidney and bone disease in adults
Restore normal growth and preventing kidney stones are the major goals of therapy
- sodium bicarbonate or sodium citrate to treat acidosis (1-2 mEq/kg/day)
- > correction of low k, salt depletion and Ca leakage..without Ca leakage, also decrease kidney stone development
Type 2 RTA
HCO3, the major buffer in the body, is among the good stuff normally reclaimed by the proximal tubules
Treat renal tubular acidosis type 2 (PT HCO3 wasting, very rare, often part of faconi)
Identify the correcting the underlying causes of acquired forms of proximal RTA
Children with this disorder would likely receive large doses of potassium citrate, and oral alkali (10-15 mEq/kg/day)
- correcting acidosis and low potassium levels restores normal growth patterns, allowing bone to mature while preventing further renal disease
- vitamin D supplements may also be needed to help prevent bone problems
Type 4 RTA
Low Aldo
High K
Low NH3 synthesis by pT
Recall how new HCO3 is generated by having NH3 accept H->NH4 to maintain acid base homeostasis
Treat renal tubular acidosis
Type 4 (most common; hyperkalemia from no Aldo or failure to respond to it)
- patients may require alkaline agents to correct acidosis, but therapy is aimed primarily at reducing serum K
- low K diet and a loop diuretic
- alter drug doses and/or change drugs (spironolactone, ACE inhibitors, angiotensin receptor blockers, NSAIDS)
