Exam 1 (Lectures 2-12) Flashcards

Question

What's the mechanism of action, drug target, and toxicities of: Na+-K+-2Ck- symport inhibitors

Answer 1

**loop diuretics, high-ceiling diuretics** MOA: Block the Na+-K+-2Cl- symport, thus blocking Na+, K+, and Cl- from getting through the cell to be reabsorbed. Site: Ascending limb of loop of henle Toxicities: - Hyperuricemia - Hypomagnesemia: Blocking Na+ and K+ also messes with Ca2+ and Mg2+ being able to cross into the interstitial space, thus leading to hypomagnesemia. - Hypokalemic metabolic alkalosis: Due to the K+ not leaving the lumen, the blood gets more basic. - Ototoxicity - Dehydration Ex. Furosemide, Bumetanide, Ethacrynic acid, Torsemide

Answer 2

**thiazides** MOA: Block the Na+-Cl- symport, thus making NA+ unable to get reabsorbed. Site: Distal convoluted tubule Toxicities: - Hypokalemia metabolic alkalosis: Blocking Na+ from getting into cell also stops K+ from getting out of the cell, so more K+ gets excreted, leading to hypokalemia and causing the cell to be more basic. - Hyponatremia - Hyperlipidemia - Hyperuricemia - Impaired carbohydrate tolerance Ex. Thiazides, Chlorthalidone, Indapamide, Metolazone

Answer 3

**K+ sparing** MOA: blocks Na+ channels so that Na+ cannot get into the interstitial space for reabsorption. Site: Late distal tubule & collecting duct Toxicities: - Hyperkalemia: Due to Na+ not leaving the lumen, K+ isn't transported to the lumen, leaving more K+ to be reabsorbed?? - Hyperchloremic metabolic acidosis: Bicarbonate is affected, leading to less of the buffer in the blood, leading to acidosis. Ex. Amloride, Triamterene

Answer 4

**aldosterone antagonists, K+-sparing diuretics** MOA: Block the mineralocorticoid receptor, which blocks aldosterone induced protein production, meaning Na+ channels don't get made. Site: In the cell in late DCT and collecting duct. Toxicities: - Hyperkalemia: Na+ not being pumped out, so K+ not being pumped in?? - Hyperchloremic metabolic acidosis - Gynecomastia - Impotence - Benign prostatic hyperplasia Ex. Spironolactone, Eplerenone, Canrenone, Potassium canrenoate

Answer 5

MOA: Block the channels that let ions in, thus reducing the amount of Na+ that is able to be reabsorbed Site: Lumen anywhere with CNGCs Ex. Nesiritide (Natrecor)

Answer 6

MOA: Block vasopressin from binding to V2 receptors, thus blocking the phosphorylation of aquaporins, which inhibits their ability to relocate to the collecting duct to allow water to pass. (Keeps water in the lumen) Site: Collecting duct Ex. Conivaptam, Tolvaptam

Answer 7

- Site of action is in the lumen (except MRAs) - CA inhibitors, furosemide, and thiazides are highly bound to plasma protein, so they are secreted, not filtered. - Secretion is saturable, so increased doses won't increase the effect, it's most likely better to increase frequency of dose instead - Braking phenomenon: More drug is needed to have the same effect. - CHF decreases efficacy, CRF decreases potency

Answer 8

Serum Creatinine - Mainly removed by filtration in glomerulus, so if there's an increase in SCr, it means the kidneys are messed up. BUN (Blood Urea Nitrogen) - This is a measure of waster from the liver's breakdown of amino acids, so if there's an increase, it means we aren't excreting enough waster from the kidneys. Creatine Clearance - Used to predict secretion and drug clearance (used for dosing). GFR (Glomerular Filtration Rate) - Measures how quickly filtrate is being made in the glomerulus.

Answer 9

We lose nephrons as we get older, so our single-nephron GFR gradually goes up to compensate that, but the total GFR still goes down. Eventually, around age 70-75, there will be a compensatory effect in which the nephrons increase in capacity and filter things really fast, but that can't last for very long. This hypertrophy leads to sclerosis and more loss of nephrons, leading to death.

Answer 10

Uremia - The accumulation of organic waste products that are normally cleared by the kidneys. There are lots of signs and symptoms of uremia; ex. proteins and nucleosides in the urine. Glomerulonephritis - Inflammation of glomerulus. Can be acute or chronic. Primary cause is due to Alport syndrome, but it can also be caused by drugs. Pyelonephritis - Inflammation of kidney tissues due to bacteria in the blood or urinary tract. This may lead to sepsis if untreated. Interstitial Nephritis - Autoimmune response that reduces the kidney's ability to filter. A primary injury to the renal tubules results in edema in the interstitium. Mostly caused by drugs (antibiotics, esp. penicillins). Nephrolithiasis - Kidney stones formed due to supersaturation of solutes like calcium. When the solute doesn't get reabsorbed, they start to crystallize. We usually want these patients to drink lots of fluid and we will treat their pain. Contrast-induced nephropathy - Seen when SCr increases after patient uses contract media. This causes 1/3 of hospital-acquired AKI. We try to hydrate the patient to avoid this and we try to avoid concurrrent nephrotoxins.

Answer 11

Both involves issues with filtration in the glomerulus by compromising the membrane. Nephritic - Inflammation disruption glomerular basement membrane, leading to blood cells in the urine. Nephrotic - Spillage of protein into the urine, generally caused by compromising the podocyte layer. - We will see a decrease in the serum albumin, which keeps the appropriate osmotic gradient in the body, so water spills out of blood, causing edema.

Answer 12

1. Antibody-associated injury - Antibodies circulate in body, they engage the glomerulus, the membrane rejects these large antibodies, which results in the activation of the immune system (T cells), leading to a cascade that eventually causes inflammation of the glomerulus. 2. Cell-mediated immune - Damage to the membrane causes a change of shape and function of the podocytes. Now we have lost the ability to filter across the membrane. 3. Other - Involves toxic agents that cause damage to cells in the nephron, leading to cell death. Necrosis in particular leads to a lot of inflammation (cascade). DAMPs and PRRs recruit immune cells that release toxic factors. (Because of this, we may treat it with immunosuppressants to try to stop this pathway).

Answer 13

Autosomal dominant - Intially have resonably good renal function, but cysts grow as person gets older, which leads to HTN due to lack of filtering. When the person is in 40-50s, we will start seeing lack of renal function. Transplantation is necessary. Autosomal recessive - The cysts form very quickly. These patients usually make it past 2-3 years old.

Answer 14

Diabetes mellitus - Glucose is big and sticky, which makes the blood very viscous. The kidney has a lot of intricate vasculature, so the blood with glucose messes with the filtering. Hypertension - Messes with the pressure that is going into the glomerulus. Glomerulonephritis - Inflammation messes with the intricate vasculature of the kidney.

Answer 15

- It's a good predictor of GRF and it's easy to use - It's only accurate in pts with stable kidney function (includes CKD because the decline is steady) - With declining kidney function, the CrCL will appear to be higher than it actually is due to secretion - CrCL is used for dosing stuff, whereas GRF is used for staging

Answer 16

1. Excrete waste products of metabolism from the blood (ex. urea, ammonia, bilirubin, uric acid, etc.) - Complication: Uremia - Build up of waste products in the blood (presents like the flu) 2. Regulate body's conc. of water and salt - Complication: Fluid retention - Edema, fluid overload, CV complications due to HTN 3. Maintain acid balance of plasma (secretes H+ ions) - Electrolyte balances: Metabolic acidosis, hyperkalemia, etc. 4. Synthesize calcitriol (active from of Vit D) - Complication: Mineral and bone disorder - Due to decreased absorption of Ca2+ 5. Secrete hormones (erythropoietin, renin, PGAs) - Anemia: Hemoglobin decreases, supplemental iron and ESAs needed

Answer 17

Uremia - Associated with ESRD. Symptoms are due to the accumulation of waste molecules in the blood that are usually removed by the kidneys. Effects - Breath smells like urine, skin gets really itchy to do the acid concentration getting so high, anemia due to EPO deficiency, GI symptoms like anorexia, N/V, constipation, metallic taste, mineral and bone disorder, etc. These patients need dialysis. (SCr ~10 and BUN~100)

Answer 18

- Don't really need to fluid restrict, as long as their Na intake is controlled. Diuretics won't work unless the pt has working kidneys, but they can be used to treat volume overload and HTN in pts with renal insufficiency - If loop diuretic doesn't work, they all won't work - Thiazides won't work with a CrCL under 30mL/min, but loops will - Don't use K+ sparing (MRAs and Na+ channel inhibitors) - Thiazide can be added if loop by itself doesn't work

Answer 19

Sodium - Don't have to severely restrict sodium besides a "no salt added diet" unless there's HTN or edema. Make pts away of high sodium content foods, be careful when using saline containing IV solutions. - <2g Na/day or <5g NaCl/day Potassium - Restrict to 3g/day (4.5-5.5 mEq/L for ESRD pt before dialysis. Avoid high potassium foods, treat hyperkalemia if needed.

Answer 20

Mechanisms: 1. Kidney disease causes impaired phosphate excretion, and that retained phos causes an increase in PTH production, which ends up causing Ca2+ to be taken from bone because it thinks it needs for calcium. 2. Kidney disease causes decreased amount of activated Vit D (1,25-dihydroxyvitamin D3), which leads to increased PTH production. 3. Hypocalcemia causes increased PTH production. Treatment: 1. Treat hyperphosphatemia - Phosphate binders to bind phos from diet before it gets to blood - Dietary restrictions - 800-1000mg Phos daily if phos > 4.6 in CKD 3-4 or phos > 5.5 in CKD 5, or if PTH is > range for states 3-5 2. Treat Vit D insufficiency 3. Treat calcium homeostasis and secondary hyperparathyroidism (cinacalcet (Sensipar) to lower PTH, but contraindicated in hypocalcemia (Ca <7.5mg/dL))

Answer 21

**all must be given with meals or else they do nothing (never give IV...) - Calcium carbonate (40% elemental calcium): cheap; don't exceed 1500mg elemental Ca2+ - Calcium acetate (PhosLo; 25% elemental calcium); may bind phos better than tums, but it's more expensive; don't exceed 1500mg elemental Ca2+ - Sevelamer carbonate: wonder drug, but expensive; Not absorbed, so low risk of toxicity, decreases uric acid concentrations (good for gout), no ADRs, decreases LDLs - Lanthanum carbonate: Has a greater range of activity over spectrum of pHs. - Sucroferric oxyhydroxide (Velphoro): Has iron, but it binds so tightly to phos that there is no change seen in iron concentrations. - Auryxia (ferric citrate): Has iron, and it does get absorbed - Aluminum hydroxide: Bad because it can cause aluminum toxicity. Don't use this.

Answer 22

Vitamin D that still requires kidney function to activate: - Ergocalciferol (D2) - Cholecalciferol (D3) Already activated Vitamin D: - Calcitriol: has greater risk of hypercalcemia and hyperphosphatemia, but it's cheap - Paricalcitol: Most favorable in terms of AEs - Doxercalciferol: Prohormone that becomes activated in the liver (don't give if pt has liver problmes)

Answer 23

1. Decreased production of erythropoietin 2. Uremia causes a decreased life span of RBCs 3. Vitamin losses during dialysis (folate, B12, B6) 4. Dialysis (loss of blood through dialyzer)

Answer 24

MCV - Mean corpuscular volume, average size of RBCs Low - Iron deficiency, aluminum toxicity Normal - Anemia of chronic disease, GI bleed, erythropoietin deficiency High - Folate deficiency, B12 deficiency RDW - Red cell distribution width. If it's over 14.5%, then we know the distribution of points is not normal. Ex. when pts have folate AND iron deficiency.