Trachte: ADH and Diuretics Flashcards
How much plasma does the kidney filter each day?
180 L
What does the kidney do?
- Returns ions/nutrients to blood via specific transporters
2. Excretes toxins/metabolites in the urine
How does using different permeabilities to water and different ionic transport processes over the course of the nephron affect the kidney?
It results in DRASTICALLY different OSMOLARITIES in different regions of the kidney
Where do carbonic anyhydrase inhibitors act?
Proximal tubule
*Aren’t really used clincially
Where do loop diuretics act? What do they do?
Ascending limb of the loop of Henle
Inhibit Na/K/2Cl pump
EXTREMELY useful
Where do thiazide diuretics act? What do they do?
Distal convoluted tubule
Inhibit Na/Cl transport
What drugs are especially useful in hypertension?
Thiazide diuretics
Where do K sparing diuretics work? What do they do?
Cortical collecting tubule
Inhibit aldosterone receptors or block Na exchange for K and H
Where do antidiuretic hormones work? What do they do?
Medullary collecting duct
Recruit aquaporin channels
Where do osmotic diuretics work?
Proximal tubule or descending limb of the loob of henle
What are the major loop diuretics?
Furosemide (lasix)
Bumetanide
What normally happens in the ascending loop of henle?
The ascending loop of Henle normally accounts for 25% of Na reabsorption in the kidney.
NORMALLY…
Na/K/2Cl pump in the thick ascending limb of the Loop of Henle>
Na/K/CL are pumped out but water remains inside (no aquaporins)>
HYPO-OSMOLAR
What do the loop diuretics do in the ascending loop of henle??
LD prevent the DECREASE in osmolarity>
greater retention of ions and water in later segments of the nephron
What effect do loop diuretics have on urine composition?
- Increased NaCl excretion
2. Increased K excretion
What are the major uses of loop diuretics?
- pulmonary edema
- edematous conditions
- Hyperkalemia
- Acute renal failure
- anion overdose (bromide, fluoride, iodide)
What are the major thiazide diuretics?
Chlorthalidone
Hydrochlorothiazide
Metalazone
What do thiazide diuretics do?
Block the NaCl transporter in the distal convoluted tubule
What normally happens in the distal convoluted tubule? What happens when you block this transport mechanism?
Accounts for 8% of NaCl reabsorption
Blocking this mechanism results in EXCRETION of water, Na, Cl and K in urine
Why does K get excreted with thiazide diuretics?
Some of the increased Na is exchanged for K in the cortical collecting tubule
What are thiazides primarily used for?
- HTN
- HF
- Nephrolithiasis caused by hypercalcemia
- Nephrogenic diabetes insipidus
What are the major SE of thiazides?
- Hyperglycemia
- Hyperuricemia
- Hypokalemia
- hyperlipidemia
- hyponatremia
- allergic rxns
How do thiazides cause hyperglycemia?
Thiazides are sulfonylureas>
bind to SUR on K channel controlling insulin release>
opens the channel and hyperpolarizes the beta cell>
suppresses insulin release
What are the K sparing diuretics and what are the mechanisms by which they act?
- Inhibit aldosterone receptors (spironolactone)
2. inhibit the Na exchange for K and H in the cortical collecting duct (amiloride, triamterene)
How do K sparing diuretics spare K?
By blocking the exchange of intaluminal Na for extraluminal K, less K is excreted
What is the major use of K sparing diuretics?
Hyperaldosterionism or to prevent K wasing caused by other diuretics
What does eplerenone do?
Prevents fibrotic changes in kidneys and hearts caused by aldosterone, and has been shown to improve survival in heart failure
What are the side effects of K sparing diuretics?
Hyperkalemia
Hypercholeremic metabolic acidosis
Acute renal failure
Kidney stones
What K sparing diuretic causes gynecomastia?
Spironolactone
What are 2 antidiuretic hormones?
- Vasopressin
2. Desmopressin
What are antidiuretic hormones used for?
Treat diabetes insipidus
bed wetting!
What is the MOA of antidiuretic hormones?
Stimulation of G protein coupled receptors in the collecting duct>
recruits aquaporin channels>
water moves by osmosis through the AQP cahnnels>
hyperosmolar medullary region of the kidney
How are vasopressin and desmopressin administered?
parenterally
intranassally
orally
What can be used to treat syndromes involving inappropriate ADH secretion?
Convaptan- ADH antagonist
What antibiotic has some activity as an ADH antagonist?
Demecocyline
What is the major osmotic diuretic?
Mannitol
How does mannitol cause a retention in water?
It’s NOT reabsorbed by the nephron so it exerts an OSMOTIC effect to retain water.
What is mannitol used for?
- reduce body water
2. reduce intracranial/intraocular pressure
What are toxicities associated with mannitol?
- Extracellular volume expansion
- Dehydration, hyperkalemia, hypernatremia
- hyponatremia when renal function is impaired
What is a major carbonic anhydrase inhibitor?
Acetazolamide (diamox)
Are anhydrase inhibitors useful as diuretics?
Not really….CA is too important of an enzyme. Blocking it leads to a number of SE.
what are CAIs used for?
- Glaucoma
- urinary alkalinization
- Metabolic acidosis
- Acute mountain sickness
What are hte SE of CAIs?
- Hyperhchloremic metabolic acidosis
- renal stones
- renal K wasting
What do organic anion transport inhibitors do?
Transport small hydrophillic molecules into or OUT of the nephron. Driven by symport or antiport exchange of molecules for dicarboxylates.
What are OATIs used to treat?
Gout!
How do you treat gout?
- Reduce inflammation w/ NSAIDS (NOT salicylates)
2. Reduce uric acid
What drugs reduce uric acid? How do they work?
- Allopurinol- inhibits xanthine oxidase
2. Probenicid or sulfinpyrazone- inhibits a renal organic acid transporter to facilitate excretion
What is colchicine?
Microtubule inhibitor with anti-inflammatory properties
How do probenicid and sulfinpyrazone work?
Inhibit uric acid reabsorption by organic acid transporter
Why are loop diuretics ototoxic?
Also block the pump in the ear, which is critical for K concentrations in the ear
What do loop diuretics do to extracellular Na, K, Cl and water?
Decrease Na, K, Cl and reduce water
Why are we so sensitive to K imbalance?
Theres very little in our extracellular fluid, so if you change it slightly it can have a large effect. There is a far greater amount of Na, so altering it does not do much.
Why is it important to monitor electrolytes when giving loop diuretics?
They have the potential to be toxic
How do thiazides prevent uric acid secretion?
Thiazide and UA are transported by same transporters so they interfere with the transfer of UA
What affect do thiazides have on extracellular Na, K, Cl and water?
Deplete Na, K and water
Much less than loop diuretics
have milder affect so they’re safer to use
What part of the bp equation do thiazides affect?
BP= HR x SV X TPR (Decrease SV!…also decreases TPR)
This affects the venous return curve
What are the compelling reasons/perfect conditions for use of thiazides in HTN? What are ACE inhibitors good for?
Stroke- lower bp and reduce incidence of stroke
Diabetes- they do elevate glucose, but are still ok
CAD
ACE inhibitors are ALWAYS GOOD b/c they are synergetic with other drugs.
They have milder affects than loop diuretics
What effects do K sparing diuretics have on extracellular na, k, cl and water?
Mild decrease in Na
ELEVATE K levels
Little affect on Cl or water
How does aldosterone work?
Aldosterone works on a receptor in the cytosol. Once activated it is a transcriptional activator or inhibitor.
Where is aldosterone synthesized?
Adrenal gland (glomerulosa- the outermost layer)
What are the compelling reasons for use?
Heart failure
post MI
Where does ADH come from?
Posterior Pituitary
What stimulates the release of ADH?
Decrease in blood volume Increase osmolarity (osmosensor in the brain)
What receptors does it stimulate?
Gs aplha- g protein that couples between the receptor that stimulates adenylate cyclase
What do thiazides do to UA?
- inhibit secretion of UA by OAT1
- Serve as substrates for URAT
Net effect is to INCREASE blood UA
