Fek - 5-6 - Pharm - Diuretics And Other Kidney Things

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Primary mech of diuretics

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Increased excretion of sodium (natriuresis)

Want to reduce extracellular fluid volume (edema) without reducing plasma volume.

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factors contrib to edema

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sympathetics (arteriolar vasoconstriction), hormones (AII --> aldo), less plasma oncotic pressure.

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Delivery of drugs to renal

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filtered if not bound to albumin or alpha-1 acid glycoprotein.

OATPs secrete them at PT site. (into urine)

Reabs by diffusion

so filtered in, secreted in, and not reabsorbed back keeps drug in renal system

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OATPs are ___ sensitive

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probenecid

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multidrug resistant p-glycoproteins are ____ sensitive

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verapimil

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slide 11

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adf

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main toxicity to monitor of diuretics

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normal serum electrolyte []s

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where na is reabsorbed

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PT mostly.
then decreasing order - LOH, distal tubule, CDuct

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Osmotic diuretics - mech, uses, example

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Substance filtered but not reabs bc of polarity.

Water retention (especially at descending limb)

Risk of expanding extracellular volume (so use only acutely)

e.g. mannitol

Not for renal indications - mainly for acute renal failure from hypovolemia and nephrotoxins. Also to acutely reduce intraocular or cranial pressure.

Front 10

where osmotic agents work (e.g. mannitol)

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proximal conv tubule

Front 11

CA inhibitors - effects at PT and SE and example

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Blocks bicarb reabs. So sodium can't follow.

More urinary bicarb and Na.

Metabolic acidosis may result leading to a loss of the diuretic effect.

Acetazolamide

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other drugs that inhib CA

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thiazides and loop diuretics

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CA inhibitors - effect at distal sites

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There is less H+ availability in the urine because bicarb is there too. So lots of K+ wasting.

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uses of CA inhibitors

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metabolic alk
Hypokalemic periodic paralysis (the drug also shifts K+ from cells to plasma - prob has to do with K+ wasting due to bicarb in the urine)

open angle glaucoma

mountain sickness (metab acidosis stimualtes respiration)

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SEs of CA inhibitors (acetazolamide)

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hypokalemia, ca++ stones (urine alkalinized), hypersensitivity (sulfonamide deriv)

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Site of loop and thiazides

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loop - ascending limb of henle

thiazides - distal convoluted tubule

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thiazide mech of action

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Inhib of NaCl symporter in the cortical diluting site of the DCT

Blocks urinary diluting capacity and increases Na andd Cl excretion.

Some CA inhibiton so bicarb excretion.

"can't generate free water clearance"

more Na deliv distally leads to more K excretion.

Enhances Ca reabsorption (driving force is present)

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uses of thiazides

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HTN - also increases bone density in women (more ca retention)

edema

calcium nephrolithiasis

nephrogenic DI (not sure abt mechanism)

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SEs of thiazides

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hypokal and hyponat are the most dangerous.

also hyperuricemia, hyperglycemia, hyperlipidemia, hypersensitivity rxns (has sulfa moiety)

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Loop diuretics struc

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sulfa moiety and caroxylic group (- charge so not reabsorbed easily)

short half life for this reason.

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mech of loop diuretics

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Inhib Na-K-2Cl symporter in thick ascending limb.

Increases Na, Cl, [Ca and Mg] excretrion. [] contrast to thiazides

blocks urinary diluting and [] capacity. "obliterates the hypertonicity of renal medulla so can't generate a hyperosmotic urine bc no driving force for water reabs)

More distal na so more K excretion.

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efficacy of loops vs thiazides

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loops - more efficacious but narrow range of dosing.

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uses of loop diuretics

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acute pulmonary edema - LOOP DIURETICS ARE KEY TO RELIEVE SX!! because of rapid rise in venous capicitance.

Edema from cardiac, hepatic, renal causes.

HTN refractory to other diuretics.

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SEs of loop diuretics

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hypokal, hyponat, metabolic alkalosis (due to hypokal), excess Ca and Mg excretion.

Less salt uptake into macula densa so there is no tubuloglomerular feedback. With more sodium in the urine, this inhibits shunting away from glomeruli and thus maintains renal blood flow and GFR. However, renin is greatly increased.

hyperuricemia, ototoxicity (dose limiting), hypersensitivity

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pharmacokin of furosemide (loop diuretic)

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IV and po. most bound to albumin. 1/2 renal excretion unchanged.

NSAIDs antagonize its effects bc PGs contribute to diuresis.

OATP inhibitors (probenecid, penicillin) also antag it's effects - less renal clearance, higher toxicity, BUT NOT CHANGE IN DRUG URINARY EXCRETION RATE VS. RESPONSE CURVE!!! it just has a higher plasma []. this is bc secretion is blocked.

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how chronic renal insuff and nephrotic syndrome effects diuretic efficacy

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chronic renal insuff - less renal blood flow so use higher than normal doses.

nephrotic - hypoalbuminemia increases Vd and decreases renal excretion rate. you need to use more of the drug.

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thiazides and loops

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CAUSE HYPOKALEMIA!!!!

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K sparing diuretics mech

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stop sodium reabs, stop K excretion.

act on epithelial Na channel or antag of aldosterone at the mineralocorticoid receptor.

works at principle cells of late distal tubules and collecting ducts. (aldo receptor and Na channel are both at the principle cell. aldo at interstitium, Na at luminal side)

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amiloride

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na channel blocker (K sparing)

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indications for amiloride

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combo with thiaz or loop to decrease hypokal risk

Liddle's disease - overactive epith Na channel protein. to stop excessive Na uptake.

comb with lithium bc lithium inhibits ADH and this drug stop lithium uptake into principle cell.

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spironolactone

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aldo receptor antag (K sparing)

results in alteration in txpn of many proteins.

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indic for spironolactone

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hyperaldosteronism

combo with thiaz or loops to stop hypokal

combo with loops, ace in heart failure to enhance survival.

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SEs of spironolactone

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hyperkalemia, gynecomastia, impotence.

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eplerenone

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alternative to spironolactone - no gynecomastia or impotence

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ENaC and Mineralocorticoid receptor blockers....

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may cause hyperkalemia.

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diuretic resistance/braking phenomenon

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Less potency because less renal clerance bc less renal blood flow, hyponat, compensatory physiological responses (RAA activation), more ENaC and distal sodium reabs.

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how to get around diuretic resistance

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more diuretic dose, use loops or thiaz in combo, less fluid and salt intake, block RAA, avoid vasodilators that impair renal perfusion.

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ACE inh or ARBs

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prevent diab nephropathy
(renal efferent vasodilation).

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Immunosupp agents indic

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type II or III hypersens rxns in kidney. and for transplants.

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Inhib or T-cell membrane receptors

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MAbs against IL-2 receptor
or polyclonals against human thymocytes (e.g. antithymocyte globulins)

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Inhibs of B and T cell replic

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purine antimetabolites such as mycophenolate and azathioprine

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Inhibs of intracell T cell signaling

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glucocorticoids, calcineurin inhibitors (such as cyclosporine or tacrolimus), or mTOR agents like sirolimus.(molec target of rapamycin)

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Issues with drugs in renal transplant

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durg isn't effective (late graft loss), nonimmune toxicities (like nephro or diabetes), or immune-related toxicities (cancer or infection)

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how to get around issue of a renally cleared drug in a pt with renal impairment (not diuretics)

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nonrenal excreted drug chosen instead

or less infusion rate or maint dose/dosing interval according to fraction of renal to total clerarance.

this is to prevent toxicity.

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steady state is...

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dosing rate relative to total clearance. so consider the creatinine if renal clearance.

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renal clearance of imipenem

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interesting bc "non renal" clearance includes ezymtic modif in the kidney (renal literally means unchanged in urine)

so renal failure will affect the nonrenal metabolism as well.

Front 47

A 68 year old woman with type 2 diabetes, angina, and obesity had an uncomplicated below knee amputation.
Baseline creatinine 133 µmol/l (estimated glomerular filtration rate 36 ml/min).
In first 36 hours after surgery she received 50 mg morphine, 76 mg codeine.
On the second day she developed oliguria despite iv fluid resuscitation; her serum creatinine rose to 213 µmol/l. She became increasingly drowsy and her respiratory rate fell to 8 breaths/min.

Back 47

her opioids are building because the METABOLITES (morphine-6-glucuronide) from liver glucorinadation which are renally cleared are building and those actually have opioid effects as well.

so it would have been better to use fentanyl (cleared to inactive metabolites)

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Nephrotoxic agents that cause ATN

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radiocontrast, cisplatin, aminoglycosides (e.g. gentamycin)

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clincial pres of aminoglycoside nephrotoxicity

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enzymuria, small MW proteinuria, transport defects (glycosuria and Mg and K loss), less GFR, polyuria.

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gentamicin and renal toxicity - mech

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90% renal clearance and it accum in PT cells. wanna reduce dose in pts with renal impairment.

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nephrotoxic effects of calcineurin inhibitors (cyclosporin or tacrolimus)

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Decreases GFR, aff art vasoconstriction and obliterative vascular pathology, tubular vacuolization and atrophy, interstitial fibrosis.

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analgesic nephropathy

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papillary necrosis, calcifications, more risk of ESRD

acetaminophen induced effect linked to CYP450 reactive metabolites.

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NSAID/COX2 inhibitor nephropathy

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acute reversible renal insuff. na retention and edema. less synth of renal PGs which vasodilate.

risk inc with HTN, diuretics, diabetes

will see tubular damage, granulomas, eos

Front 54

vasopressin released from...

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posterior pituitary

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vasopressin and ethanol, lithium

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ethanol - inhib release from post pt

lithium - less downstream signaling mediated by V2 receptor in distal tubule. gets to distal cell through epithelial na channel!

both casue more urine flow.

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excess vasopressin leads to...

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hytponatremia

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drugs causing increased vasopressin secretion

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oral hypoglycemics (sulfonylureas), antineoplastics (vincristine), psychoactive agents (haloperidol)

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tx of SIADH

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saline to increase serum sodium, furosemide (decrease medullary hypotonicity that is the driving force for water reabs), V2 receptor antag (end in "vaptan")

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caffeine

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inhibits prox tubule na reabs. does this by blocking adenosine receptors so their vasconstriction is blocked.