RAAS Drugs and diuretics Flashcards
What physiological changes/homeostasis are under control of RAAS system?
short and long term regulation of BP, regulation of blood plasma, modulation of SNS activity, stimulate thirst
What are some pathophysiological conditions (and drugs) that effect or are effected by RAAS?
hypertension (many anti-hypertensives), cardiac hypertrophy (ACE inhibitor), MI, Atherosclerosis, Diabetic nephropathy (ACE inhibitors can protect kidney and delay dialysis)
What is renin?
proteolytic enzyme, stored in renal JG cells, primary regulator of formation and maintenance of Ang II levels in blood
What is the relationship between Angiotensinogen and Renin?
Level of AngII (thus BP) dependent on amount of circulating renin and angiotensinogen
What is the relationship of PRA and sodium?
plasma renin activity (PRA) has an inverse relationship with dietary sodium intake
Where is Angiotensinogen formed and secreted? What effects it’s synthesis?
formed and secreted continuously by liver; synth. increased by insulin, estrogens and glucocorticoids
What is the rate limiting step in the AngII formation?
conversion of angiotensinogen to AngI by renin
What are the stimulus and the mechanisms of control on renin secretion?
decreased BV->JG release renin (t1/2=15); intrarenal baroreceptor pathway, Macula Densa (MD) pathway, Beta Adrenergic Pathway
What is the mechanism of action of the MD feedback pathway?
macula densa cells adjacent to glomerular afferent and efferent arterioles, sensitive to change in NaCl flux (involving Na/K/Cl blocked by loop diuretics), signals adenosine (-) and prostaglandins (+); (inc. NaCl-> dec renin)
What is the mechanism of action of B adrenergic pathway to JG cells?
B-1 receptors on JG, increase sympathetic activity-> increase renin, CNS modulation of renin mediated by symp. outflow to JG cells
What is the short loop feedback inhibition on renin? long loop?
AngII stim of AT1 receptor on JG cell; AngII induced increase in BP
What are the differences in the two major subtypes of AngII receptors?
AT1- Gq GPCR, mediate most biological effects of AngII, vasoconstriction, cardiac remodel and aldosterone; AT2- Gi GPCR, poorly defined, may exert antiproliferative, proapoptotic, vasodilatory, and anti-hypertensive, highly expressed fetal tissues
What is the function of Angiotensin I?
Inactive, rapidly converted to Ang II by ACE (endothelial cell surface esp. lungs) regulates conversion of Ang I to II in all vascular beds
What are the functions of Ang II?
major active component of RAS; increase TPR, alter renal function, alter cardiovascular structure via AT1 (alternate pathway to activate w/o ACE)
How does AngII increase TPR?
direct vasoconstrictor effect (AT1 on VSM cells), augments SNS, combo effects rapid rise in MAP
How does Ang II alter renal function?
stimulate aldosterone synth. and release from adrenal cortex, reduce urinary excretion of Na and H2O, increase excretion of K, alter GFR
How does Ang II alter GFR?
vasoconstriction of afferent (dec. glomerular pressure and GFR) or efferent arterioles (inc. glomerular pressure and GFR), contraction of mesangial cells- decrease glomerular SA-> dec. GFR
What is AngIII?
metabolite of Ang II, similar biological activity to Ang II
Which drugs inhibit ACE?
captopril, enalapril, and enalaprilat
What is the mechanism of action of ACE inhibitors?
inhibit conversion of Ang I to Ang II by ACE (won’t affect alt. pathways), inhibit degradation of bradykinin (ACE kinase II), results in vasodilation and decreased TPR
What are the pharmacological effects of ACE inhibitors?
increase release of renin (disrupt - feedback), increase circulating levels Ang I, decrease aldosterone release, prevent/reverse remodeling of heart and BV
How do the ACE inhibitors differ?
captopril and enalaprilat are active form (parenteral), enalapril (oral) is ester containing prodrug, vary in potency, captopril has 2 hr t1/2 (dose 2x daily), newer have longer t1/2, most clear renally (reduce dose if insufficient)
What are the therapeutic uses of ACE inhibitors?
hypertension, CHF (left ventricular systolic), after acute MI, high risk cardio events, diabetic nephropathy
Why are ACE inhibitors indicated in diabetic nephropathy?
independent from reduction in systemic BP, reduce glomerular capillary pressure, delay disease progression
What are the adverse effects of ACE inhibitors?
hypotension, cough, angioedema, hyperkalemia, increased serum creatinine, acute renal failure, pregnancy issues, rash and dysgeusia
What are the features of hypotension with ACE inhibitors?
first dose effect in patients with elevated PRA (Plasma renin activity, CHF and salt depleted patients)
What are the features of a cough with ACE inhibitors?
5-20%, persistent dry cough related to elevated bradykinin in lungs, may require drug withdrawal
What are the features of angioedema with ACE inhibitors?
0.1-0.5% related to elevated bradykinin, rapid swelling of lips, tongue, nose, throat, airway obstruction can be fatal, discontinue immediately, protect airway, Epi if necessary, antihistamines and/or glucocorticoids, 4.5x more prevalent in African-American patients
What are the features of hyperkalemia in ACE inhibitors?
in patients with poor renal function and/or diabetes
How is creatinine increased with ACE inhibitors?
due to decreased vasoconstriction of renal efferent arterioles (up to 30% increase acceptable)
How does ACE inhibitors cause acute renal failure?
bilateral renal arterial stenosis- when renal perfusion is low, Ang II maintains GFR by constricting efferent arterioles
What are the concerns of taking ACE inhibitors in pregnancy?
potential teratogen, fetopathic in 2nd/3rd trimester due to fetal hypotension, withdraw drug ASAP after diagnosis of pregnancy
What drugs interact and how with ACE inhibitors (ACEI)?
Antacids- reduce bioavailability, NSAIDS- reduce antihypertensive efficacy (PG vasodilatory), hyperkalemia with NSAIDS, K-sparing diurteics and K+ supplements
What drug is the prototype angiotensin receptor blocker (ARB)? MOA?
losartan; competitive antagonist of AT1 receptor (inhibits most effects of AngII, 10k-fold higher affinity for AT1 vs. AT2, inhibits aldosterone secretion
How do ARBs differ from ACEI?
ARB reduce AT1 receptor activation more effectively, ARBs increase circulating AngII levels thus maintain beneficial effects of AT2 activation, ARB have no effect on bradykinin (other ACE substrates)
What are the therapeutic uses of ARBs?
hypertension (particularly intolerant to ACEI), reno-protective in DMII, CHF
What are the adverse effects of ARBs?
incidence of cough and angioedema less than ACEI (not 0), Teratogenic and fetopathic, excessive hypotension and renal failure in patients with RAS-dependent BP (renal artery stenosis), hyperkalemia
What drug is the prototype direct renin inhibitor? MOA?
aliskiren; block conversion of angiotensinogen to AngI (RLS), more effective in decreasing Ang II formation than ACE (alternate AngII conversion paths), decrease PRA but increase plasma renin level due to loss of Ang II mediated negative feedback of renin release, little or no effect bradykinin
What is the therapeutic use of aliskiren?
alone or in combo with other agents for hypertension, long term advantage over RAS drugs not established
What are the adverse effects of aliskiren?
similar to ARB: incidence of cough and angioedema less than ACEI (not 0), Teratogenic and fetopathic, excessive hypotension and renal failure in patients with RAS-dependent BP (renal artery stenosis), hyperkalemia
What is the main functions of the kidneys?
filter large quantities of plasma to remove toxins while reabsorbing water and required substances, maintain BV and H/NH3 balance
What are the layers plasma is filtered through in the glomerulus?
fenestrated endothelial cells, basement membrane, and then filtration slit diaphragms formed by epithelial cells covering BM on urinary (Bowman’s) space side
What is solvent drag?
water filtered in glomerulus pulls small solutes with it, macromolecuels retained by filtration barrier
Where is the PCT and what is moves there?
contiguous w/ bowman’s, reabsorbs 65% filtered Na (highly water permeable) other ions follow
What are the portions of the LOH?
descending thin limb (DTL), ascending thin limb (ATL), thick ascending limb (TAL) adjacent to the macula densa (MD)
What is the DTL permeable to?
highly water permeable, low permability to NaCl and Urea
What is the ATL permeable to?
permeable to Na Cl and Urea but impermeable to water
What is the function of the MD?
sense NaCl leaving LOH, if [NaCl] too high a chemical signal (adenosine or ATP) is sent to afferent arteriole causing constriction (TGF)
What is TAL permeable to what moves there?
impermeable to water and urea, 25% filtered NaCl reabsorbed via active transport
Where is the DCT and what is it permeable to?
just pass MD, actively transport NaCl and is impermeable to H2O
What segments are collectively call the diluting segment?
DCT and LOH
what is the function of the collecting duct?
fine control of ultrafiltrate, final electrolyte composition modulated by aldosterone, water reabsorption modulated by ADH.
What are the various methods of Na transport?
diffusion down EC gradient, transported across luminal membrane by exchangers and symporters, Na/K-ATPase on basolateral membrane
How does movement of Na and other solutes effect on water?
accumulation of solutes in intercellular spaces creates small osmotic pressure differential on epithelial cells pulling water in leading to solvent drag-> increase in hydrostatic pressure bulk water flow and solvent drag in to interstitial space then capillaries
How is Cl reabsorbed in the kidney?
generally follows Na, PT and TAL Cl moves paracellularly, but also can move transcellularly (PT, TAL, DCT, and CD)
How and where is K reabsorbed in the kidney? secreted?
80-80% in PT via solvent drag (diffusion), paracellularly in TAL; secreted in DCT and CD by conductive path (channel mediated)
How and where is Ca reabsorbed in the kidney?
~70% in PT by passive diffusion paracellularly, 25% reabsorbed in TAL, remaining 5% in DCT by transcellular path
Where is Pi reabsorbed in the kidney?
largely reabsorbed (80%) by PT
Where is the bulk of Mg reabsorbed?
TAL, paracellularly, driven by lumen + voltage, 20-25% in PT and 5% DCT and CD
How do the kidneys handle organic acids and bases?
highly protein bound won’t filter much and must be excreted, 9 different organic acid and 5 different organic base transporters
What are some general features of diuretics?
used to lower BP and reduce edema, disrupt sodium conservation, Na transporters and channels are targets, not only alter Na excretion, tubule will try to compensate for changes down stream usually resulting in K+ loss.
When a diuretic is given with a drug (ex NSAID) that utilizes the same renal transporter what are the effects?
drug-drug interaction, prolonged effects of other drug and decreased effects of diuretic (because needs transporter to get to site of action- nephron tubule)
What are the various classes of diuretics?
carbonic anhydrase inhibitor (CAI), Na/K/2Cl Symport Inhibitors (Loop diuretics), Na/Cl symport inhibitors, K sparing diuretics (ENaCI and Aldosterone Antagonists, Osmotic diuretics, and Non-peptide Vasopressin Receptor Antagonists
What type of diuretic is acetazolamide? Site of action? Efficacy of drug?
CAI; PT, efficacy moderate because distal segments can compensate for reduced Na uptake in PCT
What is the mechanism of action of acetazolamide?
competitive inhibitor of carbonic anhydrase, CA is responsible for NaHCO3 reabsorption and acid secretion, inhibits apical membrane bound type IV and cytosolic type II CA, blocks formation of CO2 at the luminal surface and protons in the cytosol
What effects does acetazolamide effect on urinary excretion? Renal hemodynamics?
increase in volume, pH, Na(big), K (big), Cl (slight), HCO3 (large); increase delivery of NaCl to MD -> dec. RBF (constrict renal afferent arterioles) and GFR
What are the therapeutic uses of acetazolamide?
rarely diuretic; open-angle glaucoma (major use), altitude sickness, and epilepsy
How does acetazolamide treat altitude sickness?
Mt. Sickness: severe headaches, N/V, fatigue, SOB, dec. coordination (ataxia); there is decreased O2 with inc. altitude, fluid leaks from capillaries in lung and brain, builds up (reason for acclimation), drug increases HCO3 excretion acidifying the blood-> inc. vent-> inc. O2 intake
What are the adverse effects of acetazolamide?
hypokalemia, urinary alkalization and metabolic acidosis producing secondary effects
What are the secondary effects of urinary alkalization and metabolic acidosis with acetazolamide
renal stones (Ca salts insoluble in alkaline), inc. Na presented to CD inc. K secretion, and diversion of ammonia from renal origin into systemic circulation worsening hepatic encephalopathy
What is the prototype Na/K/Cl symport inhibitor? Another name for this class? Site of action? Drug efficacy?
furosemide; Loop diuretic; TAL of LOH, high efficacy
What is the mechanism of action of furosemide?
inhibit Na/K/Cl symporter, abolish transepithelial potential difference that drives paracellular transport of Ca and Mg
What are the effects furosemide has on urinary electrolyte excretion?
increase in volume and K; marked increase in Na, Cl, Ca, Mg, decrease uric acid excretion (chronically), reduce ability to concentrate urine in hydropenia or dilute urine in diuresis
What effects does furosemide have on renal hemodynamics?
increase RBF and redistribute to renal cortex (prostaglandin mediated), stimulate renin release (block TGF by inhibiting NaCl transport into MD), volume depletion-> reflex activation of SNS and stim. intrarenal baroreceptors
What are the vascular effects of furosemide? why is it beneficial?
acutely inc. systemic venous capacitance and decrease left ventricular filling pressure, (prostaglandin mediated); pt. w/ pulmonary edema even before diuresis ensues
What are the pharmacokinetic properties of furosemide?
highly protein bound, not filtered, delivered to apical membrane by tubular secretion (OAT1- inhibited by probenecid or other drugs using this transport), short elimination half-lives, can produce post-diuretic Na retention (prevent by proper dosing)
What are the therapeutic uses of furosemide?
acute pulmonary edema (inc. venous capacitance)- used IV for rapid action, CHF (volume depletion)- used orally +/- thiazide, hypercalcemia (given with IV isotonic saline-> supplement Na)
What are the adverse effects of furosemide?
mostly caused by fluid and electrolyte imbalance- hyponatremia and hypokalemia, hypocalcemia (PM women, long term), ototoxicity (tinnitus, deafness, vertigo- altered electrolyte comp. of endolymph, hyperuricemia, hyperglycemia (caution w/ DM on sulfonylamides-> dec rate of glucose utilization by adipose) NSAIDs (red. direct efficacy); orthostatic hypotension, and skin rash
What drug group does chlorothiazide belong to? site of action? efficacy?
Thiazide Diuretic; DCT; moderate (5% filtered load) and dose-response shallow (compared to loop diuretics)- substantially reduced when GFR is low in CHF
What is the mechanism of action of cholorthiazide?
NaCl symport inhibitor, weak inhibitor of CA in PT
What drug group is chlorthalidone in? MOA? Site of action? Efficacy?
Thiazide like diuretic; NaCl inhibitor in DCT, weak CA inhibitor in PT; reduced when GFR is low (CHF), moderate (5% filtered load)
What are the urinary effects of chlorothiazide and chlorthalidone?
decrease excretion Ca (NCX and PTH regulated channels enhanced by inhibition of NaCl symporter), increase- volume, pH, Na, K, Cl, HCO3, attenuate ability to dilute urine during diuresis, concentration ability unchanged
What are the pharmacokinetic properties of chlorothiazide and chlorthalidone?
delivered to lumen via OAT, generally longer 1/2 life than loops (1x daily dosing)
What are the therapeutic uses of chlorothiazide and chlorthalidone?
hypertension (1st line mild hypertensive, inexpensive), mild edema, nephrogenic diabetes Insipidus (paradoxical), Ca nephrolithiasis and osteoporosis
What are the adverse effects of chlorothiazide and chlorthalidone?
hypokalemia, hyponatremia, hyperuricemia, hyperglycemia and hyperlipidemia, erectile dysfunction (impotence)
How does chlorothiazide and chlorthalidone help nephrogenic diabetes Insipidus?
decrease polydipsia and polyuria, decrease plasma volume leading to decrease GFR enhancing PT reabsorption indirectly
What are the drug interactions to watch for with chlorothiazide and chlorthalidone?
NSAIDS- reduce diuretic efficacy (OAT), Quinidine- hypokalemia increases risk of torsades de pointes
What is the mechanism of action of triamterene?
block renal epithelial Na channels (ENaC) on apical membrane of epithelial (principle) cells, abolish transepithelial potential that drives tubular secretion of K (ROMK) and H (type A intercalated cell H-ATPase)
What is the mechanism of action of amiloride?
block renal epithelial Na channels (ENaC) on apical membrane of epithelial (principle) cells, abolish transepithelial potential that drives tubular secretion of K (ROMK) and H (type A intercalated cell H-ATPase)
What is the mechanism of action of spironolactone?
block cytosolic mineralocorticoid receptors in principal cells, reduce expression of aldosterone induced proteins (all of which promote Na reabsorption by multiple mechanisms), abolish transepithelial potential that drives tubular secretion of K (ROMK) and H (type A intercalated cell H-ATPase)
What is the mechanism of action of eplerenone?
block cytosolic mineralocorticoid receptors in principal cells, reduce expression of aldosterone induced proteins (all of which promote Na reabsorption by multiple mechanisms), abolish transepithelial potential that drives tubular secretion of K (ROMK) and H (type A intercalated cell H-ATPase)
What effects do potassium sparing diuretics have on urinary excretion?
slight increase: volume; moderate increase: pH and HCO3; large increase: Na and Cl; decrease: K
What are the types of K sparing diuretics? Drugs in each type? Site of action?
ENaC inhibitor: triamterene and amiloride; Aldosterone antagonist: spironolactone and eplerenone; late DCT and CD
What are the therapeutic uses of ENaCI?
used with K wasting diuretics to prevent hypokalemia, liddle syndrome, cystic fibrosis, and lithium induced diabetes insipidous
what are the therapeutic uses of aldosterone antagonists?
used with K wasting diuretics to prevent hypokalemia, primary hyperaldosteronism, hepatic cirrhosis, CHF (reduce mortality), weak diuretic to treat mid edema
What are the adverse effects of ENaCI?
hyperkalemia (potentially life threatening, cautious w/ ACE inhibitors and NSAIDS- same transporter), metabolic acidosis
What are the adverse effects of aldosterone antagonists?
spironolactone only: gynecomastia, impotence, hirsutism, decreased libido, irregular mentrual cycle hyperkalemia (potentially life threatening, cautious w/ ACE inhibitors and NSAIDS- same transporter), metabolic acidosis, gastritis, CNS effects, and peptic ulcers
What is the prototype osmotic diuretic? site of action? MOA?
mannitol; PT, LOH and CD; increase osmolality of tubular fluid (and plasma), reduce renal medullary tonicity (Mannitol 1 compound NaCl is 2 therefore less tonicity), reducing passive reabsorption of NaCl in ascending LOH (mannitol equally effects osmolality and pull of water as NaCl), expands ECF volume and inhibits release of renin
what are the urinary effects of mannitol? renal hemodynamics?
increased excretion of all electrolytes; increase RBF, GFR unchanged
What are the pharmacokinetic properties of mannitol?
given IV (glycerol/isosorbide are orally active) and is filtered
What are the therapeutics uses of mannitol?
dialysis disequilibrium syndrome, reduce pre-and post-operative CSF and intraocular pressure, minimize acute tubular necrosis (damage tubular epithelial tissues due to acute renal failure, 5% hospital pts), not effective as chronic diuretic
What are the adverse effects of mannitol?
contraindicated in heart failure (edema) and active cranial bleeding, flash pulmonary edema, hyponatremia- due to ECF Vol expansion, w/o adequate H2O can lead to hypernatremia
What is ADH? It’s function?
peptide hormone, similar to oxytocin, released by post. pit., potent vasoconstrictor, regulate fluid reabsorption in kidney in response to change in plasma osmolality and arterial BP
What receptors does vasopressin act on?
GPCR (Gq and Gs), V1a in VSM-> vasoconstriction, V2- basolateral membrane in CD principle cells-> increased trafficking (exocytosis, decreased endocytosis) of aquaporin-2 vesicles to apical membrane, increase Na and urea reabsorption (TAL and CD respectively), greatly increase medullary tonicity (driving force H2O thru AquaPorin 2)
What is the analog of vasopressin that acts only on V2 receptors?
desmopressin
What is the mechanism of action of demeclocycline? Other features?
competitive V2 receptor antagonist, tetracycline antibiotic, diabetes Insipidus is known side effect, increased renal free water excretion w/ little/no change in electrolyte excretion or renal hemodynamics
What is the mechanism of action tolvaptan? Other features?
selective competitive V2 receptor antagonist, 2009- newer vapten class of aquaretics, increased renal free water excretion w/ little/no change in electrolyte excretion or renal hemodynamics
What are the therapeutic uses of non-peptide vasopressin receptor antagonists?
(demeclocycline and tolvapten) hyponatremia associated with SIADH, used when fluid restriction is ineffective
What are the adverse effects of demeclocycline?
photosensitivity, pediatric tooth discoloration/bone growth retardation, GI upset, superinfection
What are the adverse effects of tolvapten?
GI effects, hyperglycemia and pyrexia
