Antihypertensive AgentsAntihypertensive Agents
Emel Songu-Mize, PhDEmel Songu-Mize, PhD
568-2240568-2240
[email protected]@lsuhsc.edu
Lecture OutlineLecture Outline
HypertensionHypertensionDefinition, classificationDefinition, classificationPrevalencePrevalenceComplicationsComplicationsContributing factorsContributing factors
Update on VIIUpdate on VIIthth report of the JNC report of the JNC
Drugs that lower blood pressureDrugs that lower blood pressure
Blood Pressure ClassificationBlood Pressure Classification
ClassificationClassification SBP (SBP (mmHgmmHg)) DBPDBP ((mmHgmmHg))____________________________________________________________________________________________________________
NormalNormal <120<120 andand <80<80
PrehypertensionPrehypertension 120–139120–139 or or 80–8980–89
HypertensionHypertension >140/90>140/90 Stage 1 HypertensionStage 1 Hypertension 140–159140–159 or or 90–9990–99
Stage 2 HypertensionStage 2 Hypertension >>160160 or or >>100100__________________________________________________________________________________________
Essential HypertensionEssential Hypertension
In 90–95% of cases the cause isn'tIn 90–95% of cases the cause isn't
known = ESSENTIAL HYPERTENSIONknown = ESSENTIAL HYPERTENSION
Symptomatic treatment, i.e. reduceSymptomatic treatment, i.e. reduce
blood pressure. No real cure yet.blood pressure. No real cure yet.
Identifiable Causes of Identifiable Causes of Secondary HypertensionSecondary Hypertension
Sleep apnea Drug-induced or related causes Chronic kidney disease Primary aldosteronism Renovascular disease Chronic steroid therapy and Cushing’s
syndrome Pheochromocytoma Coarctation of the aorta Thyroid or parathyroid disease
Prevalence Prevalence
High in this country: 50% of adults, High in this country: 50% of adults, 60% of whites, 71% of African 60% of whites, 71% of African Americans, 61% Mexican Americans Americans, 61% Mexican Americans over the age of 60over the age of 60
More prevalent in men than in More prevalent in men than in womenwomen
Highest prevalence in elderly Highest prevalence in elderly African-American femalesAfrican-American females
ComplicationsComplications
Cardiovascular systemCardiovascular system CNSCNS Renal systemRenal system Retinal damageRetinal damage
Target Organ DamageTarget Organ Damage
Heart Left ventricular hypertrophy Coronary artery disease Myocardial infarcts Heart failure
Brain Stroke or transient ischemic
attacks Chronic kidney disease, kidney failure Retinopathy
Contributing FactorsContributing Factors
ObesityObesity StressStress Lack of exerciseLack of exercise Diet (excess dietary salt)Diet (excess dietary salt) Alcohol intakeAlcohol intake Cigarette smokingCigarette smoking
National Heart Lung Blood National Heart Lung Blood Institute National High Blood Institute National High Blood Pressure Education ProgramPressure Education Program
The Seventh Report of the The Seventh Report of the JJoint oint NNational ational CCommittee on ommittee on Prevention, Detection, Prevention, Detection, Evaluation, and Treatment of Evaluation, and Treatment of High Blood Pressure (JNC 7, High Blood Pressure (JNC 7, 2003)2003)
http://www.nhlbi.nih.gov/guidelines/http://www.nhlbi.nih.gov/guidelines/hypertension/index.htmhypertension/index.htm
Why Guidelines forHypertension?
50 million people with hypertensionin USA 10 years ago – 1:4 overall (Currently 31 %), half of people > age 60
Only 1 in 2 on drug treatmentto lower BP
Only 1 in 4 age 18-74 controlled to<140/<90 in USA
New BP Goals
<140/<90 and lower if tolerated
<130/<80 in diabetics
<130/<85 in cardiac failure
<130/<85 in renal failure
<125/<75 in renal failure with
proteinuria>1.0 g/24 hours
Highlights of CurrentGuidelines
JNC, WHO/ISH, BHS,Canada, and More
New aggressive treatment strategies based on a patient’s medical profile
Treat to goal and hit the target, not to be satisfied with less
Treatment OverviewTreatment Overview
Goals of therapy Lifestyle modification Pharmacologic treatment
Algorithm for treatment of hypertension
Classification and management of BP for adults
Follow-up and monitoring
Lifestyle ModificationsLifestyle Modifications
Reduce weight to normal BMI Reduce weight to normal BMI (<25kg/m(<25kg/m22): 5-20 mmHg/10kg loss): 5-20 mmHg/10kg loss
DASH eating plan: 8-14 mmHgDASH eating plan: 8-14 mmHg
Dietary sodium reduction: 2-8 mmHgDietary sodium reduction: 2-8 mmHg
Increase physical activity: 4-9 mmHgIncrease physical activity: 4-9 mmHg
Reduce alcohol consumption: 2- 4 Reduce alcohol consumption: 2- 4 mmHgmmHg
DASH Diet
Dietary
Approaches
to
Stop
Hypertension
• Emphasizes: Fruits, vegetables, low fat dairy foods, and reduced sodium intake
• Includes whole grains, poultry, fish, nuts
• Reduced amounts of red meat, sugar, total and saturated fat, and cholesterol
Sacks FM et al: NEJM 344;3-10, 2001
Algorithm for Treatment of Algorithm for Treatment of HypertensionHypertension
Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling Indications
Lifestyle Modifications
Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)
2-drug combination for most (usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Stage 1 Hypertension(SBP 140–159 or DBP 90–99
mmHg) Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Without Compelling Indications
Not at Goal Blood Pressure
Optimize dosages or add additional drugs until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Renalfunction
Bloodvolume
Venoustone
Venousreturn
Heartrate
Nervouscontrol
Muscularresponsiveness
Myocardialcontractility
Strokevolume
Cardiacoutput
CNSfactors
Reninrelease
Angiontensin II formation
Intrinsic vascularresponsiveness
Peripheralresistance
Nervouscontrol
Renalfunction
Mean arterialpressure
Factors that Govern the Mean Arterial
Pressure
Mean Arterial PressureMean Arterial Pressure
MAP = MAP = COCO
CO = HR X SVCO = HR X SV
SNSSNS Blood Blood volumevolume
Heart Heart contactilitycontactility Venous toneVenous tone
X X PVRPVR
myogenic tonemyogenic tonevascular vascular
responsivenesresponsivenesnervous controlnervous control
vasoactive vasoactive metabolitesmetabolites
endothelial factorsendothelial factorscirculating circulating
hormoneshormones
Antihypertensive DrugsAntihypertensive DrugsClassificationClassification
DiureticsDiuretics Agents affecting adrenergic Agents affecting adrenergic
functionfunction VasodilatorsVasodilators Agents affecting Agents affecting RRenin enin
AAngiotensin ngiotensin SSystem (RAS)ystem (RAS)
DiureticsDiuretics
Used as initial therapy alone or in combination with Used as initial therapy alone or in combination with drugs from other groupsdrugs from other groups
Adverse effects: renin secretion due to volume and Na Adverse effects: renin secretion due to volume and Na depletiondepletion
Thiazides:Thiazides: chlorothiazide, hydrochorothiazide chlorothiazide, hydrochorothiazide
Loop Diuretics:Loop Diuretics: furosemide, bumetanide, furosemide, bumetanide, ethacrynic acidethacrynic acid
Potassium sparing diuretics:Potassium sparing diuretics: spironolactone, spironolactone, triamterene, amiloridetriamterene, amiloride
About Diuretics
Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. Diuretics enhance the antihypertensive efficacy of multidrug regimens, can be useful in achieving BP control, and are more affordable than other anti-hypertensive agents.
Despite these findings, diuretics remain under-utilized.
Agents that affect Agents that affect adrenergic functionadrenergic function
a)a) Agents that prevent adrenergic Agents that prevent adrenergic transmission transmission (reserpine, guanethedine, (reserpine, guanethedine, guanadrel)guanadrel)
b)b) Selective alpha-1 adrenergic receptor Selective alpha-1 adrenergic receptor blockers blockers (prazosin, terazosin, doxazosin)(prazosin, terazosin, doxazosin)
c)c) Beta-adrenergic blocking agents Beta-adrenergic blocking agents (propranolol and others)(propranolol and others)
d)d) Agents that act on the CNS Agents that act on the CNS (methyldopa, (methyldopa, clonidine, guanabenz, guanfacine)clonidine, guanabenz, guanfacine)
a) a) Agents that prevent adrenergic Agents that prevent adrenergic transmission:transmission: Reserpine Reserpine (Serpasil)(Serpasil) Mechanism:Mechanism: depletes neurotransmitters depletes neurotransmitters
(NE, DA, 5HT) in the storage vesicle of the (NE, DA, 5HT) in the storage vesicle of the centralcentral and and peripheralperipheral nerve endings nerve endings
Main effects:Main effects: depress SNS function depress SNS function centrally and peripherally centrally and peripherally decreased decreased HR, contractility and PVRHR, contractility and PVR
Adverse effects:Adverse effects: depressiondepression, insomnia, , insomnia, nightmares, ulcers, diarrhea, abdominal nightmares, ulcers, diarrhea, abdominal cramping, nasal stuffinesscramping, nasal stuffiness, orthostatic orthostatic hypotensionhypotension, dry mouth,, dry mouth, impotence impotence
Pharmacokinetics:Pharmacokinetics: onset is slow and full onset is slow and full effect is seen in weekseffect is seen in weeks
Use:Use: infrequently infrequently
Mechanism:Mechanism: Depletes the nerve ending of NE Depletes the nerve ending of NE
in the in the peripheryperiphery Main effects:Main effects: decrease in PVR and decrease decrease in PVR and decrease
in HR in HR decrease in BP decrease in BP Adverse effects:Adverse effects: Orthostatic hypotensionOrthostatic hypotension, Na, Na++
and water retention. Other side-effects and water retention. Other side-effects similar to reserpine except the CNS effectssimilar to reserpine except the CNS effects
Pharmacokinetics:Pharmacokinetics: Poorly absorbed from the Poorly absorbed from the G.I. Onset slow (1-2 weeks). Metabolites G.I. Onset slow (1-2 weeks). Metabolites excreted in urineexcreted in urine
Use:Use: Not used anymore because of severe Not used anymore because of severe side effectsside effects
a) a) Agents that prevent adrenergic Agents that prevent adrenergic transmission:transmission: Guanethedine Guanethedine (Ismelin)(Ismelin)
Mechanism and main effectsMechanism and main effects Similar to Similar to
guanethidineguanethidine
Adverse effects are less than gunethidine: Adverse effects are less than gunethidine: lessless orthostatic hypotension, orthostatic hypotension, lessless diarrhea, diarrhea, lessless effect on sexual function. effect on sexual function.
Pharmacokinetics:Pharmacokinetics: better absorption, rapid better absorption, rapid onset, shorter duration of action than onset, shorter duration of action than guanethidineguanethidine
a) a) Agents that prevent adrenergic Agents that prevent adrenergic transmission: transmission: Guanadrel Guanadrel (Hylorel)(Hylorel)
b) Selective alpha-1 adrenergic b) Selective alpha-1 adrenergic receptor blockers receptor blockers (prazosin-(prazosin-MinipresMinipres, , terazosin-terazosin-HytrinHytrin, doxazosin-, doxazosin-CarduraCardura))
They favorably influence plasma lipid profile, and do not They favorably influence plasma lipid profile, and do not
interfere with glucose metabolisminterfere with glucose metabolism..
Mechanism:Mechanism: block block 1 receptors in 1 receptors in vasculaturevasculature
Main effects:Main effects: decreased PVR decreased PVR decrease decrease BPBP
Adverse effects:Adverse effects: 11stst dose phenomenon dose phenomenon, , fluid retention, dizziness, headachefluid retention, dizziness, headache
Pharmacokinetics:Pharmacokinetics: t t1/21/2= 4.5, 12, 20, = 4.5, 12, 20, respectivelyrespectively
Use:Use: used in stage 1 and stage 2 HT in used in stage 1 and stage 2 HT in
combination with a diuretic and a combination with a diuretic and a --blockerblocker
c) Beta-adrenergic blocking c) Beta-adrenergic blocking agents agents (see table)(see table)
Classification Classification Nonselective (Nonselective (11stst generation generation)) Cardioselective (Cardioselective (-1 selective, -1 selective, 22ndnd
generationgeneration)) blockers with intrinsic blockers with intrinsic
sympathomimetic activity (ISA)sympathomimetic activity (ISA) With additional CV actions (With additional CV actions (33rdrd
generationgeneration))
Proposed mechanisms: Proposed mechanisms: Block cardiac Block cardiac 1 receptors 1 receptors lower CO lower COBlock renal Block renal 1 receptors 1 receptors lower lower
renin, lower PVRrenin, lower PVRDecrease SNS outputDecrease SNS output
Non-Selective
PropranololTimolol (hydrophylic)*Pindolol*Penbutolol*Cartelol*Labetalol ( & )Carvedilol ( & )*Carteolol
1-Selective (in low dose)
Metoprolol*AcebutololAtenolol (hydrophylic)BetaxololBisoprolol
(Diabetes and Asthma)
Intrinsic (ISA)
PindololAcebutololPenbutololCartelolLabetalol ( & )
(Reynaud’s)
*has ISA as well
3rd generation
Propranolol (Inderal)Propranolol (Inderal)
Mechanism: Mechanism: Block cardiac Block cardiac 1 receptors 1 receptors lower CO lower CO Block renal Block renal 1 receptors 1 receptors lower renin, lower renin,
lower PVRlower PVR
Main effects:Main effects: decrease HR and PVR decrease HR and PVRAdverse effects:Adverse effects: bradycardiabradycardia, depression, , depression, 22
blockade in airwaysblockade in airways, glucose and lipid , glucose and lipid metabolism, vasoconstriction in extremities metabolism, vasoconstriction in extremities
Pharmacokinetics:Pharmacokinetics: GI, GI, 30-50% metabolized in 30-50% metabolized in thethefirst-pass in liver. Tfirst-pass in liver. T1/21/2: 3-5 hours, Slow- : 3-5 hours, Slow- release propranolol availablerelease propranolol available
Use:Use: used in stage 1 and 2 HT alone or in used in stage 1 and 2 HT alone or in combinations with a diuretic and/or combinations with a diuretic and/or vasodilatorvasodilator
Drug InteractionsDrug Interactions: verapamil, diltiazem, : verapamil, diltiazem, digitalis (caution AV Block)digitalis (caution AV Block)
Labetalol (Trandate)Labetalol (Trandate)
A combined alpha-1, beta-1, A combined alpha-1, beta-1, and beta-2 blocker. Beta and beta-2 blocker. Beta blocking action is more blocking action is more prominent. It also has some prominent. It also has some ISA property.ISA property.
Can be given Can be given i.v. i.v. for for hypertensive emergencies hypertensive emergencies
d) Agents that act on the CNSd) Agents that act on the CNS((methyldopamethyldopa--AldometAldomet,, clonidine-clonidine- CatapresCatapres, , guanabenzguanabenz--WytensinWytensin, , guanfacineguanfacine--TenexTenex))
Favorable effect: lower PRAFavorable effect: lower PRAMechanism:Mechanism: -me-dopa metabolized to -me-dopa metabolized to -me--me-
norepinephrine, an norepinephrine, an -2 agonist, that -2 agonist, that suppresses SNS output from the CNS. Others suppresses SNS output from the CNS. Others are are -2 agonist themselves.-2 agonist themselves.
Main effects:Main effects: decreases PVR and HR decreases PVR and HR
Adverse effects:Adverse effects: sedationsedation, drowsiness, dry , drowsiness, dry mouth, impotence, bradycardia, withdrawal mouth, impotence, bradycardia, withdrawal syndrome (syndrome (rebound HTrebound HT), false (+) Coombs’ ), false (+) Coombs’ antiglobulin testantiglobulin test
Pharmacokinetics:Pharmacokinetics: oral or parenteral, oral or parenteral, transdermal; Ttransdermal; T1/2 1/2 = 2, 10, 6, 14-17 h, = 2, 10, 6, 14-17 h, respectivelyrespectively
Use:Use: stage 1 and 2 HT stage 1 and 2 HT
Vasodilator DrugsVasodilator DrugsCommon adverse effects: fall in BP Common adverse effects: fall in BP reflex tachycardia, also fall in BP reflex tachycardia, also fall in BP renin renin Na/H Na/H22O retentionO retention
a)a) Calcium entry blockers Calcium entry blockers (nifedipine (nifedipine and others)and others)
b)b) Potassium channel openers Potassium channel openers (minoxidil, diazoxide (minoxidil, diazoxide i.vi.v., pinacidil)., pinacidil)
c)c) Direct acting vasodilators Direct acting vasodilators (hydralazine, Na-nitroprusside (hydralazine, Na-nitroprusside i.vi.v.).)
a) Calcium entry blockersa) Calcium entry blockers((mechanismmechanism: inhibit Ca entry through L-: inhibit Ca entry through L-type voltage gated channels)type voltage gated channels)
Phenylalkylamines:Phenylalkylamines: verapamil verapamil
Benzothiazepines:Benzothiazepines: diltiazem diltiazem
Dihydropyridines:Dihydropyridines: nifedipine, nifedipine,nicardapine, isradapine, nicardapine, isradapine, felodopine, amlodipinefelodopine, amlodipine
Nifedipine Nifedipine (Procardia)(Procardia)
Mech: Mech: selective blockade of selective blockade of vascularvascular Ca Ca channelschannels
Main effectMain effect:: vasodilatation vasodilatation lower PVR lower PVR lower BP lower BP
Adverse effects:Adverse effects: headache, flushing, headache, flushing, nausea, nausea, ankle edemaankle edema, dizziness, , dizziness, reflex reflex tachycardiatachycardia with short acting version with short acting version (now have Procardia SR)(now have Procardia SR)
((nono reflex tachycardia with reflex tachycardia with verapamilverapamil and and diltiazemdiltiazem))
Use:Use: Hypertension (more effective in Hypertension (more effective in African-Americans), angina. Not useful African-Americans), angina. Not useful as an antiarrhythmic drug as an antiarrhythmic drug
Verapamil and Verapamil and DiltiazemDiltiazemMechanism:Mechanism: Blockade of Ca channels in the Blockade of Ca channels in the
vasculature, heart muscle and the AV nodevasculature, heart muscle and the AV node
Main effects:Main effects: same as nifedipine group same as nifedipine group
Adverse effectsAdverse effects: Similar to nifedipine except : Similar to nifedipine except that they that they do notdo not cause reflex tahycardia cause reflex tahycardia
Drug interactionsDrug interactions: Caution for AV block with : Caution for AV block with beta blockers, and digitalisbeta blockers, and digitalis
Use:Use: Hypertension, angina, arrhythmias Hypertension, angina, arrhythmias
b) Potassium channel openers b) Potassium channel openers (minoxidil-(minoxidil-LonitenLoniten, diazoxide , diazoxide i.vi.v.-.-HyperstatHyperstat, , pinacidil)pinacidil)
Mechanism:Mechanism: open K-channels of vascular smooth open K-channels of vascular smooth muscle cells muscle cells K-efflux K-efflux hyperpolarization hyperpolarization vasodilatationvasodilatation
Main effectMain effect:: vasodilation vasodilation lower PVR lower PVR lower BP lower BP
Adverse effectsAdverse effects: : reflex tachycardiareflex tachycardia, , Na Na and fluid retentionand fluid retention, (minoxidil: hirsutism-, (minoxidil: hirsutism-Rogaine. Diazoxide: hyperuricemia, Rogaine. Diazoxide: hyperuricemia, hyperglycemia –used in hypoglycemia)hyperglycemia –used in hypoglycemia)
Use:Use: Diazoxide Diazoxide i.v.i.v. in hypertensive in hypertensive emergenciesemergencies
c) Direct acting vasodilatorsc) Direct acting vasodilators ((Na-Na-nitroprusside nitroprusside i.vi.v. . NiprideNipride))
Mechanism:Mechanism: metabolite is nitric oxide metabolite is nitric oxide cGMP. NO is a rapid acting venous and cGMP. NO is a rapid acting venous and arteriolar vasodilatorarteriolar vasodilator
Main effectMain effect:: vasodilation vasodilation lower PVR lower PVR lower BPlower BP
Adverse EffectsAdverse Effects: : Reflex tachycardiaReflex tachycardia, , severe hypotension, possible cyanide severe hypotension, possible cyanide poisoning poisoning
PharmacokineticsPharmacokinetics:: rapid acting, rapid acting, i.v.i.v. drip, short plasma half-lifedrip, short plasma half-life
Use:Use: Hypertensive Hypertensive emergenciesemergencies
c) Direct acting vasodilatorsc) Direct acting vasodilators ((hydralazine-hydralazine-ApresolineApresoline))
Mechanism:Mechanism: Direct vasodilator of Direct vasodilator of arteriolesarterioles
Main effectMain effect:: vasodilation vasodilation lower PVR lower PVR lower BPlower BP
Adverse effects:Adverse effects: reflex tachycardiareflex tachycardia, , Na Na retentionretention, hirsutism, lupus–like , hirsutism, lupus–like syndromesyndrome
Pharmacokinetics:Pharmacokinetics: oral, slow onset oral, slow onset
Use:Use: with a beta blocker and a diuretic with a beta blocker and a diuretic
AAngitensin ngitensin CConverting onverting
EEnzymenzyme
ACEACE
Angiotensin I Angiotensin I Angiotensin II Angiotensin II
ACEACE
Bradykinin (vasodilator) Bradykinin (vasodilator) Inactive Inactive peptidepeptide
ANGIOTENSIN I ANGIOTENSIN IIACE ANGIOTENSIN I ANGIOTENSIN IIACE BRADYKININ (vasodialtor) INACTIVE PEPTIDEACE BRADYKININ (vasodialtor) INACTIVE PEPTIDEACE
Agents that affect RASAgents that affect RAS
a) ACE inhibitorsa) ACE inhibitors
captopril, enalapril, lisinoprilcaptopril, enalapril, lisinopril
b) Angiotensin II receptor b) Angiotensin II receptor blockers (ARB)blockers (ARB)
losartan, valsartan, irbesartanlosartan, valsartan, irbesartan
a) ACE inhibitors (a) ACE inhibitors (captopril-captopril-CapotenCapoten, , enalapril-enalapril-VasotecVasotec, lisinopril-, lisinopril-PriviniPrivinil, rampiril-l, rampiril-Altace)Altace)No adverse effects on plasma lipids, glucose, sexual No adverse effects on plasma lipids, glucose, sexual function. Drug of choice in diabetes-related early stage function. Drug of choice in diabetes-related early stage proteinuria. Contraindicated in pregnancy. Not as effective proteinuria. Contraindicated in pregnancy. Not as effective in African-Americansin African-Americans
Mechanism: Mechanism: inhibit ACE inhibit ACE low circulating Ang II low circulating Ang II decreased PVRdecreased PVR
Main effectsMain effects:: decreased PVR decreased PVR decreased BP decreased BP
Adverse effectsAdverse effects:: skin rash, taste, skin rash, taste, coughcough, , hyperkalemiahyperkalemia
PharmacokineticsPharmacokinetics:: TT1/21/2 = 3, 11, 12, respectively = 3, 11, 12, respectively
Use:Use: used in stage 1 and 2 HT; also for congestive heart used in stage 1 and 2 HT; also for congestive heart failurefailure
b) Angiotensin II receptor blockers b) Angiotensin II receptor blockers (ARB) (ARB) (losartan-(losartan-CoozarCoozar, valsartan-, valsartan-DiovanDiovan, , irbesartan-irbesartan-AvaproAvapro))
Mechanism: Mechanism: selectivelyselectively block Ang II AT-1 block Ang II AT-1 receptor receptor decrease PVR decrease PVR decrease BP decrease BP
Adverse effectsAdverse effects:: NoNo Cough, very few adverse Cough, very few adverse similar to ACE inhibitorssimilar to ACE inhibitors
BP BV
Na+ depletion
NE release from nerve
ending
RENIN RELEASE
BP BV
Na+ retention+ -
Vasoconstriction
Aldosteronesecretion
Angiotensin release
++ +
++
+
Stimulants for ADH 1) ECF volume 2) osmolality of plasma
+
Renin-Angiotensin-Aldosterone SystemRenin-Angiotensin-Aldosterone System
