Antihypertensive AgentsAntihypertensive Agents

Emel Songu-Mize, PhDEmel Songu-Mize, PhD568-2240568-2240emize@lsuhsc.eduemize@lsuhsc.edu

Lecture OutlineLecture Outline HypertensionHypertension

Definition, 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'tknown = ESSENTIAL HYPERTENSIONknown = ESSENTIAL HYPERTENSION

Symptomatic treatment, i.e. reduceSymptomatic treatment, i.e. reduceblood 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 60Only 1 in 2 on drug treatmentto lower BPOnly 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 CurrentGuidelinesJNC, 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 Renin

release

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 PVRPVRmyogenic 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 DiureticsAntihypertensive 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 functiona)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

vasculaturevasculatureMain effects:Main effects: decreased PVR decreased PVR decrease decrease

BPBPAdverse effects:Adverse effects: 11stst dose phenomenon dose phenomenon, ,

fluid retention, dizziness, headachefluid retention, dizziness, headachePharmacokinetics:Pharmacokinetics: t t1/21/2= 4.5, 12, 20, = 4.5, 12, 20,

respectivelyrespectivelyUse: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 well3rd 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 PVRMain 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 HRAdverse 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

channelschannelsMain effectMain effect:: vasodilatation vasodilatation lower PVR lower PVR

lower BP lower BPAdverse 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 nodeMain effects:Main effects: same as nifedipine group same as nifedipine groupAdverse effectsAdverse effects: Similar to nifedipine except : Similar to nifedipine except

that they that they do notdo not cause reflex tahycardia cause reflex tahycardiaDrug interactionsDrug interactions: Caution for AV block with : Caution for AV block with

beta blockers, and digitalisbeta blockers, and digitalisUse: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 lower BP BP

Adverse effectsAdverse effects: : reflex tachycardiareflex tachycardia, , Na and Na and fluid retentionfluid 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, drip, short plasma half-lifeshort 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 onsetUse: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 inhibitorscaptopril, 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 RELEASEBP BV

Na+ retention+ -

Vasoconstriction

Aldosteronesecretion

Angiotensin release

++ +

++

+

Stimulants for ADH 1) ECF volume 2) osmolality of plasma

+

Renin-Angiotensin-Aldosterone SystemRenin-Angiotensin-Aldosterone System