DIURETICS(only those used for antihypertensive therapy) 

SYMPATHOLYTICSPeripheral adrenergic receptor blockersCentrally acting 

RENIN-ANGIOTENSIN SYSTEM INHIBITORSAngiotensin Converting Enzyme (ACE) InhibitorsAngiotensin II receptor blockers 

VASODILATORSCa2+ -channel blockersOthers

Antihypertensive Drugs

Treatment Guidelines from The Medical LetterDrugs for Hypertension January 2009

Fall ‘09

Hypertension

The most common cardiovascular disease•Affecting ~50 million people in the US•Defined as sustained systolic BP 140

mmHg and/or•Sustained diastolic BP 90 mmHG

Causes:~90-95% unknown origin (essential or primary hypertension)

~5-10% due to renal, endocrine or neurogenic disease

Risks associated with chronic elevated BP

Heart DiseaseHeart FailureArrhythmiasMyocardial Infarcts

Stroke

Renal Failure

Strategies for treating hypertension

Stepped care approach:•Life style changes (e.g., lower dietary Na+, weight loss)

•Single-drug therapy•Multiple-drug therapy

Careful consideration should be taken when patients present with co-morbidities:

diabetes, lipid disorders, ischemic heart disease and failure, migraines, asthma,

etc...

Specific patients may respond better to certain therapies (factors include; ethnicity, age, etc…)

AM Meds:Digitek (digoxin) 250 mcgVerapamil SR Tab, 180 mgHydralazine 25mgFish Oil 1000 units Enalapril Mal Tabs (5 mg in AM, 5mg in PM)ASA 350mg Chlorathalidone 25mgMultivitamin Ester C 1000 units/ MSM 1000 unitsGlucosamine/chondroitin/MSM 1000 unitsAcetaminophen 1000 mg (for arthritis discomfort)

PM Meds:Terazosin (5 mg at noon, 5mg in PM)Hydralazine 25mg Lipitor 10mgFish Oil 1000 unitsFlomax .4mg Singulair 10mgAcetaminophen 1000 mg (for arthritis discomfort)Glucosamine/chondroitin 1000 units/ MSM 1000 units

For allergies/ asthma:Advair Discus 100/50, 1 one puff in AM, PMFluticasone, 2 puffs each nostril once a dayMaxair Autohailer, q4-6hr (rescue only)Claritin (generic) 10mg

JDM is an 81 year old caucasian male who has been active until the last 6 months. He lives in New England for 4 months of the year, and in the Bahamas for the remainder of the year. He exercises every day (typically a long walk), fishes and gardens. His longstanding PCP retired last year, and complains to his new PCP that he has bouts of light headedness and elevated heart rates. His wife is a retired nurse so she makes him take his blood pressure and heart rate often. Systolic pressure is usually normal, but diastolic pressure is low.

Can you identify potential interactions among the drugs based on sympotoms?

Brenner Fig 10-1

==

4

SYMPATHOLYTICSVASODILATORSANGIOTENSIN INHIBITORSAngiotensin Converting Enzyme (ACE) InhibitorsAngiotensin II receptor blockersRenin inhibitorDIURETICS

8

SYMPATHOLYTICS (see Table 9-1, Brenner)

Peripheral adrenergic receptor blockers -blockers:

propranolol, pindolol, metoprolol, atenolol -blockers:

prazosin (1-blocker), phenoxybenzamine (1- and 2-blocker)

1-, 2- and 1- blockers:

carvedilol, labetalol

Centrally acting drugs clonidine (2-agonist)

methyldopa (false transmitter)

Ganglionic blockers: trimethaphan (rarely used in the US, if at all, only for hypertensive emergencies only)

Relative Receptor Affinities

Alpha agonistsPhenylephrine 1>2>>>> Clonidine 2 >1>>>>

Mixed alpha and beta agonistsNorepinephrine (NE) 1=2; 1>> 2 Epinephrine (Epi) 1=2; 1= 2

Beta agonistDobutamine 1> 2 >>>>

Dopamine agonistDopamine D1=D2>> >>

modified from Katzung Table 9-2

Lippincott Fig 19-7

ADH

1

Brenner Fig 8-1

Presynaptic inhibitionof NE release

vasodilation (Epi)

vasoconstriction (NE)

+ inotropic+ chronotropic

NE

blood glucose(from muscle and liver)bronchodilation

Not on same tissue

-Adrenergic Receptor Blockers

Non-selective: 1-, 2-blockerpropranolol

Selective: 1-blockermetoprolol, atenolol1-, 2- and 1- blocker:carvedilol, labetalol

both indicated for hypertension carvedilol also approved for heart failure

patients

See Drugs for angina and heart failure for details

Note: Nebivolol (approved 1/08) 1-blocker with antioxidant and increases endothelial nitric oxide release (vasodilator)

Selective 1-blockers TPR because of vasodilation

(not typically first line drugs)•No adverse metabolic or lipid effects

**therefore, advantage over –blockers with co-morbidities

•Side effects: (Why might these be expected?)Postural hypotension (especially after first

dose)Occasional reflex tachycardia – tries to

compensateFluid retentionDoxazosin significant increase in CHF compared to diuretics

alone (ALLHAT) perhaps because of fluid retention

-blockers: Prazosin

Brenner Fig 9-4

PrazosinIntact feedback inhibition of NE release by 2 receptors

unless dose is too high

vascular1 receptors

1

= ? blockers

= ? blockers

Brenner Fig 9-3

TPR

CO

MAP

Before

Before

Before

After

After

After

-Methyldopa (false neurotransmitter)Chronic therapyReplaces NE: Less effective for stimulating 1-receptors More effective for stimulating 2-receptors

Centrally acting sympatholytics: TPR

Clonidine (2-agonist)For severe, refractory hypertensionSide effects include: sedation, dry mouth, and

rebound hypertension upon withdrawal after chronic use

-Methyldopa

**Clonidine X

X

2

Brenner Fig 8-1

RENIN-ANGIOTENSIN SYSTEM INHIBITORS

Angiotensin Converting Enzyme (ACE) Inhibitors: Captopril, Lisinopril

(many on the market: enalapril, ramipril...)

Angiotensin II receptor blockers (ARBs): Losartan

(many on the market: candesartan, irbesartan, valsartan...)

Direct renin inhibitor (DRI):Aliskiren

Examples of indications and clinical uses:Mild/moderate essential hypertensionHeart Failure (especially early stages)Diabetic nephropathy!!!!

AntidiureticHormone(ADH = vasopressin)

Brain

(AT1)

H2O retention &vasoconstriction

Na+ retention

PGsNO+

modified Brenner Fig 10-3

PGs = prostaglandins

ACE-Inhibitors• Differ in their pharmacokinetics

Half-life (T1/2), metabolism

•No adverse effects on lipid profiles or glycemic control

•All have cardioprotection independent of BPespecially in CAD patients (HOPE Trials, NEJM 2000)

• Also effective in reducing vascular complications associated with diabetes (type 1 definitely, maybe type 2)

especially effective with nephropathies (via anti-inflammatory mechanisms?)

Less effective in blacks unless combined with thiazide diuretics (Medline 2003; Circulation 2005; 112:3654-3666)

Captopril (prototype)•Highest oral bioavailability•Shortest t1/2 How would this affect dosing?

ACE-Inhibitors (con’t)

Side effects related to:Suppression of angiotensin II (AngII)

(hypotension and renal insufficiency)Increased in bradykinin

(cough and edema)Why?

Also:Hyperkalemia (caution with K+ sparing diuretics)Fetotoxic (do not use with pregnancies)Renal failure (with bilateral renal a. stenosis)

Bonus: Bradykinin stimulates vasodilation and

Prostraglandin/NO vasodilation

(high doses of NSAIDs may interfere with PGI2-mediated vasodilation)

LosartanBlocks AngII from binding to AT1 receptors

Allows AT2 receptors to be stimulated by circulating AngII

(promoting vasodilation????)

Relatively few side effectsless cough than with ACE-Ibut fetotoxic like ACE-I

Diabetes: slows progression of nephropathy (RENNAAL)

Cardioprotection (maybe??): reduces cardiac remodeling

Typically reserved for patients who do not tolerate ACE-I Some evidence ACE2 metabolizes AngII to Ang1-7 (a vasodilator), and there are non-ACE sources of AngII, therefore ARB’s might be more effective than ACE-I (stay tuned, more data is needed)Less effective antihypertensive in blacks (same as with ACE-I)

Aliskiren:Direct renin inhibitor (DRI)New class of nonpeptide, oral inhibitorBinds to a site on renin, preventing formation of angiotensin (Ang) ILowers plasma renin activity, Ang I, Ang II, and aldosterone

Safety and tolerance appear similar to ACE-I and ARBs

Significance of inhibiting renin?ACE-I and ARBs may increase renin

(because no negative feedback)Hydrochlorothiazides also increase renin

Pro(renin) receptors were recently identified• Activate MAP kinases and profibrotic signaling• May be involved in vascular remodeling (e.g., with

diabetes)

VASODILATORS

Ca2+ -channel blockers:DHPs: amlodipine, nifedipineDiltiazemVerapamil

Others: less frequently used for chronic TxHydralazineMinoxidil

Note: nitrates not used for chronic hypertensionTx

sodium nitroprusside (SNP):used for hypertensive emergencies and surgery)(cyanide toxicity due to metabolite – obsolete story)

VASODILATORS (con’t)

•Promote vascular smooth muscle relaxation, TPR

•Most (not all) produce concomitant reflexes if not dosed properly:

cardiac contractility and HR myocardial O2 consumption renin-angiotensin-aldosterone system

•Usually no effects on serum lipidsWhy would this be an advantage over other drugssuch as -blockers?

Ca2+ channel blockers (CCBs)

Site of action dependent on tissue selectivity

•Verapamilmost cardiac selective (nodal cells and myocytes)

•Diltiazemintermediate selectivity

•Dihydropyridines (DHPs)most vascular selective

Which is most likely used for antihypertensive therapy?Which is most likely to cause reflex tachycardia?

All have some coronary vasodilatory effects

See also Angina drug & Antiarrhythmic drug lectures

Side effects of DHPs include:•Headaches•Peripheral edema

Short acting DHPsImmediate-release nifedipine, nisoldipine, felodipineMay cause reflex tachycardia

Longer acting DHPsSustained-release nifedipine, amlodipine, isradipineDo not cause significant increases in HR(neither do verapamil or diltiazem)

Why?

Toxicities associated with DHPs(selected)

Doses to achieve BP goals will likely differ from anti-anginal goals,therefore side effects may be different

Hydralazine and Minoxidil•Typically reserved for severe hypertension•Often co-administered with a diuretic and/or -

blocker•Dilates arterioles, not veins

contraindicated for patients with angina, ischemic heart disease

Hydralazine• May act by increasing cGMP (similar to NO)(in combination with isosorbide dinitrate – see HF lecture)

Minoxidil (oral, not topical)• Opens KATP channels, thus hyperpolarizes cells

NOEndothelial cell

Vascular Smooth Muscle Cellsites of antihypertensive drug action

AcetylcholineBradykinin

cGMP

contractionMLCK Ca2+

GMP cAMP AMPPDE PDE

SR Ca2+

Ca2+

K+ATP

NE

1

AT1

AII

Epi2

PDE = phosphodiesterase

SildenafilcGMP PDE5 inhibitor (not used for systemic hypertension, but maybe pulmonary arterial hypertension)

blockeragonist

ACEIRenin inhibitor

ARBLosartan

A1 BlockerPrazosin

CCBDHP

Minoxidil

Hydralazine

DIURETICS:(those used for antihypertensive therapy)

•Thiazide diuretics: hydrochlorothiazide

•Loop diuretics: furosemide

•Potassium-sparing diuretics: amiloride, spironolactone, eplerenone

Discussed previously

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Int Med 2008, 168(2) update

Thiazides are DOC in hypertensive patients with metabolic syndrome

No evidence that ACEI, CCB, alpha blockers offer any advantage of clinical outcomes over thiazides in these patients (particularly in blacks with metabolic syndrome)

chlorthalidone, lisinopril, amlodipine, doxazosin

Doxazosin arm stopped early because of increased CV events, with 2x more HF compared to thiazide group

Clinical-Trial BasisCompelling Indication

ALLHAT, HOPE, ANBP2,LIFE, CONVINCE

High CAD Risk

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

Post-MI

MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT,

RALES

Initial Therapy Options

Diuretic, BB, ACEI, CCB

BB, ACEI, Aldo Ant

Diuretic, BB, ACEI,ARB, Aldo Ant

Heart Failure

JNC VII Compelling Indications for Drug Classes

ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction

Chobanian AV et al. JAMA. 2003;289:2560-2572

Recurrent Stroke Prevention PROGRESSDiuretic, ACEI

NKF-ADA Guideline,UKPDS, ALLHAT

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

ACEI, Diuretic, BB, ARB, CCB

ACEI, ARB

Diabetes Mellitus

Chronic Kidney Disease

Clinical considerations:Most effective treatment, ethnicity differences*Least side effects (most patients are

asymptomatic)Frequency of dosingCost

Fixed-drug combinations:-blocker and thiazide diureticACE inhibitor and thiazide diureticAII receptor blocker and diureticCa2+ channel blocker and ACE inhibitor

What are advantages and disadvantages of fixed-drug combinations?

Thiazide diuretics and -blockers:• Often used in combination• However, both may adversely affect lipid profiles

and insulin sensitivity (exaccerbate CAD, atherosclerosis, type 2 diabetes)

Presence of co-morbidities (considerations)

ACE inhibitors:• May also be beneficial for diabetic nephropathies

-blockers or Ca2+ channel blockers:• Useful for patients with angina

ACE inhibitors and diuretics:• Useful for patients with CHF

Diuretics and Ca2+ channel blockers:• Blacks respond better to each, rather than

to -blockers and ACE inhibitors

ARBs = angiotensin receptor blockers; AT-1 = angiotensin II sub-type 1; DHPs = dihydropyridines; SVR = systemic vascular resistance. (LH Opie, 2004.)

Antihypertensive Targets

(-)

Guidelines for treatment and prevention of hypertensionare published by the Joint National Committee (JNC) on the Detection, Prevention and Treatment of Hypertension

Guidelines and updates (including power point presentations, treatment algorhythms, etc…) can be found (free) through the NHLBI website

http://www.nhlbi.nih.gov/health/prof/heart/index.htm#hbp

http://www.nhlbi.nih.gov/guidelines/hypertension/

http://www.nhlbi.nih.gov/guidelines/hypertension/

http://www.nhlbi.nih.gov/health/prof/heart/index.htm#hbp