PHARMACOLOGY OF HYPERTENSION

VICKI GROO, PHARM.D.

CLINICAL ASSOCIATE PROFESSOR

CLINICAL PHARMACIST, HEART CENTER

vjust@uic.edu 413-0928

OBJECTIVES

Classify hypertension and define treatment goals

Be able to describe the pharmacology of oral antihypertensives with considerations in drug choice and compelling indications

Be able to describe the pharmacology of intravenous antihypertensives used in the treatment of hypertensive emergency

CLASSIFICATION

SBP DBPNormal < 120 and < 80Prehypertension 120-139 or 80-89Hypertension Stage 1 140-159 or 90-99 Stage 2 ≥ 160 or ≥ 100

**Adults (18 yo)**Avg of 2 readings, 2 mins apart, on 2 occasions

Secondary HTN only accounts for 5-10% of populationJAMA 2003;289:2560-2572

EPIDEMIOLOGY

31% of US population with HTN

30% of US population with pre-HTN

Present in:

• 69% of patients who present with 1st MI• 77% of patients who present with 1st stroke• 74% of patients with heart failure

Only 47% have BP under control

http://www.cdc.gov/bloodpressure/facts.htm

NATIONAL HEALTH & NUTRITION EXAMINATION SURVEY

2007-200881%73%50%

TREATMENT GOALS JNC-7

REDUCE MORBIDITY AND MORTALITY

Measurable goal:

• Prehypertension: <120/80• HTN w/ diabetes or renal disease: <130/80 • Others: <140/90

Minimize/ control other CV risk factors

Reduce/ minimize adverse drug effects

JAMA 2003;289:2560-2572

AHA BP TARGETS 2007:For prevention and management of ischemic heart disease:

Circulation 2007:115:2761-88

*Don’t worry about learning these for now. They may change

ALGORITHM FOR TREATMENT OF HYPERTENSION

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.

JNC VII JAMA 2003;289:2560-2572

DRUG THERAPY CONSIDERATIONSClinical trial data

Over 2/3 of patients will require ≥2 drugs

Cost/ adverse effectsJAMA 2003;289:2560-2572

LifestyleModifications

Physical activity

Lose weight

Limit salt intake

Limit alcohol intake

DASH eatingPlan

PHARMACOLOGY OF ANTIHYPERTENSIVESDiuretics:

• Deplete sodium thereby decreasing blood volume

Agents that block production or action of angiotensin

• Reduce peripheral vascular resistance• Potentially ↓ blood volume

Sympathoplegic agents:

• ↓ peripheral vascular resistance• Inhibit cardiac function• ↑ venous pooling in capacitance vessels

Direct vasodilators:

• Relax vascular smooth muscle, thus dilating resistance vessels

DIURETIC MOA

HCTZ CTD Indapamide

benzothiadiazine thiazide-like Non-thiazidesulfonamide

VD 2.5 L 3-13 L 25 L

T ½ 8-15 hours 45-60 hours 14 hours

duration 16-24 hours 48-72 hours

24 hr SBP (-) 7.4 ± 1.7 (-) 12.4 ± 1.8

PM BP (-)6.4 ± 1.8 (-) 13.5 ± 1.9

Hypertension 2004;43:4-9,

DIURETIC COMPARISON

Indapamide

P = 0.054 and 0.009 for 24 hr and pm BP respectively

DIURETIC CONSIDERATIONSK Dose Other

Thiazides: 1st line choice

Hydrochlorothiazide ↓ 12.5-50 mg/d

Chlorthalidone ↓↓ 12.5-25 mg/d

Metolazone ↓↓↓ 2.5-10 mg/d Reserve for resistant edema

Indapamide --- 1.25-2.5 mg/d 1st line choice elderly

Aldosterone Antag Reserve for resistant HTN or HF

Spironolactone ↑ 12.5-50 mg/d avoid K > 5.0 or CrCl < 30

Eplerenone ↑ 25-100 mg/d avoid K > 5.0 or CrCl < 30

K sparing Caution, ACE/ARB, renal failure

Amiloride ↑ 5- 20 mg/d Use in combo to counteract K loss

Triamterene ↑ 37.5-50 mg/d Combo product with HCTZ available

Loop Reserve for HF or resistant edema

Furosemide ↓↓ 20-80 mg/d Bioavailability 60% or less

Bumetanide ↓↓ 0.5-4 mg/d Bioavailability 80%

Torsemide ↓↓ 5-10 mg/d Bioavailability 80%

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

DIURETICSCompelling Indications:

• Heart Failure• High CAD risk• Diabetes• Recurrent Stroke Prevention

Monitoring

• Electrolytes after initiation or dose increases• Every 6-12 months• K sparing, every 3 months if also on RAAS inhibitor

Side Effects

• Increase glucose• Increase uric acid — precipitate gout• dehydration — orthostatic hypotension• Spironolactone — gynecomastia

MECHANISM OF ACTION

ACE INHIBITORS

Drug Dose

Captopril 12.5-50 mg tid

Enalapril 2.5-40 mg/day

Lisinopril 5-40 mg/day

Benazepril 5-80 mg/day

Fosinopril* 10-80 mg/day

Moexipril 7.5-30 mg/day

Quinapril 5-80 mg/day

Ramipril 1.25-20 mg/day

Perindopril 2-16 mg/day

Trandolapril 1-8 mg/day

ARBS

Drug Dose

Candesartan (Atacand)* 4-32 mg/d

Eprosartan (Tevetan)* 400-800 mg/d

Irbesartan (Avapro)* 75-300 mg/d

Losartan (Cozaar)* 25-100 mg/d

Omelsartan (Benicar) 20-40 mg/d

Telmisartan (Micardis) 40-80 mg/d

Valsartan (Diovan) 80-320 mg/d

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

* Dual elimination: liver & kidney

* generic

Combining with thiazide usually more effective than dose increase

Direct Renin Inhibitors• Aliskiren (Tekturna)• 150-300 mg/day• As effective as ACE or ARB in HTN

ACE INHIBITORS AND ARBCompelling Indications

• Systolic Heart Failure• DM• CKD with Proteinuria• CAD

Monitoring

• 1-2 weeks after initiation or dose change for K & Cr• Every 6 months on stable doses

Side Effects

• Dry Cough Switch to ARB• Angioedema: ARB likely okay, consider severity• Hyperkalemia: supplements, diet, worsening renal fxn

Combining RAAS inhibitors is generally not recommended

• No added benefit CV or renal outcomes / Increased toxicity• ACE or ARB + aldosterone antagonist is the exception

Avoid in Pregnancy

BETA BLOCKERSMOA: Sympatholytic ↓ HR and CO / ↓ release of renin

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

ReceptorAffinity

LipidSolubility

RenalElimination

Dose

Atenolol β1 Low Yes 25-100 mg/d

Bisoprolol β1 Low No 2.5-10 mg/d

Carvedilol β1, β2, α Mod No 3.125-25 mg bid

Labetalol β1, β2, α Low No 100-400 mg bid

Metoprolol tartrateMetoprolol succinate

β1 Mod No 50-200 mg bid25-200 mg/d

Nebivolol β1 Low No 5-40 mg/d

Propranolol β1, β2 High No 40-120 mg bid

Avoid sudden discontinuation Rebound HTN d/t up regulation of ᵦ receptors

BETA BLOCKERSCompelling Indications

• CAD• Systolic Heart Failure

Monitoring

• ECG if bradycardic- AV block• Avoid combining with other AV nodal blocking agents

Side Effects

• Bronchoconstriction—Reactive Airway Disease• Choose B1 selective agent and keep at lower doses

• Metabolic—↓HDL, ↑ LDL and triglycerides• Diabetes—↓ insulin sensitivity

• Mask symptoms of hypoglycemia, delay recovery• Carvedilol may have advantage as it ↑’s insulin sensitivity

• Peripheral Vascular Disease—↑ symptoms, use B1 selective• Depression—Choose agent with low lipid solubility• Fatigue

CALCIUM CHANNEL BLOCKERS

http://www.accesspharmacy.com/content.aspx?aID=6543820

http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html

CCB CONSIDERATIONS

AVNode

SA Node

Contractility Vasodilation

DHP

Nifedipine^ 0 1 1 5

Amlodipine 0 1 1 5

Felodipine 0 1 1 5

Nicardipine 0 1 0 5

Non-DHP#

Diltiazem^ 4 2 2 3

Verapamil^ 5 4 4 3

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

^ Do not use short acting agents in treatment of HTN# Do not combine with beta-blockers: increased risk of bradycardiaDoses provided in Dr DiDomenico’s lecture on angina

CALCIUM CHANNEL BLOCKERS

Compelling Indications

• High CAD risk• Diabetes

Monitoring / Side Effects

• Dihydropyridine (DHP)• peripheral edema• reflex tachycardia• dizziness

• Non DHP• Bradycardia• Contra-indicated in heart failure• Constipation (especially verapamil)

VASODILATORS: ALPHA-1 BLOCKERS

http://cvpharmacology.com/vasodilator/alpha.htm

Doxazosin: start 1 mg daily: max 8 mg dailyPrazosin: start 1 mg bid-tid: max 15 mg/dayTerazosin: start 1 mg qhs: max 20 mg/day

VASODILATORS: ALPHA-1 BLOCKERS

Compelling Indications: None

Second line therapy

• Also used to treat BPH (benign prostatic hypertrophy)

Monitoring:

• Na and H20 retention with high doses

Side Effects:

• Dizziness — Orthostatic hypotension, first dose syncope• Headaches• Reflex tachycardia• Fatigue

VASODILATORS: DIRECTMOA: vascular smooth muscle relaxation

Compelling Indications: None

Second line therapy: Resistant HTN

Hydralazine

• 10 – 50 mg qid; max 300 mg /day• Often dosed bid or tid to improve adherence• Rare but serious SE: Lupus erythematosus, blood dyscrasias,

peripheral neuritis• Headaches, tachycardia, angina, nausea, diarrhea, rash

Minoxidil

• Start 5 mg daily; usual 10-40 mg daily; max 100 mg daily• Rare but serious SE: Stevens-Johnson syndrome• Hypertrichosis — used topically to promote hair growth• Headache, edema, tachycardia, paresthesia

VASODILATORS: DIRECT

Caution: Increased myocardial workUse in combination with B-blocker / diuretic to combat these effects

CENTRAL ALPHA 2 AGONISTSBind to and activate α2 receptors in the brain

↓ sympathetic outflow to the heart → CO and HR

↓ sympathetic outflow to vasculature → ↓ vascular tone

http://www.cvpharmacology.com/vasodilator/Central-acting.htm

CENTRAL ALPHA 2 AGONISTSCompelling Indications: None

Second line therapy: Resistant HTN

Clonidine

• Start 0.1 mg bid, titrate up weekly: max 2.4 mg/day• Available as a transdermal patch changed weekly• Severe rebound HTN if stopped abruptly• Side Effects: sedation, depression, bradycardia + many more

Methyldopa

• Start 250-500 mg bid-tid, adjust every 2-3 days, max 3gm/day• Can be used in pregnancy• Serious but uncommon SE: blood dyscrasias, myocarditis,

pancreatitis• Side effects: sedation, orthostatic hypotension + many more

ANTIHYPERTENSIVES:

Centrally Acting:• Methlydopa• ClonidineSedation, dry mouth

B-blockers:• Atenolol• Carvedilol• Metoprolol• PropranololBradycardia

α 1 blocker:• Prazosin, Doxazosin,

TerazosinDizziness, edema

Vascular Smooth Muscle:• Hydralazine, Minoxidil• CCBsHeadache, Dizziness, edema,

Diuretics:• Thiazide• Loop• Otherhypokalemia

Angiotensinogen Angiotensin I

Angiotensin IIRenin

Aliskiren

ACE

ACE Inhibitors

ARBs

Hyperkalemia, dry cough

ALGORITHM FOR TREATMENT OF HYPERTENSION

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.

JNC VII JAMA 2003;289:2560-2572

INADEQUATE BP RESPONSE WITH INITIAL AGENT

Increase dose

Substitute new drug from different class

• Little to no response to initial drug • No compelling indication for the drug• Troublesome SE

Add a new drug from a different class

• Initial drug produces some response and is well tolerated• Compelling indication for the initial drug• Add thiazide if not used initially

HTN: SPECIAL POPULATIONSElderly

• Isolated systolic HTN common• SBP rises and DPB declines with aging

• Generally salt sensitive • Use lower initial drug doses and slower dose titration

• Avoid 1-blockers, labetalol, central 2 agonists

• JNC-8 – higher BP goal?

AHA Consensus Statement on the Elderly 2011

• Goal SBP < 140 mm Hg• Age > 80, goal SBP < 150 mmHg• No evidence for lower BP goals for elderly patients at high risk, eg

DM, CAD, CKD.• Maintain DBP > 65 mmHg --- coronary perfusion

Circulation 2011;123:2434-2506

HTN ELDERLY GUIDELINESCanada 2013

• In the very elderly (age ≥ 80), the target for SBP should be < 150 (grade C)

• No changes for those age 65-79; ie goal remains at < 140/90

Europe 2013

• In elderly < 80 years old with SBP ≥160 mmHg there is solid evidence to reducing SBP to 150 and 140 mmHg (IA)

• In fit elderly patients < 80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability (IIb C)

• If > 80 years and with initial SBP ≥160 mmHg, it is recommended to reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental conditions (IB)

Benefit in treating elderly, ↓ stroke, CV events, heart failureCanadian Journal of Cardiology 2013;29:528-542

HTN: SPECIAL POPULATIONS

African Americans

• Prevalence, severity and impact increased compared to other populations

• Onset at younger age• More Na+ sensitive, lower plasma renin activity• Good response to Na restriction and diuretic therapy• response to ACE inhibitors, ARBs, and -blockers as

monotherapy• HOWEVER, can be overcome by adding a diuretic• Still indicated if compelling indication exists!

• ACE inhibitor angioedema 2-4 x more frequent

HYPERTENSIVE CRISIS

HYPERTENSION CRISES

EMERGENCY

BP >180/120

Acute Target Organ Damage

Life threatening

GOAL: BP now

IV therapy

URGENCY

BP >180/120

No Target Organ Damage

Not life-threatening

GOAL: BP over days

Oral therapy

HYPERTENSIVE EMERGENCIES

Heart

• Acute coronary syndrome• Acute heart failure with pulmonary edema• Dissecting aortic aneurysm

CNS

• Intra-cerebral hemorrhage / CVA• Encephalopathy

Eclampsia

Acute Renal Failure

Eyes:

• Papilledema, hemorrhage

Goal: • Lower MAP no greater than 20-25% in a few hours• Maintain DBP 100-110 mmHg• Too rapid or too much cerebral hypoperfusion

Continuous BP monitoring

TREATMENT FOR HYPERTENSIVE EMERGENCIES

IV Vasodilators

Sodium Nitroprusside

Nicardipine

Nitroglycerin

Enalaprilat

Fenoldopam

Hydralazine

IV Adrenergic Inhibitors

Labetalol

Esmolol

Phentolamine

IV VASODILATORS

MOA Indication

Nitroprusside Vasodilator* Most HTN emergencies• Caution high ICP or azotemia

Nicardipine CCB Most HTN emergencies• Except acute heart failure• Caution coronary ischemia

Nitroglycerin Vasodilator* Coronary Ischemia

Enalaprilat ACE inhibitor Acute heart failure• Avoid in acute MI

Fenoldopam Dopamine 1 agonist* Most HTN emergencies• Caution glaucoma

Hydralazine Direct vasodilator Eclampsia

* See next slide

IV VASODILATORS: MOA

Pro drugRelease

Nitroprusside: • arteriole and venous• No tolerance• Less effect on HRNitroglycerin• 1° venodilator• Arteriole dilator at high doses• + tolerance

Fenoldopam

D1 receptor agonistmoderate affinity α2

vasodilation

http://cvpharmacology.com/vasodilator/nitrodilator%20mech.gif http://www.drugabuse.gov/sites/default/files/imagecache/content_image_landscape/images/colorbox/dopamine.gif

IV VASODILATORSDose Onset Adverse Effects

Nitroprusside 0.25-10 ug/min immediate ThiocyanateCyanide toxicity

Nicardipine 5-15 mg/hr 5-10 min ↑ HR, HA, flushing

Nitroglycerin 5-100 ug/min 2-5 min HA, vomitingTolerance with prolonged use

Enalaprilat 1.25-5 mg q6h 15-30 min High renin states: ↓↓↓ BPVariable response

Fenoldopam 0.1-0.3 ug/kg/min < 5 min ↑ HR, HA, flushing, nausea

Hydralazine 10-20 mg IV10-50 mg IM

10-20 min20-30 min

↑ HR, HA, flushing, vomiting, angina

Duration of action varies from 1-2 min to 6 hours

NITROPRUSSIDE TOXICITY

Metabolism releases Cyanide Increased Risk if:• Rate at ≥ 5 ug/kg/min • 2 ug/kg/min for prolonged

use (24-48 hours)• Renal insufficiency• Can administer Na

Thiosulfate to enhance metabolism of cyanide

Cyanide Toxicity• Weakness• Headaches• Vertigo• Confusion / giddiness• Perceived difficulty breathingThiocyanate Toxicity• Anorexia / nausea• Fatigue• Toxic psychosis

http://www.biomedcentral.com/content/figures/1471-2253-13-9-1-l.jpg

IV ADRENERGIC BLOCKERSMOA Indication

Labetalol B1, B2, α blocker Most HTN emergenciesExcept acute heart failure

Esmolol B1 blocker Aortic dissectionPerioperative

Phentolamine α antagonist Catecholamine excess

Dose Onset(min)

AdverseEffects

Labetalol 20-80 mg q 10 min0.5-2.0 mg/min

5-10 Heart block

Esmolol 250-500 ug/kg/min x 1 min50-100 ug/kg/min x 4 min

1-2 Hypotension, nausea

Phentolamine 5-15 mg 1-2 ↑ HR, HA, flushing

Duration of action varies from 3-10 min to 6 hours