Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies

AbbreviationsACE: angiotensin-converting enzyme

ARB: angiotensin II receptor blocker

AHA: American Heart Association

BP: blood pressure

CCB: calcium channel blocker

CV: cardiovascular

DBP: diastolic blood pressure

GFR: glomerular filtration rate

HF: heart failure ISA: intrinsic sympathomimetic activityJNC 7: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

MI: myocardial infarction

RAAS: renin-angiotensin aldosterone system

SBP: systolic blood pressure 2

OverviewDefinition, classification of hypertension (HTN)Goals of therapy Compelling indicationsLifestyle modifications Hypertension in pregnancyTreatment Orthostatic hypotensionHypertensive crisisMonitoring antihypertensive drug therapy

3

HypertensionPersistent elevation of arterial blood pressure (BP)National Guideline

7th Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)

~72 million Americans (31%) have BP > 140/90 mmHg

Most patients asymptomatic Cardiovascular morbidity & mortality risk directly

correlated with BP; antihypertensive drug therapy reduces cardiovascular & mortality risk

4Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

Target-Organ DamageBrain: stroke, transient ischemic attack,

dementiaEyes: retinopathy Heart: left ventricular hypertrophy, anginaKidney: chronic kidney disease Peripheral Vasculature: peripheral arterial

disease

5

6

EtiologyEssential hypertension:

> 90% of caseshereditary component

Secondary hypertension:< 10% of casescommon causes: chronic kidney disease,

renovascular diseaseother causes: Rx drugs, street drugs, natural

products, food, industrial chemicals

7

Causes of 2˚ HypertensionDiseases

chronic kidney diseaseCushing's syndromecoarctation of the aortaobstructive sleep apneaparathyroid diseasepheochromocytomaprimary aldosteronismrenovascular diseasethyroid disease

8

Causes of 2˚ HypertensionPrescription drugs:  

prednisone, fludrocortisone, triamcinoloneamphetamines/anorexiants: phendimetrazine,

phentermine, sibutramineantivascular endothelin growth factor agentsestrogens: usually oral contraceptivescalcineurin inhibitors: cyclosporine, tacrolimusdecongestants: phenylpropanolamine & analogserythropoiesis stimulating agents: erythropoietin,

darbepoietin

9

Causes of 2˚ HypertensionPrescription drugs:

NSAIDs, COX-2 inhibitorsvenlafaxine bupropionbromocriptinebuspironecarbamazepineclozapineketaminemetoclopramide

10

Causes of 2˚ HypertensionSituations:

β-blocker or centrally acting α-agonists when abruptly discontinued

β-blocker without α-blocker first when treating pheochromocytoma

Food substances:  sodiumethanol licorice

11

cocainecocaine withdrawalephedra alkaloids

(e.g., ma-huang)“herbal ecstasy” phenylpropanolamin

e analogsnicotine withdrawal

anabolic steroidsnarcotic withdrawalmethylphenidatephencyclidineketamineergot-containing

herbal productsSt. John's wort

12

Street drugs, other natural products:  

Causes of 2˚ Hypertension

Mechanisms of PathogenesisIncreased cardiac output (CO):

increased preload: increased fluid volume excess sodium intake renal sodium retention

venous constriction: excess RAAS stimulation sympathetic nervous system overactivity

13

Mechanisms of PathogenesisIncreased peripheral resistance (PR):

functional vascular constriction: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors

structural vascular hypertrophy: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors hyperinsulinemia due to obesity, metabolic syndrome

14

Arterial Blood PressureSphygmomanometry: indirect BP measurement MAP = 1/3 (SBP) + 2/3 (DBP)BP = CO x TPR

MAP: Mean Arterial Pressure SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure BP: Blood Pressure CO: Cardiac Output TPR: Total Peripheral Resistance

15

Arterial Pressure Determinants

16

Adult Classification Classification

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Normal Less than 120 and Less than 80

Prehypertension 120-139 or 80-89

Stage 1 hypertension

140-159 or 90-99

Stage 2 hypertension

> 160 or > 100

17Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

Clinical ControversyWhite coat hypertension: elevated BP in

clinic followed by normal BP reading at homeAggressive treatment of white coat

hypertension is controversialPatients with white coat hypertension may

have increased CV risk compared to those without such BP changes

18

Classification for AdultsClassification based on average of > 2

properly measured seated BP measurements from > 2 clinical encounters

If systolic & diastolic blood pressure values give different classifications, classify by highest category

> 130/80 mmHg: above goal for patients with diabetes mellitus or chronic kidney disease

Prehypertension: patients likely to develop hypertension

19

Clinical ControversyAmbulatory BP measurements may be more

accurate & better predict target-organ damage than manual BP measurements using a sphygmomanometer in a clinic setting (gold standard)

many patients may be misdiagnosed, misclassified

poor technique, daily BP variability, white coat HTN

Validated ambulatory BP monitoring: role in the routine HTN management unclear

20

Treatment GoalsReduce morbidity & mortality Select drug therapy based on evidence

demonstrating risk reduction

21

Patient Population Target Blood Pressure

Most patients < 140/90 mmHg

Diabetes mellitus < 130/80 mmHg

Chronic kidney disease

<130/80 mmHg

Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

2007 AHA RecommendationsMore aggressive BP lowering for high risk

patients

22

Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788.

Most patients for general prevention <140/90 mmHgPatients with diabetes (CAD risk equivalent), significant CKD, known CAD (MI, stable angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke, TIA, PAD, abdominal aortic aneurism [CAD risk equivalents]), Framingham risk score > 10%

<130/80 mmHg

Patients with left ventricular dysfunction (HF) <120/80 mmHg

ALLHATAntihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial (ALLHAT)

Primary endpointsfatal CHD nonfatal MI

Secondary endpointsother hypertension-related complications

HF stroke

23

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.

ALLHATProspective, double-blind trial

randomized patients to: chlorthalidone amlodipine doxazosin lisinopril-based therapy

42,418 patients: age > 55 yr with HTN + 1 additional CV risk factor (mean subject participation 4.9 years)

Thiazide-type diuretics remain unsurpassed for reducing CV morbidity & mortality in most patients

24

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.

JNC7 RecommendationsThiazide-like diuretics preferred 1st line

therapy based on clinical trials showing morbidity & mortality reductionsALLHAT confirms 1st line role of thiazide

diureticsCompelling indications: comorbid conditions

where specific drug therapies provide unique long-term benefits based on clinical trialsdrug therapy recommendations are in

combination with or in place of a thiazide diuretic

25Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

Clinical ControversyAvoiding Cardiovascular Events through

COMbination Therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH)

Endpoint: composite of death from CV causes, hospitalization for angina, nonfatal MI or stroke, coronary revascularization, & resuscitation after cardiac arrest

Prospective, double-blind, industry sponsored trialrandomized patients to benazepril + amodipdine or

benazepril + HCTZ11,506 patients with HTN & high CV risk

Combination benazepril + amlodipine superior to benazepril + HCTZ for reducing CV events in high risk patients

26Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J Med. 2009;359(23):2417-2428.

Compelling IndicationsHeart FailurePost Myocardial InfarctionHigh Coronary Disease Risk Diabetes MellitusChronic Kidney DiseaseRecurrent Stroke Prevention

27

Recommendations & EvidenceStrength of recommendations

A: good, B: moderate, C: poor Quality of evidence

1: more than 1 properly randomized, controlled trial2: at least 1 well-designed clinical trial with

randomization; cohort or case-controlled analytic studies; dramatic results from uncontrolled experiments or subgroup analyses

3: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities

28

29

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DBP: diastolic blood pressure; SBP: systolic blood pressure

3030

Lifestyle ModificationsModification Recommendation

Approximate Systolic Blood Pressure Reduction (mm Hg)a

Weight loss Maintain normal body weight (body mass index 18.5–24.9 kg/m2)

5–20 per 10-kg weight loss

DASH-type dietary patterns

Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat

8–14

Reduced salt intake

Reduce daily dietary sodium intake as much as possible, ideally to 65 mmol/day (1.5 g/day sodium, or 3.8 g/day sodium chloride)

2–8

Physical activity

Regular aerobic physical activity (at least 30 min/day, most days of the week)

4–9

Moderation of alcohol intake

Limit consumption to 2 drinks/day in men and 1 drink/day in women and lighter-weight persons

2–4

31

DASH, Dietary Approaches to Stop Hypertension.a Effects of implementing these modifications are time and dose dependent and could be greater for some patients.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Clinical ControversyPrehypertension: patients do not have HTN

but at risk for developing itTrial of Preventing Hypertension (TROPHY)

showed treating prehypertension with candesartan decreased progression to stage 1 hypertension

Unknown whether managing prehypertension with drug therapy and lifestyle modifications decreases CV events or if this approach is cost-effective

32Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354(16):1685–1697.

Hypertension in PregnancyImportant to differentiate preeclampsia from

chronic, transient, & gestational hypertensionPreeclampsia: >140/90 mmHg after 20

weeks’ gestation with proteinuriarestricted activity, bed rest, close monitoring

beneficialdefinitive treatment: delivery

Methyldopa: drug of choice

33

Chronic HTN in PregnancyDrug/Class Comments

Methyldopa Preferred based on long-term follow-up data supporting safety

β-Blockers Generally safe, but intrauterine growth retardation reported

Labetolol Increasingly preferred over methyldopa because of fewer side effects

Clonidine Limited data

Calcium channel blockers

Limited data; no increase in major teratogenicity with exposure

Diuretics Not first-line, probably safe in low doses

ACE inhibitors, ARBs

Pregnancy category C in 1st trimester, category D in 2nd & 3rd trimester. Major teratogenicity has been reported with exposure (fetal toxicity, death)

34DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

DiureticsExact hypotensive mechanism unknownInitial BP drop caused by diuresis

reduced plasma & stroke volume decreases CO and BP

causes compensatory increase in peripheral vascular resistance

Extracellular & plasma volume return to near pretreatment levels with chronic useperipheral vascular resistance becomes lower

than pretreatment values results in chronic antihypertensive effects

35

DiureticsThiazide

chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metolazone

Loopbumetanide, furosemide, torsemide

Potassium-sparingamiloride, triamterene

Aldosterone antagonistseplerenone, spironolactone

36

Thiazide DiureticsDose in morning to avoid nocturnal diuresisAdverse effects:

hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction

lithium toxicity with concurrent administrationMore effective antihypertensives than loop

diuretics unless CrCl < 30 mL/minChlorthalidone 1.5 to 2 times as potent as

HCTZ

3737

Loop Diuretics Dose in AM or afternoon to avoid nocturnal

diuresisHigher doses may be needed for patients

with severely decreased glomerular filtration rate or heart failure

Adverse effects:hypokalemia, hypomagnesemia, hypocalcemia,

hyperuricemia, hyperuricemia

38

Potassium-sparing DiureticsDose in AM or afternoon to avoid nocturnal

diuresisGenerally reserved for diuretic-induced

hypokalemia patientsWeak diuretics, generally used in combination

with thiazide diuretics to minimize hypokalemiaAdverse effects:

may cause hyperkalemia especially in combination with an ACE inhibitor, angiotensin-receptor blocker or potassium supplements

avoid in patients with CKD or diabetes

39

Aldosterone antagonistsDose in AM or afternoon to avoid nocturnal diuresisDue to increased risk of hyperkalemia, eplerenone

contraindicated in CrCl < 50 mL/min & patients with type 2 diabetes & proteinuria

Adverse effects:may cause hyperkalemia especially in combination

with ACE inhibitor, angiotensin-receptor blocker or potassium supplements

avoid in CKD or DM patients Gynecomastia: up to 10% of patients taking

spironolactone

40

ACE Inhibitors2nd line to diuretics for most patients Block angiotensin I to angiotensin II conversion ACE (Angiotensin Converting Enzyme)

distributed in many tissuesprimarily endothelial cellsblood vessels: major site for angiotensin II

productionBlock bradykinin degradation; stimulate

synthesis of other vasodilating substances such as prostaglandin E2 & prostacyclin

Prevent or regress left ventricular hypertrophy by reducing angiotensin II myocardial stimulation

41

4242

ACE InhibitorsMonitor serum K+ & SCr within 4 weeks of

initiation or dose increaseAdverse effects:

cough up to 20% of patients due to increased bradykinin

angioedema hyperkalemia: particularly in patients with CKD

or DMneutropenia, agranulocytosis, proteinuria,

glomerulonephritis, acute renal failure 43

ARBs Angiotensin II Receptor BlockersAngiotensin II generation

renin-angiotensin-aldosterone pathwayalternative pathway using other enzymes such

as chymasesInhibit angiotensin II from all pathways

directly block angiotensin II type 1 (AT1) receptor

ACE inhibitors partially block effects of angiotensin II

44

ARBs Do not block bradykinin breakdown

less cough than ACE InhibitorsAdverse effects:

orthostatic hypotensionrenal insufficiencyhyperkalemia

45

4646

ACE Inhibitor/ARB WarningsReduce starting dose 50% in some patients

due to hypotension riskpatients also taking diureticvolume depletion elderly patients

May cause hyperkalemia in: CKD patients patients on other K+ sparing medications

K+ sparing diuretics aldosterone antagonists

47

ACE Inhibitor/ARB WarningsCan cause acute kidney failure in certain

patients severe bilateral renal artery stenosis severe stenosis in artery to solitary kidney

Pregnancy category C in 1st trimesterPregnancy category D in 2nd & 3rd trimester

48

Clinical ControversyCV events risk further reduced when ARB

combined with an ACE inhibitor for patients with left ventricular dysfunction

Data supports ACE/ARB combination therapy for patients with severe forms of nephrotic syndrome

Combination ACE/ARB therapy not well studied as standard treatment for HTN

Significantly higher risk of adverse effects such as hyperkalemia

49

Clinical ControversyONgoing Telmisartan Alone and in combination with

Ramipril Global Endpoint Trial (ONTARGET)Endpoint: composite of death, dialysis, SCr doubling Prospective, randomized, multicenter, double-blind

trial; patients randomized patients to ramipril, telmisartan, combination of both25,620 patients > age 55 yr with diabetes & end-organ

damage or established atherosclerotic vascular diseaseCombination therapy reduces proteinuria more than

monotherapy but worsens major renal outcomes

50Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-543.

Renin Inhibitor1st agent FDA approved in 2007: aliskirenInhibits angiotensinogen to angiotensin I conversionFDA approved as monotherapy & combination

therapy with other antihypertensives Efficacy demonstrated with other antihypertensives

including amlodipine, HCTZ, ACEIs/ARBsDoes not block bradykinin breakdown

less cough than ACE InhibitorsAdverse effects: orthostatic hypotension,

hyperkalemia

51

5252

β-BlockersInhibit renin release

weak association with antihypertensive effectNegative chronotropic & inotropic cardiac

effects reduce CO β-blockers with intrinsic sympathomimetic

activity (ISA) do not reduce CO lower BP decrease peripheral resistance

Membrane-stabilizing action on cardiac cells at high enough doses

53

β-BlockersAdverse effects:

bradycardiaatrioventricular conduction abnormalitiesacute heart failureabrupt discontinuation may cause rebound

hypertension or unstable angina, myocardial infarction, & death in patients with high coronary disease risk

bronchospastic pulmonary disease exacerbationmay aggravate intermittent claudication,

Raynaud’s phenomenon

54

β-ReceptorsDistributed throughout the body

concentrate differently in certain organs & tissuesβ1 receptors:

heart, kidneystimulation increases HR, contractility, renin

releaseβ2 receptors:

lungs, liver, pancreas, arteriolar smooth musclestimulation causes bronchodilation & vasodilation mediate insulin secretion & glycogenolysis

55

Cardioselective β-BlockersGreater affinity for β1 than β2 receptors

inhibit β1 receptors at low to moderate dosehigher doses block β2 receptors

Safer in patients with bronchospastic disease, peripheral arterial disease, diabetesmay exacerbate bronchospastic disease when

selectivity lost at high doses dose where selectivity lost varies from patient

to patientGenerally preferred β-blockers for HTN

56

β-BlockersCardioselective

atenolol, betaxolol, bisoprolol, metoprolol, nebivolol

Nonselectivenadolol, propranolol, timolol

Intrinsic sympathomimetic activityacebutolol, carteolol, penbutolol, pindolol

Mixed α- and β-blockerscarvedilol, labetolol

57

Nonselective β-Blockers Inhibit β1 & β2 receptors at all dosesCan exacerbate bronchospastic diseaseAdditional benefits in:

essential tremormigraine headachethyrotoxicosis

58

Intrinsic sympathomimetic activityPartial β-receptor agonists

do not reduce resting HR, CO, peripheral blood flow

No clear advantage except patients with bradycardia who must receive a β-blocker

Contraindicated post-myocardial infarction & for patients at high risk for coronary disease

May not be as cardioprotective as other β-blockers

Rarely used 59

Clinical ControversyMeta-analyses suggest β-blocker based therapy

may not reduce CV events as well as other agents

Atenolol t½: 6 to 7 hrs yet it is often dosed once dailyIR forms of carvedilol & metoprolol tartrate have

6- to 10- & 3- to 7-hour half-lives respectively: always dosed at least BID

Findings may only apply to atenolol may be a result of using atenolol daily instead of

BID60

Mixed α- & β-blockersCarvedilol reduces mortality in patients with

systolic HF treated with diuretic & ACE inhibitor

Adverse effects:additional blockade produces more orthostatic

hypotension

61

CCBsCalcium Channel BlockersInhibit influx of Ca2+ across cardiac & smooth

muscle cell membranesmuscle contraction requires increased free

intracellular Ca2+ concentrationCCBs block high-voltage (L-type) Ca2+ channels

resulting in coronary & peripheral vasodilationdihydropyridines vs non-dihydropyridines

different pharmacologically similar antihypertensive efficacy

62

CCBsDihydropyridines:

amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, clevidipine

Non-dihydropyridines: diltiazem, verapamil

Adverse effects of non-dihydropyridines:bradycardiaatrioventricular blocksystolic HF

63

CCBsDihydropyridines:

baroreceptor-mediated reflex tachycardia due to potent vasodilating effects

do not alter conduction through atrioventricular node not effective in supraventricular tachyarrhythmias

Non-dihydropyridines:decrease HR, slow atrioventricular nodal

conductionmay treat supraventricular tachyarrhythmias

64

Non-dihydropyridine CCBsER products preferred for HTNBlock cardiac SA & AV nodes: reduce HRMay produce heart blockNot AB rated as interchangeable/equipotent

due to different release mechanisms & bioavailability

Additional benefits in patients with atrial tachyarrhythmia

65

Dihydropyridine CCBsAvoid short-acting dihydropyridines

particularly IR nifedipine, nicardipineDihydropyridines more potent peripheral

vasodilators than nondihydropyridines may cause more reflex sympathetic discharge:

tachycardia, dizziness, headaches, flushing, peripheral edema

Additional benefits in Raynaud’s syndromeEffective in older patients with isolated

systolic HTN

66

α1-BlockersNot appropriate monotherapy for HTNInhibit smooth muscle catecholamine uptake in

peripheral vasculature: vasodilation & BP lowering

Adverse effects: orthostatic hypotension1st dose phenomenon: transient dizziness, faintness,

palpitations, syncope within 1 to 3 hours of 1st doselassitude, vivid dreams, depressionpriapismNa+/H2O retention

67

α1-Blockers1st dose at bedtimeUsed with diuretics to minimize edemaCaution in elderly patients Reduce benign prostatic hypertrophy

symptomsblock postsynaptic α1-adrenergic receptors on

the prostate relaxation decreased urinary outflow resistance

68

Central α2-AgonistsStimulate α2-adrenergic receptors in the

brain reduces sympathetic outflow from the brains

vasomotor center increases vagal tone

peripheral stimulation of presynaptic α2-receptors may further reduce sympathetic tone

decrease HR, CO, TPR, plasma renin activity, baroreceptor activity

69

Central α2-AgonistsAdverse effects:

sodium/water retentionabrupt discontinuation may cause rebound

HTNdepressionorthostatic hypotension dizziness

Clonidine: anticholinergic side effectsMethyldopa: can cause hepatitis, hemolytic

anemia (rare)70

Central α2-AgonistsMost effective if used with a diuretic

minimizes fluid retentionUse caution in elderly patients Clonidine transdermal patch: placed weekly

may result in fewer adverse effects avoids high peak serum drug concentrations

delayed onset: 2 to 3 days overlap with PO formulation at

initiation/discontinuation

71

Direct Arterial Vasodilators Direct arterial smooth muscle relaxation

causes antihypertensive effect (little or no venous vasodilation)reduce impedence to myocardial contractilitypotent reductions in perfusion pressure

activate baroreceptor reflexesbaroreceptor activation: compensatory

increase in sympathetic outflow; tachyphylaxis can cause loss of antihypertensive effect counteract with concurrent β-blocker clonidine if β-blocker contraindicated

72

Direct Arterial Vasodilators Adverse effects:

sodium/water retentionangina

Hydralazine can cause lupus-like syndromeMinoxidil can cause hypertrichosis

73

ReserpinePeripheral adrenergic antagonist

depletes norephinephrine from sympathetic nerve endings; blocks norephinephrine transport into storage granules

reduces norephinephrine release into synapse following nerve stimulation reduced sympathetic tone peripheral vascular resistance reduction decreased BP

depletes catecholamines from brain & myocardium Maximum antihypertensive effect: 2 to 6 weeks

74

ReserpineAdverse effects:

sedationdepressiondecreased COsodium/water retentionincreased gastric acid secretiondiarrheabradycardia

Use with diuretic (preferably thiazide) to avoid fluid retention

75

Direct Arterial Vasodilators Use with diuretic (preferably thiazide) & β-

blocker to reduce fluid retention & reflex tachycardiaminoxidil

more potent vasodilatorhydralazine

76

Orthostatic HypotensionDecrease in SBP > 20 mmHg or DBP > 10

mmHg when changing from supine to standing position

Older patients with isolated systolic hypertension at risk at initiation of drug therapy

Prevalent with diuretics, ACE inhibitors, ARBs

Treatment should remain the same with low initial doses & gradual dose titrations

77

Hypertensive CrisisBP > 180/120 mmHg

reduce gradually Hypertensive urgency

elevated BPno acute or progressing target-organ injury

Hypertensive emergencyacute or progressing target-organ damage

encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, eclampsia

78

Hypertensive EmergencyDrug Dose Onset

(min)Duration

(min)Adverse Effects Special Indications

Sodium nitroprusside

0.25–10 mcg/kg/min intravenous infusion (requires special delivery system)

Immediate 1–2 Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication

Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease

Nicardipine hydrochloride

5–15 mg/h intravenous

5–10 15–30; may exceed 240

Tachycardia, headache, flushing, local phlebitis

Most hypertensive emergencies except acute heart failure; caution with coronary ischemia

Clevidipine butyrate

1-2 mg/h intravenous infusion; may double dose every 90 sec initially; maximum: 32 mg/h; typical maintenance dose: 4 to 6 mg/h

2-4 5-15 Headache, syncope, dyspnea, nausea, vomiting

Most hypertensive emergencies except severe aortic stenosis; caution with heart failure

Fenoldopam mesylate

0.1–0.3 mcg/kg/min intravenous infusion

< 5 30 Tachycardia, headache, nausea, flushing

Most hypertensive emergencies; caution with glaucoma

79DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Hypertensive EmergencyDrug Dose Onset

(min)Duration

(min)Adverse Effects Special

IndicationsNitroglycerin 5–100 mcg/min

intravenous infusion2–5 5–10 Headache, vomiting,

methemoglobinemia, tolerance with prolonged use

Coronary ischemia

Hydralazine hydrochloride

12–20 mg intravenous10–50 mg intramuscular

10–2020–30

60–240240–360

Tachycardia, flushing, headache vomiting, aggravation of angina

Eclampsia

Labetalol hydrochloride

20–80 mg intravenous bolus every 10 min; 0.5–2.0 mg/min intravenous infusion

5–10 180–360 Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension

Most hypertensive emergencies except acute heart failure

Esmolol hydrochloride

250–500 mcg/kg/min intravenous bolus, then 50–100 mcg/kg/min intravenous infusion; may repeat bolus after 5 min or increase infusion to 300 mcg/min

1–2 10–20 Hypotension, nausea, asthma, first-degree heart block, heart failure

Aortic dissection; perioperative

80DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Monitoring Antihypertensives Class Parameters

Diuretics blood pressureBUN/serum creatinineserum electrolytes (K+, Mg2+, Na+)uric acid (for thiazides)

β-Blockers blood pressureheart rate

Aldosterone antagonistsACE inhibitorsAngiotensin II receptor blockers Direct Renin inhibitors

blood pressureBUN/serum creatinineserum potassium

Calcium channel blockers blood pressureheart rate

81DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Combination TherapyMost patients require > 2 agents to control

BPA thiazide-type diuretic should be one of

these agents unless contraindicatedCombination regimens should include a

diuretic (preferably a thiazide)Resistant hypertension: failure to achieve BP

goal on full doses of 3 drug regimen including a diuretic

82

AcknowledgementsPrepared By/Series Editor: April Casselman, Pharm.D.

Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

Chapter Authors: Joseph J. Saseen, Pharm.D., FCCP, BCPSEric J. Maclaughlin, Pharm.D., BS Pharm

Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

83