Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies

Abbreviations

ACE: 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 activity JNC 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

Overview
Definition, classification of hypertension (HTN)
Goals of therapy Compelling indications Lifestyle modifications Hypertension in pregnancy Treatment Orthostatic hypotension Hypertensive crisis Monitoring antihypertensive drug therapy
3

Hypertension
Persistent 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
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):12061252. 4

Target-Organ Damage
Brain: stroke, transient ischemic attack, dementia
Eyes: retinopathy Heart: left ventricular hypertrophy, angina Kidney: chronic kidney disease Peripheral Vasculature: peripheral arterial disease

Etiology
Essential hypertension: > 90% of cases hereditary component Secondary hypertension: < 10% of cases common causes: chronic kidney disease, renovascular disease other causes: Rx drugs, street drugs, natural products, food, industrial chemicals

Causes of 2 Hypertension
Diseases chronic kidney disease Cushing's syndrome coarctation of the aorta obstructive sleep apnea parathyroid disease pheochromocytoma primary aldosteronism renovascular disease thyroid disease
8

Causes of 2 Hypertension
Prescription drugs: prednisone, fludrocortisone, triamcinolone amphetamines/anorexiants: phendimetrazine, phentermine, sibutramine antivascular endothelin growth factor agents estrogens: usually oral contraceptives calcineurin inhibitors: cyclosporine, tacrolimus decongestants: phenylpropanolamine & analogs erythropoiesis stimulating agents: erythropoietin, darbepoietin
9

Causes of 2 Hypertension
Prescription drugs: NSAIDs, COX-2 inhibitors venlafaxine bupropion bromocriptine buspirone carbamazepine clozapine ketamine metoclopramide
10

Causes of 2 Hypertension
Situations: -blocker or centrally acting -agonists

when abruptly discontinued

-blocker without -blocker first when treating

pheochromocytoma

Food substances: sodium ethanol licorice

11

Causes of 2 Hypertension
Street drugs, other natural products: cocaine anabolic steroids cocaine withdrawal narcotic withdrawal ephedra alkaloids methylphenidate (e.g., ma-huang) phencyclidine herbal ecstasy ketamine phenylpropanolamine ergot-containing herbal analogs products nicotine withdrawal St. John's wort

12

Mechanisms of Pathogenesis
Increased cardiac output (CO): increased preload:

increased fluid volume excess sodium intake renal sodium retention excess RAAS stimulation sympathetic nervous system overactivity

venous constriction:

13

Mechanisms of Pathogenesis
Increased peripheral resistance (PR): functional vascular constriction:

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

structural vascular hypertrophy:

14

Arterial Blood Pressure

Sphygmomanometry: 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) Less than 120 and Diastolic Blood Pressure (mmHg) Less than 80 Normal

Prehypertension

120-139

or

80-89

Stage 1 hypertension

140-159

or

90-99

Stage 2 hypertension

> 160

or

> 100

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):12061252.

17

Clinical Controversy
White coat hypertension: elevated BP in clinic

followed by normal BP reading at home Aggressive treatment of white coat hypertension is controversial Patients with white coat hypertension may have increased CV risk compared to those without such BP changes

18

Classification for Adults

Classification 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 Controversy
Ambulatory 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 Goals
Reduce morbidity & mortality
Select drug therapy based on evidence demonstrating

risk reduction
Patient Population Most patients Diabetes mellitus Chronic kidney disease Target Blood Pressure < 140/90 mmHg < 130/80 mmHg <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):12061252.

21

2007 AHA Recommendations

More aggressive BP lowering for high risk patients
Most patients for general prevention <140/90 mmHg Patients with diabetes (CAD risk equivalent), <130/80 mmHg 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%

Patients with left ventricular dysfunction (HF)

<120/80 mmHg

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):27612788.

22

ALLHAT
Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT) Primary endpoints

fatal CHD nonfatal MI

Secondary endpoints other hypertension-related complications

HF stroke

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):29812997.

23

ALLHAT
Prospective, 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

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):29812997. 24

JNC7 Recommendations
Thiazide-like diuretics preferred 1st line therapy based

on clinical trials showing morbidity & mortality reductions

ALLHAT confirms 1st line role of thiazide diuretics

Compelling indications: comorbid conditions where

specific drug therapies provide unique long-term benefits based on clinical trials
drug therapy recommendations are in combination with

or in place of a thiazide diuretic

Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and 25 Treatment of High Blood Pressure. Hypertension 2003;42(6):12061252.

Clinical Controversy
Avoiding 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 trial
randomized patients to benazepril + amodipdine or

benazepril + HCTZ 11,506 patients with HTN & high CV risk

Combination benazepril + amlodipine superior to

benazepril + HCTZ for reducing CV events in high risk patients

26

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

Compelling Indications
Heart Failure
Post Myocardial Infarction High Coronary Disease Risk Diabetes Mellitus Chronic Kidney Disease Recurrent Stroke Prevention

27

Recommendations & Evidence

Strength of recommendations A: good, B: moderate, C: poor Quality of evidence 1: more than 1 properly randomized, controlled trial 2: 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
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ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DBP: diastolic blood pressure; SBP: systolic blood pressure

29

30 30

Lifestyle Modifications
Modification
Weight loss

Approximate Systolic Blood Recommendation Pressure Reduction (mm Hg)a Maintain normal body weight (body mass 520 per 10-kg weight loss 2 index 18.524.9 kg/m )

DASH-type dietary patterns

Reduced salt intake

Physical activity Moderation of alcohol intake

Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat 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) Regular aerobic physical activity (at least 30 min/day, most days of the week) Limit consumption to 2 drinks/day in men and 1 drink/day in women and lighterweight persons

814

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49 24

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/ 31

Clinical Controversy
Prehypertension: patients do not have HTN but at risk

for developing it Trial 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

Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354(16):16851697.

32

Hypertension in Pregnancy
Important to differentiate preeclampsia from chronic,

transient, & gestational hypertension Preeclampsia: >140/90 mmHg after 20 weeks gestation with proteinuria
restricted activity, bed rest, close monitoring beneficial
definitive treatment: delivery

Methyldopa: drug of choice

33

Chronic HTN in Pregnancy

Drug/Class Methyldopa -Blockers Labetolol Clonidine Calcium channel blockers Diuretics Comments Preferred based on long-term follow-up data supporting safety Generally safe, but intrauterine growth retardation reported Increasingly preferred over methyldopa because of fewer side effects Limited data Limited data; no increase in major teratogenicity with exposure 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)
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DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Diuretics
Exact hypotensive mechanism unknown
Initial 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 use

peripheral vascular resistance becomes lower than

pretreatment values

results in chronic antihypertensive effects

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Diuretics
Thiazide chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metolazone Loop bumetanide, furosemide, torsemide Potassium-sparing amiloride, triamterene Aldosterone antagonists eplerenone, spironolactone
36

Thiazide Diuretics
Dose in morning to avoid nocturnal diuresis
Adverse effects: hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction lithium toxicity with concurrent administration More effective antihypertensives than loop diuretics

unless CrCl < 30 mL/min Chlorthalidone 1.5 to 2 times as potent as HCTZ

37 37

Loop Diuretics
Dose in AM or afternoon to avoid nocturnal diuresis
Higher 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 Diuretics
Dose in AM or afternoon to avoid nocturnal diuresis
Generally reserved for diuretic-induced hypokalemia

patients Weak diuretics, generally used in combination with thiazide diuretics to minimize hypokalemia Adverse 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 antagonists
Dose in AM or afternoon to avoid nocturnal diuresis
Due 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
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ACE Inhibitors
2nd line to diuretics for most patients Block angiotensin I to angiotensin II conversion ACE (Angiotensin Converting Enzyme) distributed in

many tissues
primarily endothelial cells
blood vessels: major site for angiotensin II production

Block 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
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42 42

ACE Inhibitors
Monitor serum K+ & SCr within 4 weeks of initiation or

dose increase Adverse effects:

cough

up to 20% of patients due to increased bradykinin

angioedema hyperkalemia: particularly in patients with CKD or DM neutropenia, agranulocytosis, proteinuria,

glomerulonephritis, acute renal failure

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ARBs
Angiotensin II Receptor Blockers
Angiotensin II generation renin-angiotensin-aldosterone pathway alternative pathway using other enzymes such as chymases Inhibit 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 Inhibitors Adverse effects: orthostatic hypotension renal insufficiency hyperkalemia

45

46 46

ACE Inhibitor/ARB Warnings

Reduce starting dose 50% in some patients due to

hypotension risk
patients also taking diuretic volume depletion elderly patients

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

K+ sparing diuretics aldosterone antagonists

47

ACE Inhibitor/ARB Warnings

Can cause acute kidney failure in certain patients severe bilateral renal artery stenosis severe stenosis in artery to solitary kidney Pregnancy category C in 1st trimester
Pregnancy category D in 2nd & 3rd trimester

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Clinical Controversy
CV 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
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Clinical Controversy
ONgoing 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 both
25,620 patients > age 55 yr with diabetes & end-organ

damage or established atherosclerotic vascular disease

Combination therapy reduces proteinuria more than

monotherapy but worsens major renal outcomes

Mann 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. 50

Renin Inhibitor
1st agent FDA approved in 2007: aliskiren
Inhibits angiotensinogen to angiotensin I conversion FDA approved as monotherapy & combination therapy

with other antihypertensives Efficacy demonstrated with other antihypertensives including amlodipine, HCTZ, ACEIs/ARBs Does not block bradykinin breakdown
less cough than ACE Inhibitors

Adverse effects: orthostatic hypotension, hyperkalemia

51

52 52

-Blockers
Inhibit renin release weak association with antihypertensive effect Negative chronotropic & inotropic cardiac effects

reduce CO
-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
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-Blockers
Adverse effects: bradycardia atrioventricular conduction abnormalities acute heart failure abrupt discontinuation may cause rebound hypertension or unstable angina, myocardial infarction, & death in patients with high coronary disease risk bronchospastic pulmonary disease exacerbation may aggravate intermittent claudication, Raynauds phenomenon
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-Receptors
Distributed throughout the body concentrate differently in certain organs & tissues 1 receptors: heart, kidney stimulation increases HR, contractility, renin release 2 receptors: lungs, liver, pancreas, arteriolar smooth muscle stimulation causes bronchodilation & vasodilation mediate insulin secretion & glycogenolysis
55

Cardioselective -Blockers
Greater affinity for 1 than 2 receptors inhibit 1 receptors at low to moderate dose higher doses block 2 receptors Safer in patients with bronchospastic disease,

peripheral arterial disease, diabetes

may exacerbate bronchospastic disease when selectivity

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

Generally preferred -blockers for HTN

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-Blockers
Cardioselective atenolol, betaxolol, bisoprolol, metoprolol, nebivolol Nonselective nadolol, propranolol, timolol Intrinsic sympathomimetic activity acebutolol, carteolol, penbutolol, pindolol Mixed - and -blockers carvedilol, labetolol

57

Nonselective -Blockers
Inhibit 1 & 2 receptors at all doses
Can exacerbate bronchospastic disease Additional benefits in: essential tremor migraine headache thyrotoxicosis

58

Intrinsic sympathomimetic activity

Partial -receptor agonists do not reduce resting HR, CO, peripheral blood flow No clear advantage except patients with bradycardia

who must receive a -blocker Contraindicated post-myocardial infarction & for patients at high risk for coronary disease May not be as cardioprotective as other -blockers Rarely used

59

Clinical Controversy
Meta-analyses suggest -blocker based therapy may not

reduce CV events as well as other agents Atenolol t: 6 to 7 hrs yet it is often dosed once daily
IR 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 BID

60

Mixed - & -blockers

Carvedilol reduces mortality in patients with systolic

HF treated with diuretic & ACE inhibitor Adverse effects:

additional blockade produces more orthostatic

hypotension

61

CCBs
Calcium Channel Blockers
Inhibit influx of Ca2+ across cardiac & smooth muscle

cell membranes
muscle contraction requires increased free intracellular

Ca2+ concentration CCBs block high-voltage (L-type) Ca2+ channels resulting in coronary & peripheral vasodilation

dihydropyridines vs non-dihydropyridines different pharmacologically similar antihypertensive efficacy

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CCBs
Dihydropyridines: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, clevidipine Non-dihydropyridines: diltiazem, verapamil Adverse effects of non-dihydropyridines: bradycardia atrioventricular block systolic HF
63

CCBs
Dihydropyridines: 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 conduction may treat supraventricular tachyarrhythmias

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Non-dihydropyridine CCBs
ER products preferred for HTN
Block cardiac SA & AV nodes: reduce HR May produce heart block Not AB rated as interchangeable/equipotent due to

different release mechanisms & bioavailability Additional benefits in patients with atrial tachyarrhythmia

65

Dihydropyridine CCBs
Avoid short-acting dihydropyridines particularly IR nifedipine, nicardipine Dihydropyridines more potent peripheral vasodilators

than nondihydropyridines
may cause more reflex sympathetic discharge:

tachycardia, dizziness, headaches, flushing, peripheral edema

Additional benefits in Raynauds syndrome

Effective in older patients with isolated systolic HTN
66

1-Blockers
Not appropriate monotherapy for HTN
Inhibit smooth muscle catecholamine uptake in

peripheral vasculature: vasodilation & BP lowering Adverse effects:

orthostatic hypotension 1st dose phenomenon: transient dizziness, faintness,

palpitations, syncope within 1 to 3 hours of 1st dose lassitude, vivid dreams, depression priapism Na+/H2O retention
67

1-Blockers
1st dose at bedtime
Used with diuretics to minimize edema Caution in elderly patients Reduce benign prostatic hypertrophy symptoms block postsynaptic 1-adrenergic receptors on the prostate

relaxation decreased urinary outflow resistance

68

Central 2-Agonists
Stimulate 2-adrenergic receptors in the brain reduces sympathetic outflow from the brains vasomotor center

increases vagal tone

peripheral stimulation of presynaptic 2-receptors may

further reduce sympathetic tone decrease HR, CO, TPR, plasma renin activity, baroreceptor activity

69

Central 2-Agonists
Adverse effects: sodium/water retention abrupt discontinuation may cause rebound HTN depression orthostatic hypotension dizziness Clonidine: anticholinergic side effects Methyldopa: can cause hepatitis, hemolytic anemia

(rare)
70

Central 2-Agonists
Most effective if used with a diuretic minimizes fluid retention Use 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

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Direct Arterial Vasodilators

Direct arterial smooth muscle relaxation causes

antihypertensive effect (little or no venous vasodilation)

reduce impedence to myocardial contractility

potent reductions in perfusion pressure activate

baroreceptor reflexes baroreceptor activation: compensatory increase in sympathetic outflow; tachyphylaxis can cause loss of antihypertensive effect

counteract with concurrent -blocker clonidine if -blocker contraindicated

72

Direct Arterial Vasodilators

Adverse effects: sodium/water retention angina Hydralazine can cause lupus-like syndrome
Minoxidil can cause hypertrichosis

73

Reserpine
Peripheral 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

Reserpine
Adverse effects: sedation depression decreased CO sodium/water retention increased gastric acid secretion diarrhea bradycardia Use with diuretic (preferably thiazide) to avoid fluid

retention
75

Direct Arterial Vasodilators

Use with diuretic (preferably thiazide) & -blocker to

reduce fluid retention & reflex tachycardia

minoxidil

more potent vasodilator

hydralazine

76

Orthostatic Hypotension
Decrease 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 Crisis
BP > 180/120 mmHg reduce gradually Hypertensive urgency elevated BP no acute or progressing target-organ injury Hypertensive emergency acute or progressing target-organ damage

encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, eclampsia
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Hypertensive Emergency
Drug Dose Onset (min) Duration Adverse Effects (min)
12 Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication

Special Indications
Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease Most hypertensive emergencies except acute heart failure; caution with coronary ischemia Most hypertensive emergencies except severe aortic stenosis; caution with heart failure

Sodium 0.2510 mcg/kg/min Immediate nitroprusside intravenous infusion (requires special delivery system) Nicardipine 515 mg/h hydrochloride intravenous 510

1530; may Tachycardia, headache, exceed 240 flushing, local phlebitis

Clevidipine butyrate

Fenoldopam mesylate

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 0.10.3 mcg/kg/min intravenous infusion

2-4

5-15

Headache, syncope, dyspnea, nausea, vomiting

<5

30

Tachycardia, headache, nausea, flushing

Most hypertensive emergencies; caution with glaucoma

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

Hypertensive Emergency
Drug Nitroglycerin Dose 5100 mcg/min intravenous infusion Onset (min) 25 Duration Adverse Effects (min) 510 Headache, vomiting, methemoglobinemia, tolerance with prolonged use Special Indications Coronary ischemia

Hydralazine hydrochloride
Labetalol hydrochloride

1220 mg intravenous 1050 mg intramuscular

2080 mg intravenous bolus every 10 min; 0.5 2.0 mg/min intravenous infusion 250500 mcg/kg/min intravenous bolus, then 50100 mcg/kg/min intravenous infusion; may repeat bolus after 5 min or increase infusion to 300 mcg/min

1020 2030
510

60240 Tachycardia, flushing, 240360 headache vomiting, aggravation of angina

180360 Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension 1020 Hypotension, nausea, asthma, first-degree heart block, heart failure

Eclampsia

Esmolol hydrochloride

12

Most hypertensive emergencies except acute heart failure Aortic dissection; perioperative

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

80

Monitoring Antihypertensives
Class Diuretics Parameters blood pressure BUN/serum creatinine serum electrolytes (K+, Mg2+, Na+) uric acid (for thiazides) blood pressure heart rate blood pressure BUN/serum creatinine serum potassium

-Blockers Aldosterone antagonists ACE inhibitors Angiotensin II receptor blockers Direct Renin inhibitors Calcium channel blockers

blood pressure heart rate

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

Combination Therapy
Most patients require > 2 agents to control BP
A thiazide-type diuretic should be one of these agents

unless contraindicated Combination 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

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Acknowledgements
Prepared 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, BCPS Eric J. Maclaughlin, Pharm.D., BS Pharm Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA
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