Transcript Hypertension

M HASANZADEH . MD,
MUMS OCT 2009
2
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
3
Overview
 Definition, classification of hypertension (HTN)
 Goals of therapy
 Compelling indications
 Lifestyle modifications
 Treatment
 Hypertensive crisis
 Monitoring antihypertensive drug therapy
4
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):1206–1252.
5
Guidelines in measuring BP
 Condition:
-Posture (sitting,supine,standing)
-Circumstances (no caffeine.no smoking)
 Equipment:
-Cuff size
-Manometer
 Technique:
-number of readings
-Performance
-recordings
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
7
8
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
9
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
10
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
11
Causes of 2˚ Hypertension
 Prescription drugs:
 NSAIDs, COX-2 inhibitors
 venlafaxine
 bupropion
 bromocriptine
 buspirone
 carbamazepine
 clozapine
 ketamine
 metoclopramide
12
Causes of 2˚ Hypertension
 Situations:
 β-blocker or centrally acting α-agonists

when abruptly discontinued
 β-blocker without α-blocker first when treating
pheochromocytoma
 Food substances:
 sodium
 ethanol
 licorice
13
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
14
Arterial Pressure Determinants
15
Mechanisms of Pathogenesis
 Increased cardiac output (CO):
 increased preload:



increased fluid volume
excess sodium intake
renal sodium retention
 venous constriction:


excess RAAS stimulation
sympathetic nervous system overactivity
16
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
 structural vascular hypertrophy:





excess RAAS stimulation
sympathetic nervous system overactivity
genetic alterations of cell membranes
endothelial-derived factors
hyperinsulinemia due to obesity, metabolic syndrome
17
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
18
Adult Classification
Classification
Normal
Systolic Blood
Pressure (mmHg)
Diastolic Blood
Pressure (mmHg)
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
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.
19
SYSTEMIC HYPERTENSION
 CLASSIFICATION



OPTIMAL
<120
<80
NORMAL
<130
<85
HIGH NORMAL 130-139 85-89
HYPERTENSION
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
22
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
23
Classification of blood pressure for
adult
 JNC7
 Normal
JNC6
SBP
and/or
optimal
<120
and
 Prehypertension
___
120_139
 ____
normal
<130
 ____
high-normal 130_139
 Hypertension:
hypertension:
 Stage 1
stage 1
140-159
 stage 2
>/=160
 _____
stage 2
160-179
 _____
stage 3
>/=180
DBP
<80
or
and
or
80_89
<85
85_89
or
or
or
or
90-99
>/=100
100-109
>/=110
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
25
26
Investigation of the New
Hypertensive
 History and examination
 Exclude secondary Hypertension
 Urea and electrolytes
 FBS and ESR
 ECG
 Lipid profile
 Chest x-ray no longer routinely indicated
LABORATORY TESTS FOR HTN
 BASIC TESTS FOR INITIAL EVALUATION:
 ALWAYS INCLUDED
 USUALL INCLUDED
 SPECIAL STUDIES
LABORATORY TESTS FOR HTN
 ALWAYS INCLUDED TESTS:
 URINE FOR PROTEIN,BLOOD,GLUCOSE.
 MICROSCOPIC URINALYSIS.
 HEMATOCRIT.
 SERUM POTASSIUM.
 SERUM CREATININE OR BUN.
 FASTING GLUCOSE.
 TOTAL CHOLESTROL.
 EKG
LABORATORY TESTS FOR HTN
 USUALLY INCLUDED TESTS:
 TSH
 WBC
 HDL,LDL,TG
 SERUM CALC& PHOS
 CHEST X RAY &ECHO
LABORATORY TESTS FOR HTN
 SPECIAL STUDIES TO SCREEN FOR
SECONDARY HTN:
 1 . RENOVASCULAR DISEASE:
 ACE INHIBITOR RADIONUCLEIDE RENAL SCAN,RENAL
DUPLEX DOPPLER FLOW STUDIES ,MRI ANGIOGRAPHY.
 2 . PHEOCHROMOCYTOMA:
 24-h URINE ASSAY FOR:
CREATININE,METANEPHRINES,&CATHECH
LABORATORY TESTS FOR HTN
 SPECIAL STUDIES TO SCREEN FOR
SECONDARY HTN:
 3 .CUSHING SYNDROME:

OVERNIGHT DEXAMETHASONE

SUPRESSION TEST.

24-h URINE CORTISOL & CREATININE.
 4 .PRIMARY ALDOSTRONISM:

PLASMA ALDOSTRONE:RENIN ACTIVITY
RISK FACTORS FOR ADVERS
PROGNOSIS IN HTN
 BLACK RACE
 EVIDENCE OF END
 YOUTH
 MALE GENDER
 SMOKING
 DM
 OBESITY
 ALCOHOL INTAKE
 HYPERCHOLESTROLEMIA




ORGAN
DAMAGE(LVH,LVSTRAIN,
MI,CHF)
RETINAL
HEMORR&EXODATE
PAPILLEDEMA
RENAL:IMP REN FUN
CVA
HYPERTENSION
EMERGENCY
URGENCY
ACCELERATED
MALIGNANT
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):1206–1252.
35
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):2761–2788.
36
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):2981–2997.
37
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):2981–2997.
38
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
39
Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
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
Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J
Med. 2009;359(23):2417-2428.
40
41
Compelling Indications
 Heart Failure
 Post Myocardial Infarction
 High Coronary Disease Risk
 Diabetes Mellitus
 Chronic Kidney Disease
 Recurrent Stroke Prevention
42
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
43
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker;
DBP: diastolic blood pressure; SBP: systolic blood pressure
44
4545
Lifestyle Modifications
Modification
Weight loss
DASH-type
dietary patterns
Reduced salt
intake
Physical activity
Moderation of
alcohol intake
Approximate Systolic Blood
Recommendation
Pressure Reduction
(mm Hg)a
Maintain normal body weight (body mass
5–20 per 10-kg weight loss
2
index 18.5–24.9 kg/m )
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
8–14
2–8
4–9
2–4
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/
46
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):1685–1697.
47
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
48
Chronic HTN in Pregnancy
Drug/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)
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
49
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
50
Diuretics
 Thiazide
 chlorthalidone, hydrochlorothiazide (HCTZ), indapamide,
metolazone
 Loop
 bumetanide, furosemide, torsemide
 Potassium-sparing
 amiloride, triamterene
 Aldosterone antagonists
 eplerenone, spironolactone
51
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
5252
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
53
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
54
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
55
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
56
5757
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
58
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
59
ARBs
 Do not block bradykinin breakdown
 less cough than ACE Inhibitors
 Adverse effects:
 orthostatic hypotension
 renal insufficiency
 hyperkalemia
60
6161
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
62
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
63
64
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
65
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.
66
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
67
68
68
β-Blockers
 Inhibit renin release
 weak association with antihypertensive effect
 Negative 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
69
β-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, Raynaud’s
phenomenon
70
β-Receptors
 Distributed throughout the body
 concentrate differently in certain organs & tissues
 β1 receptors:
 heart, kidney
 stimulation increases HR, contractility, renin release
 β2 receptors:
 lungs, liver, pancreas, arteriolar smooth muscle
 stimulation causes bronchodilation & vasodilation
 mediate insulin secretion & glycogenolysis
71
Cardioselective β-Blockers
 Greater affinity for β1 than β2 receptors
 inhibit β1 receptors at low to moderate dose
 higher doses block β2 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 β-blockers for HTN
72
β-Blockers
 Cardioselective
 atenolol, betaxolol, bisoprolol, metoprolol, nebivolol
 Nonselective
 nadolol, propranolol, timolol
 Intrinsic sympathomimetic activity
 acebutolol, carteolol, penbutolol, pindolol
 Mixed α- and β-blockers
 carvedilol, labetolol
73
Nonselective β-Blockers
 Inhibit β1 & β2 receptors at all doses
 Can exacerbate bronchospastic disease
 Additional benefits in:
 essential tremor
 migraine headache
 thyrotoxicosis
74
Intrinsic sympathomimetic activity
 Partial 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
75
Clinical Controversy
 Meta-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 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
76
Mixed α- & β-blockers
 Carvedilol reduces mortality in patients with systolic
HF treated with diuretic & ACE inhibitor
 Adverse effects:
 additional blockade produces more orthostatic
hypotension
77
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
78
CCBs
 Dihydropyridines:
 amlodipine, felodipine, isradipine, nicardipine,
nifedipine, nisoldipine, clevidipine
 Non-dihydropyridines:
 diltiazem, verapamil
 Adverse effects of non-dihydropyridines:
 bradycardia
 atrioventricular block
 systolic HF
79
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
80
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
81
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 Raynaud’s syndrome
 Effective in older patients with isolated systolic HTN
82
α1-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
83
α1-Blockers
 1st dose at bedtime
 Used with diuretics to minimize edema
 Caution in elderly patients
 Reduce benign prostatic hypertrophy symptoms
 block postsynaptic α1-adrenergic receptors on the
prostate


relaxation
decreased urinary outflow resistance
84
Central α2-Agonists
 Stimulate 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
85
Central α2-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)
86
Central α2-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
87
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 β-blocker
clonidine if β-blocker contraindicated
88
Direct Arterial Vasodilators
 Adverse effects:
 sodium/water retention
 angina
 Hydralazine can cause lupus-like syndrome
 Minoxidil can cause hypertrichosis
89
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
90
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
91
Direct Arterial Vasodilators
 Use with diuretic (preferably thiazide) & β-blocker to
reduce fluid retention & reflex tachycardia
 minoxidil

more potent vasodilator
 hydralazine
92
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
93
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
94
Hypertensive Emergency
Drug
Dose
Onset
(min)
Sodium
0.25–10 mcg/kg/min Immediate
nitroprusside intravenous infusion
(requires special
delivery system)
Nicardipine
5–15 mg/h
hydrochloride intravenous
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
0.1–0.3 mcg/kg/min
intravenous infusion
5–10
Duration Adverse Effects
(min)
1–2
Nausea, vomiting, muscle
twitching, sweating,
thiocyanate and cyanide
intoxication
15–30; may Tachycardia, headache,
exceed 240 flushing, local phlebitis
2-4
5-15
<5
30
Headache, syncope,
dyspnea, nausea,
vomiting
Tachycardia, headache,
nausea, flushing
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
Most hypertensive
emergencies; caution
with glaucoma
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
95
Hypertensive Emergency
Drug
Dose
Onset
(min)
2–5
Duration Adverse Effects
(min)
5–10 Headache, vomiting,
methemoglobinemia,
tolerance with prolonged use
Special
Indications
Coronary
ischemia
Nitroglycerin
5–100 mcg/min
intravenous infusion
Hydralazine
hydrochloride
12–20 mg intravenous
10–50 mg intramuscular
10–20
20–30
60–240 Tachycardia, flushing,
240–360 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
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
180–360 Vomiting, scalp tingling,
bronchoconstriction,
dizziness, nausea, heart
block, orthostatic
hypotension
10–20 Hypotension, nausea,
asthma, first-degree heart
block, heart failure
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/
96
Monitoring Antihypertensives
Class
Parameters
Diuretics
blood pressure
BUN/serum creatinine
serum electrolytes (K+, Mg2+, Na+)
uric acid (for thiazides)
β-Blockers
blood pressure
heart rate
Aldosterone antagonists
ACE inhibitors
Angiotensin II receptor
blockers Direct Renin
inhibitors
blood pressure
BUN/serum creatinine
serum potassium
Calcium channel blockers
blood pressure
heart rate
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
97
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
98
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
99
100