M Hasanzadeh - MD, Mums Oct 2009

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,
5
Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
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
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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
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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
 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
 Prescription drugs:
 NSAIDs, COX-2 inhibitors
 venlafaxine
 bupropion
 bromocriptine
 buspirone
 carbamazepine
 clozapine
 ketamine
 metoclopramide
12
 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
 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:
 genetic alterations of cell membranes
 endothelial-derived factors
 structural vascular hypertrophy:
 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
Systolic Blood Diastolic Blood
Classification
Pressure (mmHg) 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
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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 JNC6 SBP and/or DBP
 Normal optimal <120 and <80
 Prehypertension ___ 120_139 or 80_89
 ____ normal <130 and <85
 ____ high-normal 130_139 or 85_89
 Hypertension: hypertension:
 Stage 1 stage 1 140-159 or 90-99
 stage 2 >/=160 or >/=100
 _____ stage 2 160-179 or 100-109
 _____ stage 3 >/=180 or >/=110
 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
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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
 ALWAYS INCLUDED TESTS:
 URINE FOR PROTEIN,BLOOD,GLUCOSE.
 MICROSCOPIC URINALYSIS.
 HEMATOCRIT.
 SERUM POTASSIUM.
 SERUM CREATININE OR BUN.
 FASTING GLUCOSE.
 TOTAL CHOLESTROL.
 EKG
 USUALLY INCLUDED TESTS:

 TSH
 WBC
 HDL,LDL,TG
 SERUM CALC& PHOS
 CHEST X RAY &ECHO
 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
 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 ORGAN
DAMAGE(LVH,LVSTRAIN,
 MALE GENDER
MI,CHF)
 SMOKING
 RETINAL
 DM HEMORR&EXODATE
 OBESITY  PAPILLEDEMA
 ALCOHOL INTAKE  RENAL:IMP REN FUN
 HYPERCHOLESTROLEMIA  CVA
HYPERTENSION
EMERGENCY
URGENCY
ACCELERATED
MALIGNANT
Treatment Goals
 Reduce morbidity & mortality
 Select drug therapy based on evidence demonstrating
risk reduction
Patient Population Target Blood Pressure
Most patients < 140/90 mmHg
Diabetes mellitus < 130/80 mmHg
Chronic kidney disease <130/80 mmHg
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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 36
the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788.
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 37
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.
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 38
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.
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.
 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 40
Med. 2009;359(23):2417-2428.
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Compelling Indications
 Heart Failure
 Post Myocardial Infarction
 High Coronary Disease Risk
 Diabetes Mellitus
 Chronic Kidney Disease
 Recurrent Stroke Prevention
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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 44
4545
Lifestyle Modifications Approximate Systolic Blood
Modification Recommendation Pressure Reduction
(mm Hg)a
Weight loss Maintain normal body weight (body mass 5–20 per 10-kg weight loss
2
index 18.5–24.9 kg/m )
DASH-type Consume a diet rich in fruits, vegetables, 8–14

dietary patterns and low-fat dairy products with a reduced
content of saturated and total fat
Reduced salt Reduce daily dietary sodium intake as 2–8
intake much as possible, ideally to 65 mmol/day
(1.5 g/day sodium, or 3.8 g/day sodium
chloride)
Physical activity Regular aerobic physical activity (at least 30 4–9
min/day, most days of the week)
Moderation of Limit consumption to 2 drinks/day in men 2–4
alcohol intake and 1 drink/day in women and lighter-
weight persons
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:
46
http://www.accesspharmacy.com/
 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 47
2006;354(16):1685–1697.
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
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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 Limited data; no increase in major teratogenicity with

blockers exposure
Diuretics Not first-line, probably safe in low doses
ACE inhibitors, Pregnancy category C in 1st trimester, category D in 2nd & 3rd
ARBs trimester. Major teratogenicity has been reported with
exposure (fetal toxicity, death)
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
 hypokalemia, hypomagnesemia, hypocalcemia,
hyperuricemia, hyperuricemia
53
Potassium-sparing Diuretics
 Generally reserved for diuretic-induced hypokalemia
patients
 Weak diuretics, generally used in combination with
thiazide diuretics to minimize hypokalemia
 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
 Due to increased risk of hyperkalemia, eplerenone
contraindicated in CrCl < 50 mL/min & patients with
type 2 diabetes & proteinuria
 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
 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
 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
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 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
 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 66
(the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-543.
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
 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
 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
 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
 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
 sodium/water retention
 abrupt discontinuation may cause rebound HTN
 depression
 dizziness
 Clonidine: anticholinergic side effects
 Methyldopa: can cause hepatitis, hemolytic anemia
(rare)
86
 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
 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
 sedation
 depression
 decreased CO
 increased gastric acid secretion
 diarrhea
 bradycardia
 Use with diuretic (preferably thiazide) to avoid fluid
retention
91
 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 Duration Adverse Effects Special Indications
(min) (min)
Sodium 0.25–10 mcg/kg/min Immediate 1–2 Nausea, vomiting, muscle Most hypertensive
nitroprusside intravenous infusion twitching, sweating, emergencies; caution
(requires special thiocyanate and cyanide with high intracranial
delivery system) intoxication pressure, azotemia, or in
chronic kidney disease
Nicardipine 5–15 mg/h 5–10 15–30; may Tachycardia, headache, Most hypertensive
hydrochloride intravenous exceed 240 flushing, local phlebitis emergencies except
acute heart failure;
caution with coronary
ischemia
Clevidipine 1-2 mg/h intravenous 2-4 5-15 Headache, syncope, Most hypertensive
butyrate infusion; may double dyspnea, nausea, emergencies except
dose every 90 sec vomiting severe aortic stenosis;
initially; maximum: caution with heart
32 mg/h; typical failure
maintenance dose: 4
to 6 mg/h
Fenoldopam 0.1–0.3 mcg/kg/min <5 30 Tachycardia, headache, Most hypertensive
mesylate intravenous infusion nausea, flushing emergencies; caution
with glaucoma
95
Hypertensive Emergency
Drug Dose Onset Duration Adverse Effects Special
(min) (min) Indications
Nitroglycerin 5–100 mcg/min 2–5 5–10 Headache, vomiting, Coronary
intravenous infusion methemoglobinemia, ischemia
tolerance with prolonged use
Hydralazine 12–20 mg intravenous 10–20 60–240 Tachycardia, flushing, Eclampsia
hydrochloride 10–50 mg intramuscular 20–30 240–360 headache vomiting,
aggravation of angina
Labetalol 20–80 mg intravenous 5–10 180–360 Vomiting, scalp tingling, Most
hydrochloride bolus every 10 min; 0.5– bronchoconstriction, hypertensive
2.0 mg/min intravenous dizziness, nausea, heart emergencies
infusion block, orthostatic except acute
hypotension heart failure
Esmolol 250–500 mcg/kg/min 1–2 10–20 Hypotension, nausea, Aortic dissection;
hydrochloride intravenous bolus, then asthma, first-degree heart perioperative
50–100 mcg/kg/min block, heart failure
intravenous infusion;
may repeat bolus after 5
min or increase infusion
to 300 mcg/min
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 blood pressure
ACE inhibitors BUN/serum creatinine
Angiotensin II receptor serum potassium
blockers Direct Renin
inhibitors
Calcium channel blockers blood pressure
heart rate
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
99

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M HASANZADEH .

MAP: Mean Arterial Pressure

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

 BASIC TESTS FOR INITIAL EVALUATION:

 USUALLY INCLUDED TESTS:

 SPECIAL STUDIES TO SCREEN FOR

 SPECIAL STUDIES TO SCREEN FOR

DASH-type Consume a diet rich in fruits, vegetables, 8–14

β-Blockers Generally safe, but intrauterine growth retardation reported

Labetolol Increasingly preferred over methyldopa because of fewer side

Calcium channel Limited data; no increase in major teratogenicity with

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