Pharmacotherapy II

HYPERTENSION
Nonglek Kunawaradisai
Faculty of Pharmaceutical Sciences
Ubon Ratchathani University

OBJECTIVES
Review the diagnostic criteria for hypertension
Discuss optimal treatment plan and goal of
therapy in individual patient
Discuss pharmacological and non
pharmacological treatment for hypertension
Identify the available pharmacologic agents
available for the initial treatment
Review reasons for selecting specific agents
2

SCOPE
Review: Key features of JNC 7 & 8 and HTN
General facts about HTN
Pathophysiology
definition
classification
Major risk factors for CVD
Target organ damage (TOD)

Blood pressure (BP) measurement and clinical

evaluation
Prevention and treatment of high BP
Non-pharmacological (lifestyle modification)
Pharmacological agents
3

Hypertension in the U.S.

Source:CDC/NHNS, National Health and Nutrition Examination

Survey, 2011-2012
Available at http://www.cdc.gov. Accessed 8/24/14.

Hypertension in the U.S.

Source:CDC/NHNS, National Health and Nutrition Examination

Survey, 2011-2012
Available at http://www.cdc.gov. Accessed 8/24/14.

Joint National Committee (JNC)

Panel appointed by the
National Heart, Lung, and
Blood Institute (NHLBI)
First guidelines (JNC-1)
published in 1977
Subsequent updates published
in 3- to 6-year intervals
Last edition (JNC-7)
published in 2003
Chobanian AV et al. JAMA 2003;289:2560-72.

???

A 40 y/o sedentary WM with a FmHx of stroke

sees you for a health maintenance visit. His
BP=150/100 mmHg and an LDL cholesterol of
170 mg/dl
Which one of the following would have the
greatest impact on decreasing his future risk of
stroke?

A)
B)
C)
D)

A program of regular physical exercise

Aspirin 81 mg daily
Reduction of LDL to <130 mg/dl
Reduction of BP to normal
7

Answer:
D) Reduction of BP to normal

General Facts
Stroke is the 3rd leading cause of death in the
US
HTN is the most consistently powerful
predictor of stroke (Primary prevention of stroke. N Engl J Med
1995)

Lowering BP results in 35-40% reduction in

stroke incidence

DEFINITION
Systolic BP (SBP) > = 140 mmHg
and/or
Diastolic BP (DBP) > = 90 mmHg
While resting ...
9

PATHOPHYSIOLOGY
Primary HTN (essential)
Secondary HTN

10

BP Measurement and
Clinical Evaluation
Classification of BP
CVD Risk
Benefits of Lowering BP
BP Control Rates
BP Measurement Techniques

In-office

Patient Evaluation
Laboratory Tests and Other Diagnostic Procedures

11

JNC-7 Blood Pressure Classification

Blood
Pressure
Classification
Normal

Systolic blood Diastolic blood

pressure
pressure
(mm Hg)
(mm Hg)
< 120

< 80

Pre-hypertension

120-139

80-89

Stage 1 hypertension

140-159

90-99

Stage 2 hypertension

> 160

> 100

Chobanian AV et al. JAMA 2003;289:2560-72.

BP MEASUREMENT
Which of the following factors
can lower blood pressure
readings?
A)Obese extremities
B)Caffeine ingestion
C)Narrow BP cuff
D)Supporting the patients
back
http://www.mco.edu/org/whl/images/belissi.jpg
13

BP MEASUREMENT
Answer:
D)Supporting the patients back
relaxes the body, lowering BP an avg of 8 mmHg SBP
and DBP

Obese extremities
Caffeine ingestion
Narrow BP cuff

can result in false

elevations
14

IN-OFFICE BP MEASUREMENT
Measurement of BP should be obtained:
In all adults (age >18) at each visit
> 30 minutes after use of nicotine or caffeine
After 5 minutes of rest with arm supported at
heart level
With appropriate sized cuff
bladder should encircle 80% of the arm

15

IN-OFFICE BP (continued)
Measurement of BP should be obtained:
2X, >2min apart
repeat if >5 mm pressure difference
Seated, feet flat on floor
Back and arm supported, Arm at heart level
Manual mercury sphygmomanometer or
Recently calibrated aneroid manometer or
Validated automated device (JNCVI and VII)
16

17

CLINICAL EVALUATION
Which one of the following would be most likely to
have secondary HTN?
A) 39 y/o WM who weighs 119 kg and BP=142/94
B) 48 y/o AAF with LVH on echo and BP=162/98
C)62 y/o AAM with a strong FmHx of HTN
D) 78 y/o WF with abdominal bruits BP=182/102
E) 88 y/o WM with hemiparesis from prior stroke
BP=192/88
18

CLINICAL EVALUATION
Answer:
D) 78 y/o WF with abdominal bruits and BP is
182/102 mm Hg
Objective of the clinical evaluation:
1) Identify other CV risk factors
- assess lifestyle and concomitant
disorders
that may affect prognosis
and guide treatment
2) Reveal identifiable causes of high BP
3) Assess the presence/absence of target
19
organ damage
(TOD) and CVD

Major Cardiovascular Risk Factors

JNCVII
HTN
Smoking
Dyslipidemia
Diabetes mellitus
FmHx of *premature CAD
(women < 65 or men < 55)
Age (> 55 for men, >65 for women)
*Obesity (BMI >30 kg/m2)
*Physical inactivity
*Microalbuminuria or estimated GFR <60
mL/min
*HOPE trial N Engl J Med. 2000

20

SECONDARY HYPERTENSION
Sleep apnea
Chronic kidney disease
Primary aldosteronism
Renovascular disease
Chronic steroid therapy / Cushings syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease
21

SECONDARY HYPERTENSION
Drug-induced or related causes
NSAIDs
Cocaine, amphetamines, other illicit drugs
Sympathomimetics, oral contraceptives,
steroids
Cyclosporine and tacrolimus
Erythropoietin
Selected OTC supplements/medicines
(e.g., ephedra, ma haung, bitter orange)
22

Complications of Hypertension:
End-Organ Damage
Hypertension
Hypertension
Hemorrhage,
Stroke

Retinopathy

LVH, CHD, CHF

Peripheral
Vascular
Disease

CHD = coronary heart disease

CHF = congestive heart failure
LVH = left ventricular hypertrophy
Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Renal Failure,
Proteinuria
Slide Source
23
Hypertension Online
www.hypertensiononline.org

CLINICAL EVALUATION
Other historical factors that
may affect treatment decisions
Gout, sexual dysfunction,
bronchospasm, migraine, heart block,
pregnancy plans in female

Physical Examination
Goal is to assess for target organ
damage and clues to secondary causes
24

CLINICAL EVALUATION
Laboratory and other testing
Serum chemistries (fasting glucose,
electrolytes, renal function)
CBC, Lipids, UA, EKG
Other:
microalbuminuria
TSH
calcium
uric acid
echocardiography
25

TREATMENT
1. Non Pharmacological treatment
2. Pharmacological treatment

26

Blood Pressure Classification

SBP mmHg*

DBP
mmHg

Lifestyle
Modification

Drug
Therapy
**

<120

and <80

Encourage

No

Prehypertension

120-139

or 80-89

Yes

No

Stage 1
Hypertension

140-159

or 90-99

Yes

Single
Agent

Stage 2
Hypertension

160

or 100

Yes

Combo

BP
Classification
Normal

Treatment determined by highest BP category; **Consider

treatment for compelling indications regardless of BP

27

JNC 7 Express. JAMA. 2003 Sep 10;

PREVENTION AND
NON PHARMACOLOGIC TREATMENT

Lifestyle Modifications

28

Recommendation

Approximate SBP
Reduction Range

Weight reduction

Maintain normal body weight (body

mass index 18.524.9 kg/m2).

520 mm Hg/10 kg

DASH# eating plan

Adopt a diet rich in fruits,

vegetables, and lowfat dairy
products with reduced content of
saturated and total fat.

814 mm Hg

Dietary sodium reduction

Reduce dietary sodium intake to

<100 mmol per day (2.4 g
sodium or 6 g sodium chloride).

28 mm Hg

Aerobic physical activity

Regular aerobic physical activity at

least 30 minutes per day, most
days of the week.

49 mm Hg

Moderation of alcohol
consumption

Men: limit to <2 drinks* per

day.
Women and lighter weight
persons: limit to <1 drink*
per day.

24 mm Hg

Modification

29

Non-Pharmacologic therapy

Stop smoking !!!

30

Alcohol drink
Type of drinks
Beer

% alcohol

1 drink (mL)

normal

250

draft

4-5

300-375

11

136

35-40

37.5-43

Wine
Whiskey, Vodka

alcohol
(mL)
=

x
% alcohol
100

31

PHARMACOLOGIC THERAPY

32

Selecting Drug Therapy

Demographics
Coexisting diseases and therapies
Quality of life
Drug interactions
Economic considerations

33

Pharmacologic
Uncompelling Indication
Diuretics Thiazide type
CCBs
ACEIs/ARBs

Compelling Indication

34

35

Key elements in selecting

antihypertensive drug
Choose drug with morbidity/mortality
benefit first
Start low, titrate until effective dose

Consider add on second antihypertensive

when BP is not goal with one drug and
moderate to high dose
Prefer drug with morbidity/mortality benefit
If not, select second-line drug with favorable
side effect profile
36

Drug
Diuretics
Centrally acting

Duration Potency
+
+

+
++

Benefit

Risk

CV benefit, Cheap

Frequent Urination

Block feedback
Rebound HTN (Crisis)
regulation, Pregnancy
when abrupt cessation
(methyldopa)

++

BPH

First-dose phenomenon,
Orthostatic
hypotension

+/++

+/++

CV benefit, Compelling
indication

Exacerbation of Asthma,
COPD, HF; Metabolic
disturbance

Arteriolar vasodilators

+++

High potency

Tachyphylaxis

Ca2+ channel blockers

+/++

+/++

CV benefit, Compelling
indication

Ankle edema,
Orthostatic hypotension

+/++

++

CV benefit, Compelling
indication

Cough, Angioedema,
Renal failure,
hyperkalemia

++

++

CV benefit, Compelling
indication

Angioedema, Renal
failure, hyperkalemia

++

No dosage adjustment,
no clinical significant
DI

Angioedema, Renal
37
failure, hyperkalemia,
diarrhea

Adrenergic antagonists

Adrenergic antagonists

ACE inhibitors

AT1-receptor antagonists

Renin inhibitors

+/++

++

Monitoring
Baseline
BP, HR, basic chem, LFT, CBC

Follow-up
Monthly
More frequent for stage 2 hypertension or with comorbid

3-6 months interval when BP at goal and stable

BP, HR, BUN/SCr + K
Others as appropriate

Consider reducing dose and number of

agents after 1 year at or below goal

Monitoring Antihypertensives
Class

Parameters

Diuretics

blood pressure
BUN/serum creatinine
serum electrolytes (K+, Mg2+, Na+)
uric acid (for thiazides)

-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
39

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

Causes of Resistant Hypertension

Improper BP measurement
White coat hypertension
Volume overload: Na-water, inadequate
diuretic therapy
Drug-induced or other causes
Non-adherence
Inadequate doses
Drug associated with hypertension

Associated condition: obesity, alcohol

Disease causing secondary hypertension

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
41

Antihypertensive Agents

42

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

43

Diuretics
Thiazide
chlorthalidone, hydrochlorothiazide (HCTZ),
indapamide, metolazone

Loop
bumetanide, furosemide, torsemide

Potassium-sparing
amiloride, triamterene

Aldosterone antagonists
eplerenone, spironolactone
44

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

45

45

Additional considerations:
Diuretics
May have favorable effects on:
osteoporosis (thiazides)
May have unfavorable effects on: DM
(hyperglycemia at higher doses),
dyslipidemia (high dose), gout (> in men),
hyponatremia (> in women)
HCTZ: decreased benefit > 25mg, increased
side effects - anecdotal

46

Diuretics: Thiazide

thiazides

loop diuretics (GFR >30 ./)

loop diuretics
:
duration 1 (once daily
dose)
synergistic effect



osteoporosis
: thiazide
CrCl < 30 ml/min
:
hypokalemia, hypomagnesemia




hypercalcemia, hyperglycemia, hyperlipidemia,
hyperuricemia sexual dysfunction



47

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
48

Loop diuretics




(GFR<30 ./)

diuretics
loop diuretics

metabolic effect

hypocalcemia
:

Thiazide

serum
glucose serum lipid
hypocalcemia

osteoporosis
ototoxicity ,

49

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
50

K-sparing diuretics
Spironolactone aldosterone antagonist
competitive inhibitor aldosterone
distal tubules collecting ducts Na K
exchange natriuresis, diuresis
potassium retention.
Triamterene amiloride

distal collecting tubule

thiazide loop diuretic
hypokalemia, hypomagnesemia

HCTZ 50 mg +
amiloride 5 mg (Moduretic) HCTZ 25mg +
triamterene 50mg (Dyazide).
: hyperkalemia
renal
insufficiency, DM

potassium
ACEI, NSAIDs, potassium supplement51

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
52

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
53

CCBs
Dihydropyridines:
amlodipine, felodipine, isradipine, nicardipine,
nifedipine, nisoldipine, clevidipine

Non-dihydropyridines:
diltiazem, verapamil

Adverse effects of non-dihydropyridines:

bradycardia
atrioventricular block
systolic HF
54

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
55

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
56

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
57

CCB
Dihydropyridine

reflex
Non-dihydropyridine

AV SA node
AV conduction
diltiazem
verapamil
nifedipine

:
(sustained release)

:

immediate release SDHP

mortality
HF post MI

SDHP SL HTN crisis

diuretics beta blockers

58

Dihydropyridine: reflex tachycardia

short acting (nifedipine, nicardipine)
side effects
ankle edema,
flushing/dizziness, headache

Verapamil diltiazem bradycardia

heart block ADR

verapamil

: Bradycardia, Sinus or AV node

diseases, heart failure (

dihydropyridine
amlodipine,
felodipine)
59

ACE Inhibitors
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
60

61

61

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
62

Additional
Considerations
ACE-I
May have unfavorable effects on:
hyperkalemia
Contraindicated in pregnancy

63

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

64

ARBs
Do not block bradykinin breakdown
less cough than ACE Inhibitors

Adverse effects:
orthostatic hypotension
renal insufficiency
hyperkalemia

65

66

66

Additional
Considerations
ARB
Contraindicated in pregnancy

67

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
68

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
69

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

70

71

71

-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
72

-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

73

-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

74

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

75

-Blockers
Cardioselective
atenolol, betaxolol, bisoprolol, metoprolol,
nebivolol

Nonselective
nadolol, propranolol, timolol

Intrinsic sympathomimetic activity

acebutolol, carteolol, penbutolol, pindolol

Mixed - and -blockers

carvedilol, labetolol
76

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

77

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
78

Mixed - & -blockers

Carvedilol reduces mortality in patients
with systolic HF treated with diuretic &
ACE inhibitor
Adverse effects:
additional blockade produces more orthostatic
hypotension

79

Additional
Considerations
-blockers
May have favorable effects on: atrial
tachycardia and a-fib, essential tremor,
thyrotoxicosis, migraine, perioperative hypertension
May have unfavorable effects
on:asthma, 2nd or 3rd degree heart
block

80

 :

,
hyperthyroidism, migrane
:

bradycardia 2nd/3rd degree heart
block

fatigue :
titrate dose
heart failure :

pulmonary effect: non-selective

bronchospasm asthma, COPD.

metabolic effect: glucose interolance,
triglyceride HDL
abrupt withdrawal :

impotence, depression

: beta block
hypoglycemia insulin
81

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
vivid dreams, depression
Na+/H2O retention

82

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
83

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 2receptors may further reduce sympathetic tone

decrease HR, CO, TPR, plasma renin activity,
baroreceptor activity
84

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)
85

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
86

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
87

Direct Arterial Vasodilators

Adverse effects:
sodium/water retention
angina

Hydralazine can cause lupus-like

syndrome
Minoxidil can cause hypertrichosis

88

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

89

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
90

Direct Arterial Vasodilators

Use with diuretic (preferably thiazide) & blocker to reduce fluid retention & reflex
tachycardia
minoxidil
more potent vasodilator

hydralazine

91

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

92

Chronic HTN in Pregnancy

Drug/Class

Comments

Methyldopa

Preferred based on long-term follow-up data supporting

safety

-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)
93

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

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
94

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
95

Hypertensive Emergency
Drug

Dose

Onset Duratio Adverse Effects

(min) n (min)

Sodium
0.2510
Immedia
nitroprussid mcg/kg/min
te
e
intravenous
infusion (requires
special delivery
system)
Nicardipine 515 mg/h
hydrochlori intravenous
de

Clevidipine
butyrate

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

510

2-4

12

Special
Indications

Nausea, vomiting,
muscle twitching,
sweating,
thiocyanate and
cyanide intoxication

Most hypertensive
emergencies;
caution with high
intracranial
pressure, azotemia,
or in chronic kidney
disease
1530; Tachycardia,
Most hypertensive
may headache, flushing, emergencies except
exceed local phlebitis
acute heart failure;
240
caution with
coronary ischemia
5-15 Headache, syncope,
Most hypertensive
dyspnea, nausea,
emergencies except
vomiting
severe aortic
stenosis; caution
with heart failure

96

DiPiro
JT, Talbert RL,
Yee GC, Matzke GR, Wells <
BG,5Posey LM:
Pharmacotherapy:A
PathophysiologicMost
Approach,
7th Edition:
Fenoldopam
0.10.3
30
Tachycardia,
hypertensive
http://www.accesspharmacy.com/

Hypertensive Emergency
Drug

Dose

Onset Duratio Adverse Effects

Special
(min) n (min)
Indications
Nitroglycerin 5100 mcg/min
25
510 Headache, vomiting,
Coronary
intravenous infusion
methemoglobinemia,
ischemia
tolerance with
prolonged use
Hydralazine 1220 mg
1020 60240 Tachycardia, flushing, Eclampsia
hydrochlorid intravenous
2030
240 headache vomiting,
e
1050 mg
360 aggravation of angina
intramuscular
Labetalol
2080 mg
510
180 Vomiting, scalp tingling, Most
hydrochlorid intravenous bolus
360 bronchoconstriction,
hypertensive
e
every 10 min; 0.5
dizziness, nausea, heart emergencies
2.0 mg/min
block, orthostatic
except acute
intravenous infusion
hypotension
heart failure
Esmolol
250500
12
1020 Hypotension, nausea, Aortic
hydrochlorid mcg/kg/min
asthma, first-degree
dissection;
e
intravenous bolus,
heart block, heart
perioperative
then 50100
failure
mcg/kg/min
intravenous
infusion; may repeat
97
bolus after 5 min or
DiPiro JT, Talbert RL, increase
Yee GC, Matzke
GR,
Wells
BG,
Posey
LM:
Pharmacotherapy:A
Pathophysiologic
Approach,
7th
Edition:
infusion to
http://www.accesspharmacy.com/

QUESTION
The following are statements about the use of
diuretics for the treatment of HTN:
True or False
A) Diuretic therapy has been demonstrated to decrease
mortality rates in patients with HTN
True
B) Thiazide diuretics have been shown to reduce the
incidence of stroke in elderly individuals with isolated
systolic HTN
True

From: AAFP Core Content Review of Family Medicine 2003

98

QUESTION
C) Thiazide diuretics have been demonstrated to be as
effective as the CCB amlodipine or ACE-I lisinopril in
preventing nonfatal MI
True

D) When combined with other classes of HTN meds, lowdose diuretics can improve BP control
True

E)

In patients with HTN and normal renal function, loop

diuretics, such as furosemide, are generally more
effectice than thiazide diuretics
False

From: AAFP Core Content Review of Family Medicine 2003

99

MORE QUESTIONS
Which one of the following antihypertensive
agents can be given to diabetic patients
without adversely affecting glucose
metabolism?
A)
B)
C)
D)
E)

Hydrochlorothiazide
Chlorthalidone
Prazosin
Propranolol
Diazoxide
100

Answer:
C) Prazosin
Prazosin, a peripheral alpha blocker, has no
known adverse effects on glucose tolerance
Thiazide diuretics and Diazoxide (European) can
worsen hyperglycemia
-blockers may induce or mask hypoglycemia

101

MORE QUESTIONS
A 50 y/o WM with elevated cholesterol requires
medication for HTN. Which one of the
following can adversely affect the lipid profile?
A)
B)
C)

ACE inhibitors
Calcium channel blockers
Alpha blockers
-blockers

102

Answer:
D) -blockers
-blockers can raise triglycerides and
lower HDL
The other drugs listed have no adverse
effects on lipids
103

MORE QUESTIONS
A 40 y/o man currently being treated for HTN
abruptly stops his medication. He presents to
your office with significantly elevated BP,
palpitations, anxiety, and headache.
The patient was most likely taking
A) prazosin
B) clonidine
C) hydrochlorothiazide
D) hydralazine
E) captopril
104

Answer:
B) clonidine
Withdrawal of clonidine may produce a
hypertensive crisis
Accompanied by signs and symptoms
consistent with sympathetic overactivity
Good med to include in travel and deployment
kits
105

Back to the future JNC VII

- Evidence based
- Basic, cheap meds
- Fine tuned risk indicators
- Time spent with patient toward compliance
and success
http://www.nhlbi.nih.gov/guidelines/hypert
ension/phycard.pdf
106

107

New Guidelines for Hypertension

National Institute for Health and Clinical Excellence
(NICE), 2011
Kidney Disease: Improving Global Outcome (KDIGO),
2012
European Society of Hypertension/European Society of
Cardiology, (ESH/ESC), 2013
American Diabetes Association (ADA), 2014
American Society of Hypertension and the International
Society of Hypertension (ASH/ISH), 2014
Eighth Joint National Committee (JNC8), 2013

Comparison of JNC Guidelines

JNC7

JNC8

Nonsystematic literature
review and expert opinion
Range of study designs
No grading system for
recommendations
Recommendations:

Systematic review
Randomized, controlled
trials (RCT) only
Graded recommendations
Recommendations:

Lifestyle modifications
Initial therapy for HTN
Compelling indications
Addressed secondary HTN
and resistant HTN

No specific lifestyle
recommendations
Initial therapy for HTN
Racial, CKD, and diabetic
subgroups addressed
Addressed three key
questions

JNC8: Key Questions

In adults with HTN, does initiating antihypertensive
pharmacologic therapy at specific BP thresholds
improve health outcomes?
In adults with HTN, does treatment with
antihypertensive pharmacologic therapy to a
specified BP goal lead to improvements in health
outcomes?
In adults with HTN, do various antihypertensive
drugs or drug classes differ in comparative
benefits and harms on specific health outcomes?

JNC8: Methods
Excluded sample size < 100 and f/up period < 1 year
Only included randomized, controlled trials rated as good
or fair
Only included studies reporting effects of interventions
on:
MI
Stroke
ESRD, doubling of Scr, or halving of GFR
Heart failure (HF) or hospitalization for HF
Coronary revascularization or other revascularization
Mortality (Overall mortality, CVD-related mortality, CKDrelated mortality)

JNC8: Strength of Recommendation

Grad
e

Strength of Recommendation

Strong: High certainty net benefit is substantial

Moderate
Moderate certainty net benefit is moderate to
substantial, or
High certainty that net benefit is moderate

Weak: At least moderate certainty of small net

benefit

Expert Opinion
Insufficient evidence, or
Evidence is unclear or conflicting
Further research is recommended in this area

Recommendations for
General Population Age 60 Years
JNC 7

Evidence for JNC8

BP Goal < 140/90 mmHg

HYVET Trial

(No age recommendations)

SHEP Trial

JNC8
BP Goal < 150/90 mmHg
Rated Grade A

JATOS Trial
VALISH Trial

Recommendations for
General Population Age < 60 Years
JNC 7
BP Goal < 140/90 mmHg

JNC8
SBP Goal < 140 mmHg
Grade E

DBP Goal < 90 mmHg

Ages 30-59 years (Grade A)
Ages 18-29 years (Grade E)

Evidence for JNC8

HDFP Trial
Hypertension-Stroke

Cooperative Trial
MRC Trial
ANBP Trial
VA Cooperative Trial

Recommendations for General Non-black

Population (Including DM)
JNC 7
First-line: Thiazide diuretics
(no racial distinction made)

JNC8
First-line
Thiazide diuretics
CCB
ACE inhibitor
ARB

Grade B

Evidence for JNC8

ALLHAT Trial
BP control more important
than medication used
Alpha blockers not
recommended first-line
LIFE Study
Beta-blockers not
recommended first-line
Insufficient evidence to

recommend other classes

Recommendations for
General Black Population (Including DM)
JNC 7
First-line: Thiazide diuretics
(no racial distinction made)

JNC8
Initial treatment for black
population (Grade B)
with DM (Grade C)
Thiazide diuretics
CCB

ALLHAT Trial
Pre-specified subgroup

analysis
Thiazide more effective in
improving CV outcomes
compared to ACEi in black
patient subgroup
51% higher rate of stroke (RR

1.51; 95% CI 1.22-1.86) with

use of ACEi as initial therapy
in black patients (compared to
CCB)

46% of patients in subgroup

analysis had DM

Recommendations for
General Population Age 18 with CKD
JNC 7
Goal BP: < 130/80 mmHg
First-line agent: ACEi or ARB

JNC8
Goal BP: < 140/90 mmHg
Grade E

Initial or add-on treatment:

ACEi or ARB
Grade B
Regardless of race or DM
status

Evidence for JNC8

AASK Trial
MDRD Trial
Potential benefit of goal
<130/80 for patients with
proteinuria (>3g/24 hours)
REIN-2 Trial
No trials showed goal

<130/80 mmHg
significantly lowered
kidney or CV end points
compared to 140/90

Recommendations for
General Population Age 18 with DM
JNC 7
Goal BP: < 130/80
mmHg

JNC8
Goal BP: < 140/90 mmHg
Grade E

Evidence for JNC8

ACCORD-BP Trial
No difference in outcomes
with SBP < 140 vs. SBP <
120
No good or fair quality

trials to support DBP < 80

Comparison of JNC8 and IM HTN

Algorithm: BP Goals
IM HTN Algorithm
Age 60 years
Not addressed

JNC8
Age 60 years: < 150/90
Grade A

General population: < 140/90 General population: < 140/90

No grade of evidence

Hypertension & DM: <

130/80
No grade of evidence
ADA Guidelines: < 140/80

Hypertension & CKD

Not addressed

Grade E(Grade A:DBP,age 30-59)

Hypertension & DM: < 140/90

Grade E

Hypertension & CKD:< 140/90

Grade E

Comparison of JNC8 and IM HTN

Algorithm: Preferred Agents
IM HTN Algorithm

JNC8

General population

General population

Thiazide Diuretic : HCTZ

Black population
Not addressed

Thiazide, CCB, ACEi, ARB

(Grade B)

Black population
CCB or Thiazide (Grade B)
Grade C for black patients
with DM

DM
ACEi or ARB

CKD
Excluded from algorithm

DM
Thiazide, CCB, ACEi, ARB
(Grade B)

CKD
ACEi or ARB (Grade B)

121

*Time interval to recheck BP should be based on patient's

risk and adverse outcomes.

Figure 5. AHA/ACC/CDC treatment algorithm for hypertension.

James PA, Oparil S, Carter BL, eta!. 2014 evidence-based guideline for the management of high blood pressure in adults -report from the panel members
appointed to the Eighth Joint National Committee (JNC8). JAMA 2013. Available at http://jama.jamanetwork.com/article. aspx?articleid1791497.
Weber MA, Schiffrin EL, White WB, eta!. Clinical practice guidelines for the management of hypertension in the community. A statement by the American
122
Society of Hypertension and the International Society of Hypertension. J Clin Hyper 2013. Available at www.ash-us.org/ documents/ASH_ISHGuidelines_2013. pdf.
ACC American College of Cardiology; ACEI angiotensin-converting enzyme inhibitor; AHA American Heart Association; ARB

JNC8: Treatment Strategies (Grade E)

If goal BP not met after 1 month of treatment:
Increase dose of initial drug, or
Add a second drug (Thiazide, CCB, ACEi, or ARB)

If goal BP not met with 2 medications:

Add and titrate a third medication (Thiazide, CCB, ACEi, or
ARB)
Do not use ACE and ARB together

Other classes may be used in the following

scenarios:
Goal BP not met with 3 medications
Contraindication to thiazide, ACE/ARB, or CCB

Strategies for Reaching BP Goal

Start 1 drug, titrate to maximum dose, and
then add a second drug

Start 1 drug and then add a second drug before

achieving maximum dose of the initial drug

Begin with 2 drugs at the same time either as

2 separate pills or as a single pill combination
James PA, et al. JAMA. 2014;311:507-520.[1]

125