For student of PHARM.D , M.B.B.S , B.D.S , D.P.T and patient of high blood pressure

1. Pharmacotherapy: A Pathophysiologic Approach
The McGraw-Hill Companies
Presented by
Dr.Muhammad Umair
Pharm.D
MPhil. (Clinical)
Lecturer
Lahore Pharmacy College of
Lahore Medical & Dental College

2. AbbreviationsACE: angiotensin-converting enzyme
ARB: angiotensin II receptor blocker
AHA: American Heart Association
BP: blood pressure
CCB: calcium channel blocker
CV: cardiovascular
DBP: diastolic blood pressure
GFR: glomerular filtration rate
HF: heart failure
ISA: intrinsic sympathomimetic 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 2

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

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
4
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. 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
5

6. 6

7. 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
7

8. Causes of 2˚ Hypertension
Diseases
chronic kidney disease
Cushing's syndrome (abnormal secretion of ACTH i.e.
adreno corticotropic hormone)
coarctation of the aorta
obstructive sleep apnea
parathyroid disease
pheochromocytoma
primary aldosteronism
renovascular disease
thyroid disease
8

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

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

11. 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
11

12. cocaine
cocaine withdrawal
ephedra alkaloids
(e.g., ma-huang)
“herbal ecstasy”
phenylpropanolamine
analogs
nicotine withdrawal
anabolic steroids
narcotic withdrawal
methylphenidate
phencyclidine
ketamine
ergot-containing herbal
products
St. John's wort
12
Street drugs, other natural products:
Causes of 2˚ Hypertension

13. 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
13

14. 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 14

15. Arterial Blood Pressure
Sphygmomanometry: indirect BP measurement
MAP = 1/3 (SBP) + 2/3 (DBP)
BP = CO x TPR
MAP: Mean Arterial Pressure
SBP: Systolic Blood Pressure
DBP: Diastolic Blood Pressure
BP: Blood Pressure
CO: Cardiac Output
TPR: Total Peripheral Resistance
15

16. Arterial Pressure Determinants
16

17. Adult Classification
Classification
Systolic Blood
Pressure (mmHg)
Diastolic Blood
Pressure (mmHg)
Normal Less than 120 and Less than 80
Prehypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Stage 2 hypertension > 160 or > 100
17
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.

18. Clinical Controversy
White coat hypertension: elevated BP in clinic
followed by normal BP reading at home
Aggressive treatment of white coat hypertension is
controversial
Patients with white coat hypertension may have
increased CV risk compared to those without such BP
changes
18

19. Classification for Adults
Classification based on average of > 2 properly
measured seated BP measurements from > 2 clinical
encounters
If systolic & diastolic blood pressure values give
different classifications, classify by highest category
> 130/80 mmHg: above goal for patients with diabetes
mellitus or chronic kidney disease
Prehypertension: patients likely to develop
hypertension
19

20. Clinical Controversy
Ambulatory BP measurements may be more accurate
& better predict target-organ damage than manual BP
measurements using a sphygmomanometer in a clinic
setting (gold standard)
many patients may be misdiagnosed, misclassified
poor technique, daily BP variability, white coat HTN
Validated ambulatory BP monitoring: role in the
routine HTN management unclear
20

21. Treatment Goals
Reduce morbidity & mortality
Select drug therapy based on evidence demonstrating
risk reduction
21
Patient Population Target Blood Pressure
Most patients < 140/90 mmHg
Diabetes mellitus < 130/80 mmHg
Chronic kidney disease <130/80 mmHg
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

22. 2007 AHA Recommendations
More aggressive BP lowering for high risk patients
22
Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic
heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research
and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788.
Most patients for general prevention <140/90 mmHg
Patients with diabetes (CAD risk equivalent),
significant CKD, known CAD (MI, stable angina,
unstable angina), noncoronary atherosclerotic
vascular disease (ischemic stroke, TIA, PAD,
abdominal aortic aneurism [CAD risk equivalents]),
Framingham risk score > 10%
<130/80 mmHg
Patients with left ventricular dysfunction (HF) <120/80 mmHg

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

24. 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
24
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk
hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.

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

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

27. Compelling Indications
Heart Failure
Post Myocardial Infarction
High Coronary Disease Risk
Diabetes Mellitus
Chronic Kidney Disease
Recurrent Stroke Prevention
27

28. 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
28

29. 29
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker;
DBP: diastolic blood pressure; SBP: systolic blood pressure

30. 3030

31. Lifestyle Modifications
Modification Recommendation
Approximate Systolic Blood
Pressure Reduction
(mm Hg)a
Weight loss Maintain normal body weight (body mass
index 18.5–24.9 kg/m2
)
5–20 per 10-kg weight loss
DASH-type
dietary patterns
Consume a diet rich in fruits, vegetables,
and low-fat dairy products with a reduced
content of saturated and total fat
8–14
Reduced salt
intake
Reduce daily dietary sodium intake as
much as possible, ideally to 65 mmol/day
(1.5 g/day sodium, or 3.8 g/day sodium
chloride)
2–8
Physical activity Regular aerobic physical activity (at least
30 min/day, most days of the week)
4–9
Moderation of
alcohol
intake
Limit consumption to 2 drinks/day in men
and 1 drink/day in women and lighter-
weight persons
2–4
31
DASH, Dietary Approaches to Stop Hypertension.
a
Effects of implementing these modifications are time and dose dependent and could be greater for
some patients.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/

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

33. Hypertension in Pregnancy
Important to differentiate preeclampsia from chronic,
transient, & gestational hypertension
Preeclampsia: >140/90 mmHg after 20 weeks’
gestation with proteinuria
restricted activity, bed rest, close monitoring beneficial
definitive treatment: delivery
Methyldopa: drug of choice
33

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

35. 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
35

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

37. 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
3737

38. Loop Diuretics
Dose in AM or afternoon to avoid nocturnal diuresis
Higher doses may be needed for patients with
severely decreased glomerular filtration rate or heart
failure
Adverse effects:
hypokalemia, hypomagnesemia, hypocalcemia,
hyperuricemia, hyperuricemia
38

39. Potassium-sparing Diuretics
Dose in AM or afternoon to avoid nocturnal diuresis
Generally reserved for diuretic-induced hypokalemia
patients
Weak diuretics, generally used in combination with
thiazide diuretics to minimize hypokalemia
Adverse effects:
may cause hyperkalemia especially in combination with
an ACE inhibitor, angiotensin-receptor blocker or
potassium supplements
avoid in patients with CKD or diabetes
39

40. 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
40

41. 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
41

42. 4242

43. 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
43

44. ARBs
Angiotensin II Receptor Blockers
Angiotensin II generation
renin-angiotensin-aldosterone pathway
alternative pathway using other enzymes such as
chymases
Inhibit angiotensin II from all pathways
directly block angiotensin II type 1 (AT1) receptor
ACE inhibitors partially block effects of angiotensin II
44

45. ARBs
Do not block bradykinin breakdown
less cough than ACE Inhibitors
Adverse effects:
orthostatic hypotension
renal insufficiency
hyperkalemia
45

46. 4646

47. ACE Inhibitor/ARB Warnings
Reduce starting dose 50% in some patients due to
hypotension risk
patients also taking diuretic
volume depletion
elderly patients
May cause hyperkalemia in:
CKD patients
patients on other K+
sparing medications
 K+
sparing diuretics
 aldosterone antagonists
47

48. 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
48

49. 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
49

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

51. Renin Inhibitor
1st
agent FDA approved in 2007: aliskiren
Inhibits angiotensinogen to angiotensin I conversion
FDA approved as monotherapy & combination therapy
with other antihypertensives
Efficacy demonstrated with other antihypertensives
including amlodipine, HCTZ, ACEIs/ARBs
Does not block bradykinin breakdown
less cough than ACE Inhibitors
Adverse effects: orthostatic hypotension, hyperkalemia
51

52. 5252

53. 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
53

54. 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
54

55. 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
55

56. 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
56

57. 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
57

58. Nonselective β-Blockers
Inhibit β1 & β2 receptors at all doses
Can exacerbate bronchospastic disease
Additional benefits in:
essential tremor
migraine headache
thyrotoxicosis
58

59. 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
59

60. 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
60

61. 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
61

62. 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
62

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

64. 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
64

65. Non-dihydropyridine CCBs
ER products preferred for HTN
Block cardiac SA & AV nodes: reduce HR
May produce heart block
Not AB rated as interchangeable/equipotent due to
different release mechanisms & bioavailability
Additional benefits in patients with atrial
tachyarrhythmia
65

66. 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
66

67. 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
67

68. 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
68

69. 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
69

70. 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)
70

71. 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
71

72. 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
72

73. Direct Arterial Vasodilators
Adverse effects:
sodium/water retention
angina
Hydralazine can cause lupus-like syndrome
Minoxidil can cause hypertrichosis
73

74. Reserpine
Peripheral adrenergic antagonist
depletes norephinephrine from sympathetic nerve
endings; blocks norephinephrine transport into storage
granules
reduces norephinephrine release into synapse following
nerve stimulation
 reduced sympathetic tone
 peripheral vascular resistance reduction
 decreased BP
depletes catecholamines from brain & myocardium
Maximum antihypertensive effect: 2 to 6 weeks
74

75. Reserpine
Adverse effects:
sedation
depression
decreased CO
sodium/water retention
increased gastric acid secretion
diarrhea
bradycardia
Use with diuretic (preferably thiazide) to avoid fluid
retention
75

76. Direct Arterial Vasodilators
Use with diuretic (preferably thiazide) & β-blocker to
reduce fluid retention & reflex tachycardia
minoxidil
 more potent vasodilator
hydralazine
76

77. Orthostatic Hypotension
Decrease in SBP > 20 mmHg or DBP > 10 mmHg
when changing from supine to standing position
Older patients with isolated systolic hypertension at
risk at initiation of drug therapy
Prevalent with diuretics, ACE inhibitors, ARBs
Treatment should remain the same with low initial
doses & gradual dose titrations
77

78. 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
78

79. Hypertensive Emergency
Drug Dose Onset
(min)
Duration
(min)
Adverse Effects Special Indications
Sodium
nitroprusside
0.25–10 mcg/kg/min
intravenous infusion
(requires special
delivery system)
Immediate 1–2 Nausea, vomiting, muscle
twitching, sweating,
thiocyanate and cyanide
intoxication
Most hypertensive
emergencies; caution
with high intracranial
pressure, azotemia, or in
chronic kidney disease
Nicardipine
hydrochloride
5–15 mg/h
intravenous
5–10 15–30; may
exceed 240
Tachycardia, headache,
flushing, local phlebitis
Most hypertensive
emergencies except
acute heart failure;
caution with coronary
ischemia
Clevidipine
butyrate
1-2 mg/h intravenous
infusion; may double
dose every 90 sec
initially; maximum:
32 mg/h; typical
maintenance dose: 4
to 6 mg/h
2-4 5-15 Headache, syncope,
dyspnea, nausea,
vomiting
Most hypertensive
emergencies except
severe aortic stenosis;
caution with heart
failure
Fenoldopam
mesylate
0.1–0.3 mcg/kg/min
intravenous infusion
< 5 30 Tachycardia, headache,
nausea, flushing
Most hypertensive
emergencies; caution
with glaucoma
79
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/

80. Hypertensive Emergency
Drug Dose Onset
(min)
Duration
(min)
Adverse Effects Special
Indications
Nitroglycerin 5–100 mcg/min
intravenous infusion
2–5 5–10 Headache, vomiting,
methemoglobinemia,
tolerance with prolonged use
Coronary
ischemia
Hydralazine
hydrochloride
12–20 mg intravenous
10–50 mg intramuscular
10–20
20–30
60–240
240–360
Tachycardia, flushing,
headache vomiting,
aggravation of angina
Eclampsia
Labetalol
hydrochloride
20–80 mg intravenous
bolus every 10 min; 0.5–
2.0 mg/min intravenous
infusion
5–10 180–360 Vomiting, scalp tingling,
bronchoconstriction,
dizziness, nausea, heart
block, orthostatic
hypotension
Most
hypertensive
emergencies
except acute
heart failure
Esmolol
hydrochloride
250–500 mcg/kg/min
intravenous bolus, then
50–100 mcg/kg/min
intravenous infusion;
may repeat bolus after 5
min or increase infusion
to 300 mcg/min
1–2 10–20 Hypotension, nausea,
asthma, first-degree heart
block, heart failure
Aortic dissection;
perioperative
80
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/

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

82. 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
82

83. 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
83