Integrated pharmacotherapy for pharmacy

1. Hypertension
Mulat B.
1

2. OBJECTIVES
2
 Upon completion of the chapter , you will be able
to:
1. Classify blood pressure (BP) levels and treatment
goals.
2. Recognize underlying causes and contributing
factors in the development of hypertension.
3. Describe the appropriate measurement of BP.
4. Recommend appropriate lifestyle modifications and
pharmacotherapy for patients with hypertension.
5. Construct an appropriate monitoring plan to assess
hypertension treatment.

3.  Hypertension is a
cardiovascular
disease Xterized by
elevations of blood
pressure above
values considered
normal
 Also known as high
blood pressure
Introduction
3

4. Definition:
 Blood pressure is the force the blood
exerts against the walls of the blood
vessels.
 It is the force required for the heart to
circulate blood
 Determined by:
 Strength of the heart’s contraction
 elasticity of the arteries
 Stickiness of the blood
Blood Pressure
4

5.  Systolic reading takes the BP at the highest
point (heart contracting)
 Diastolic reading takes the blood pressure at
the lowest point(heart is relaxed)
 Systolic reading is the number on top and
diastolic reading is the number at the bottom
 Example: 120/80 120=systolic, 80=diastolic
 The difference between SBP and DBP is
called the pulse pressure and is a measure of
arterial wall tension
Cont…
5

6.  Mean arterial pressure (MAP): is the average
pressure throughout the cardiac cycle.
 It is sometimes used clinically to represent overall
arterial BP, especially in hypertensive emergency.
 During a cardiac cycle, two thirds of the time is spent
in diastole and one third in systole. Therefore, the
MAP is calculated by using the following equation:
6

7. EPIDEMIOLOGY
 1billion of the global population.
 Prevalence depends on:
Race: blacks > whites
Age: 50% among those 60-69 year,
75% in >70 year.
Gender: less in younger women. F:M=
0.6 at 30 yr but 1.1-1.2 at 65 year
7

8.  Could result from a specific cause
(Secondary HTN)
 Could result from an unknown cause
(Primary or essential HTN)
Etiology
8

9. Primary Hypertension (>90%)
 Unknown cause
 Patient is on lifelong therapy. Cannot be
cured but BP can be controlled
 May be due to genetic or environmental
factors
Secondary Hypertension (<10%)
 Primary aldosteronism
 Chronic kidney disease or renovascular
disease
 Thyroid or parathyroid disease
Etiology…
9

10.  BP=CO * TPR
 CO is the major determinant of SBP, whereas TPR
largely determines DBP
 BP mediated by baroreceptors, RAS & aldosterone
system
 Baroreceptors  sympathetic outflow causing
vasoconstriction &  CO
 The kidney controls BP by altering blood volume
 Baroreceptors in the kidney responds by releasing
renin
 Renin is converted by renin peptidase to Angio-
Angio1-Angio 2( most potent vasoconstricting
system)
Pathophysiology
10

11. PATHOPHYSIOLOGY
 Multiple factors that control BP are potential
contributing components in the development of
hypertension.
 These include malfunctions in either humoral (i.e.,
the renin–angiotensin–aldosterone system [RAAS])
or vasodepressor mechanisms, abnormal neuronal
mechanisms, defects in peripheral autoregulation,
and disturbances in sodium, calcium, and
natriuretic hormone
11

12. A. HUMORAL MECHANISMS
 Humoral abnormalities that may be involved in the
development of hypertension include the
 RAAS
 Natriuretic hormones
 Hyperinsulinemia
12

13. i. THE RENIN–ANGIOTENSIN–
ALDOSTERONE SYSTEM
 Renin is an enzyme that is stored in the
juxtaglomerular cells, which are located in the
afferent arterioles of the kidney.
 The release of renin is modulated by several
factors:
Intrarenal factors
renal perfusion pressure
Catecholamines  stimulate sympathetic
nerves on the afferent arterioles
angiotensin II
 Extrarenal factors (sodium, chloride, and
potassium).
13

14. 14
ANGIOTENSINOGEN
ANGIOTENSIN I
ANGIOTENSIN II
Adrenal
Cortex
Kidney Intestin
e
CNS PN
S
Vascular
Smooth
Muscle
Heart
↑
Aldosterone
synthesis
Vasopress
in
Sympathetic
Discharge Vasoconstriction
↑Contractilit
y
↑Cardiac
Output
↑ Total
Peripheral
Resistance
↑ Blood
Volume
↑
Sodium/Water
Reabsorption
↑ BP
ACE
Renin

15. ii. NATRIURETIC HORMONE
 Natriuretic hormone inhibits sodium and potassium-
adenosine triphosphatase and thus interferes with
sodium transport across cell membranes.
 Natriuretic hormone is thought to block the active
transport of sodium out of arteriolar smooth muscle
cells.
 The increased intracellular sodium concentration
ultimately would increase vascular tone and BP
15

16. iii. INSULIN RESISTANCE AND
HYPERINSULINEMIA
 Increased insulin concentrations may lead to
hypertension because:
 Increased renal sodium retention and enhanced
sympathetic nervous system activity.
 Insulin has growth hormone-like actions that can
induce hypertrophy of vascular smooth
muscle cells.
 Insulin also may elevate BP by increasing
intracellular calcium, which leads to increased
vascular resistance.
16

17. B. NEURONAL REGULATION
 Stimulation of presynaptic α-receptors (α2) exerts a
negative inhibition on norepinephrine release.
 Stimulation of presynaptic β-receptors facilitates
norepinephrine release
 Stimulation of postsynaptic α-receptors (α1) on
arterioles and venules results in vasoconstriction.
 Stimulation of postsynaptic β1-receptors in the
heart results in an increase in heart rate and
contractility, whereas stimulation of postsynaptic
β2-receptors in the arterioles and venules
causes vasodilation
17

18. B. NEURONAL REGULATION
 The baroreceptor reflex system is the major
negative-feedback mechanism that controls
sympathetic activity
 Baroreceptors are nerve endings lying in the walls
of large arteries, especially in the carotid arteries
and aortic arch.
 In this reflex system, a decrease in arterial BP
stimulates baroreceptors, causing reflex
vasoconstriction and increased heart rate and
force of cardiac contraction
18

19. C. VASCULAR ENDOTHELIAL
MECHANISMS
 Deficiency in the local synthesis of vasodilating
substances (prostacyclin and bradykinin) or
excess vasoconstricting substances
(angiotensin II and endothelin I) contribute to
essential hypertension, atherosclerosis, and other
CV diseases.
 Nitric oxide is produced in the endothelium,
relaxes the vascular epithelium, and is a very
potent vasodilator.
 Patients with hypertension may have an intrinsic
deficiency in NO, resulting in inadequate
vasodilation
19

20.  Periodic screening for all individuals older
than 21 years
 Patient should be seated quietly in chair
for at least 5 minutes.
 Use appropriate cuff size
 Take BP at least twice, separated by at
least 2 mins.
 The average BP on two separate visits is
required to diagnose HTN accurately.
Diagnosis
20

21.  Age > 65 yrs
 Other cardiovascular disorders e.g. coronary
artery disease,HF
 Family history
 Obesity
 Hx of smoking
 Hyperlipidemia
 Diabetes Mellitus
 Gender (men and post menopausal women)
 Excessive intake of salt, alcohol or caffeine
Risk Factors
21

22.  Hypertension is a major risk factor for
many forms of heart disease and stroke
 Can accelerate damage to the arterioles,
lead to formation of plaques on the artery
walls leading to arteriosclerosis
 Secondary to chronic hypertension, the
brain, the eyes, the heart, and the kidneys
can be affected and damaged
Cont…
22

23.  Usually no symptoms until organ damage
occurs
 Brain: (stroke, transient ischemic attack,
dementia)
 Eyes: (retinopathy)
 Heart: (left ventricular hypertrophy [LVH],
angina, prior MI, prior coronary
revascularization, heart failure)
 Kidney: chronic kidney disease (CKD)
 Peripheral vasculature (peripheral arterial
disease [PAD])
Signs and Symptoms
23

24. CLASSIFICATION OF BLOOD PRESSURE
IN ADULTS;ISH 2020
24
Classification SBP (mm
Hg)
Vs DBP(mm Hg)
Normal <130 and <85
Normal-high 130-139 or 85-89
Grade 1
Hypertension
140-159 or 90-99
Grade 2
Hypertension
≥160 or ≥100

25. Classification…
 Hypertensive crises are clinical situations
where BP values are very elevated, typically
>180/120 mm Hg.
 They are categorized as either hypertensive
emergency or hypertensive urgency.
 Hypertensive emergencies are extreme
elevations in BP that are accompanied by
acute or progressing target-organ damage.
 Hypertensive urgencies are high elevations in
BP without acute or progressing target-organ
injury
25

26.  SBP is a stronger predictor of CV disease than
DBP in adults aged 50 years and older; it is the
most important clinical BP parameter for most
patients.
 Patients are considered to have isolated
systolic hypertension when their SBP values are
elevated (i.e., ≥140 mm Hg) and DBP values are
not (i.e., <90 mm Hg, but commonly <80 mm
Hg).
 Isolated systolic hypertension is believed to
result
from pathophysiologic changes in the arterial
vasculature consistent with aging.
26

27. TREATMENT
 Goal of Therapy
 The overall goal of treating hypertension is to
reduce hypertension-associated morbidity and
mortality.
 This morbidity and mortality is related to target-
organ damage (e.g., CV events, heart failure, and
kidney disease)
 Attaining goal BP values is associated with lower
risk of CV disease and target-organ damage
27

28. General Approach to Treatment
 Most patients should be placed on both
lifestyle modifications and drug therapy
concurrently after a diagnosis of hypertension
is made.
 Lifestyle modification alone is appropriate for
most patients with nomal-high BP.
 However, lifestyle modifications alone may
not be adequate for patients with
hypertension and either additional CV risk
factors or hypertension-associated target-
organ damage.
28

29. Non-pharmacologic Therapy
Lifestyle Modifications to Prevent and Manage Hypertension
12/6/2022
29

30. Goal BP Values
<130/80 mmHg
30

31. 31

32. 32

33.  Diuretics
 ACEIs
 Angiotensin receptor antagonists
 Calcium Channel Blockers
 Beta blockers
 Central alpha adrenergic agonists
 Direct vasodilators & peripheral adrenergic
antagonists
 Renin Inhibitors
 Combination Therapy
Treatment
33

34.  Diuretics, CCB, ACEI & ARB’s are 1st line
of therapy
 CCBs or diuretics are better for the elderly
 Beta & Alpha blockers less well tolerated
due to side effects
Cont…
34

35. 35

36.  Thiazide Diuretics
 Chlorthalidone
 Chlorothiazide (Diuril®)
 Hydrochlorothiazide (Esidrix®)
 Metolazone (Zaroxolyn®) (used in renal pts)
 Loop Diuretics
 Bumetanide (Bumex®)
 Ethacrynic acid (Edecrin®) (used in sulfur
allergic pts)
 Furosemide (Lasix®)
 Torsemide (Demadex®)
Diuretics
36

37.   Na/water excretion,  decrease
extracellular volume,  CO,  BP
 Thiazides most useful when combined
with other antihypertensive agents
 Thiazides not effective in pts with renal
failure (CrCl <30ml/min), use loop diuretics
instead.
 Good in pts with osteoporosis since they
 calcium excretion
 Caution in gouty pts, since they may 
uric acid conc.
Thiazides
37

38.  Decreases mortality & morbidity in HTN
patients
 Reduces the incidence of stroke & other
cardiovascular diseases
 Side effects include:
◦ Hypokalemia, hyperuricemia, hyponatremia
◦ Increases cholesterol & glucose levels
◦ Increases uric acid, calcium, photosensitivity
◦ May cause volume depletion & metabolic
acidosis
Cont…
38

39.  Loop diuretics have a shorter period of
action than thiazide diuretics and are less
effective chronically
 Thiazide diuretics preferred for chronic
therapy
Diuretics cont…
39

40. Non-dihydropyridines
 Diltiazem
 Verapamil
Dihydropyridines
 Amlodipine
 Felodipine
 Isradipine
 Nifedipine
Calcium Channel Blockers
40

41.  MOA: block inward movement of calcium
(maintain & tone/contraction of smooth
muscle) causing relaxation and dilation
 Two subtypes of CCBs
 Dihydropyridines and
 Nondihydropyridines
Non-dihydropyridines:
 directly reduce atrioventricular nodal
conduction resulting in negative
chronotropic and inotropic actions
 Used to treat arrhythmias
Characteristics Of CCBs
41

42. Dihydropyridines:
 are potent vasodilators of peripheral/
coronary arteries
 Primary effect is vasodilatation
 Total peripheral resistance is reduced
 They do not aggravate asthma or
peripheral vascular disease
 are very effective in older patients with
isolated systolic hypertension
Characteristics Of CCBs
42

43.  All CCBs should be used in caution with
heart failure patients
 Side effects: include edema of the ankle,
flushing, constipation, nausea, gingival
hyperplasia
 Edema can be  by elevation or elastic
stockings
 They do not alter serum lipids, glucose,
uric acid, or electrolytes
Characteristics Of CCBs
43

44.  Efficacy of CCB may  by adding a
diuretic
 Very effective in older and black pts.
 May be more effective than ACEIs in
preventing strokes
 Avoid immediate release CCBs,
particularly nifedipine (used in HTN
emergencies), due to possible serious S/E
 e.g. severe hypotension, cerebral ischemia,
acute MI, conduction abnormalities and death
Characteristics Of CCBs
44

45.  All CCBs (except amlodipine and
felodipine) have negative inotropic effects
 Dihydropyridines may cause a
baroreceptor mediated reflex tachycardia
because of their potent peripheral
vasodilating effects.
 This effect appears to be more pronounced
with the first generation dihydropyridines
(e.g., nifedipine) and is significantly
diminished with the newer agents (e.g.,
amlodipine) and when given in sustained-
release dosage forms.
Characteristics Of CCBs
45

46.  Benazepril
 Captopril
 Enalapril
 Fosinopril
 Lisinopril
 Quinapril
 Ramipril
ACE Inhibitors
46

47.  Reduce after load and preload, thereby
reducing oxygen demand and myocardial
wall stress
 Increase exercise tolerance and functions
of the heart
 Dilate systemic arterial resistance vessels,
thus reducing BP
 Lots of patients have allergic rxns to ACEIs
Characteristics Of ACE Inhibitors
47

48. Side effects:
 cough,
 angioedema (more common in African
Americans),
 hyperkalemia,
 rash, loss of taste and leukopenia
 Should not be used in pregnancy
 Adjust doses with renal insufficiency
(except fosinopril due to extensive hepatic
elimination)
Characteristics Of ACE Inhibitors
48

49.  Does not cause fluid retention, thus
reducing diuretic requirements
  PVR, by  afterload
 Causes no changes in CO & HR or GFR
 Stops conversion of angiotensin 1 to
angiotensin 2
  rate of deactivation of bradykinin (which
is a potent vasodilator)
Characteristics Of ACE Inhibitors
49

50.  Standard of care in pts with MI or CHF
 Protective in renal insufficiency &
preferred HTN therapy in diabetic pts
 Administered once daily (except captopril)
 Angioedema is a life threatening side
effect that can can occur anytime after use
Characteristics Of ACE Inhibitors
50

51.  Avoid use in dialysis patient
 May cause taste disturbance in some pts
 Try to avoid potassium sparing diuretics,
because they can  potassium levels as
well
 May induce hypotension with initial
therapy in sodium or volume depleted
pts(consider  dose of other HTN agents)
Characteristics Of ACE Inhibitors
51

52.  Candesatan (Atacand®)
 Irbesartan (Avapro®)
 Losartan (Cozaar®)
 Valsartan (Diovan®)
 Eprosartan (Teveten)
 Olmesartan (Benicar)
 Telmisartan (Micardis)
Angiotensin Receptor Antagonist
52

53.  ARBs bind to AT-II receptors in tissues
preventing AT-II mediated vasoconstriction
and aldosterone release thus  BP
(candesartan block AT-II receptors more
effectively than lorsatan or valsartan)
 Since ARBs do not block down the
breakdown of bradykinins, there efficacy
compared to ACEIs is questionable
Characteristics of ARBs
53

54.  ARBs do not alter the metabolism of
bradykinins, norepinephrine or substance
P
 The addition of low dose thiazide diuretics
to an ARB significantly improves
antihypertensive efficacy
 ARBs are beneficial in diabetic
nephropathy/ albuminuria & can reduce
renal complications in these patients
Characteristics of ARBs
54

55.  Used mostly when patients are allergic to
ACEIs
 Decreased cough and hyperkalemic
effects compared to ACEIs
 May cause angioedema (but rare)
 Use regardless of kidney function
 Efficacy similar to other antihypertensives
with fewer side effects
 Sometimes used in combination with
ACEIs but it is controversial
Characteristics of ARBs
55

56.  More expensive than ACEIs and their
effect on mortality risk is not well
established
 Studies have shown cross reactivity risks
b/w ACEIs and ARBs, thus monitor for
renal insufficiency and hyperkalemia
Characteristics of ARBs
56

57.  Beta 1 selective
 Atenolol
 Metoprolol
 Bisoprolol
 Non-selectives
 Nadolol
 Propranolol
 Timolol
Beta-Adrenergic Blockers
57

58.  Intrinsic Sympathomimetic Activity
 Acebutolol (Sectral®)
 Cateolol (Catrol®)
 Penbutolol Levatol®)
 Pindolol (Viskn)
 Mixed Alpha-Beta Blockers
 Carvedilol (Coreg®)
 Labetalol (Trandate®)
Beta-Adrenergic Blockers
58

59. MOA:
 The exact hypotensive mechanism of β-
blockers is not known but may involve
1. decreased cardiac output through
negative chronotropic and inotropic
effects on the heart and
2. inhibition of renin release from the
kidney.
 Improves blood flow & heart rhythm
problems
Beta Blockers
59

60. Cont…
 β1-Receptor stimulation increases heart
rate, contractility, and renin release.
 β2-Receptor stimulation results in
bronchodilation and vasodilation.
 Insulin secretion and glycogenolysis are also
mediated by β2- receptors.
 Blocking β2-receptors may reduce these
processes and cause hyperglycemia or
blunt recovery from hypoglycemia
60

61.  Ist line agents for pts with MI & HTN
 Also used for arrhythmias ( PSVT, A fib,
VA)
  occurrence of sudden cardiac death
 Considered as initial therapy for pt with
HTN & angina pectoris
 Slows the progression of CHF
 Has been known to  mortality & morbidity
in CHF pts
  myocardial oxygen demand in pts with
IHD
Characteristics Of Beta-Adrenergic Blockers
61

62.  Side effects: coldness, fatigue, mask
hypoglycemia, depression, impotence,
SOB, bradycardia
 Avoid abrupt withdrawal due to rebound
HTN, cardiac disease and increase in the
risk of MI or sudden death
 Side effects pronounced in the elderly
  HDL &  TGs, so use caution in
hyperlipdemia pts
Characteristics Of Beta-Adrenergic Blockers
62

63.  Caution should be used in asthma patients
due to bronchospasm
 May mask insulin induced hypoglycemia
 Can decrease exercise tolerance (fatigue)
 Labetalol  risk of hyperkalemia in renal
transplant pts
 Avoid carvedilol in pts with severe hepatic
impairment
Characteristics Of Beta-Adrenergic Blockers
63

64. Recommendations for antihypertensive
medications in special situations
Condition Beneficial Agents
Pregnancy Methyldopa,BBs, arterial
vasodilators
Osteoporosis Thiazide diuretics
Arrhythmias, essential
tremors, migraine,
thyrotoxicosis, perioperative
HTN
Beta Blockers
Raynaud’s syndrome,
Arrythmias
CCBs (nodihydropyridines
for arrythmias)
Prostatism Alpha blockers may be
useful
64

65. Potential unfavorable conditions
for specific drugs
Condition Agents to avoid
Gout Thiazide diuretics
Asthma, Airway disease, 2nd
or 3rd
degree heart block
Beta Blockers
Pregnancy or possibility ACEIs, ARBs
History of angioedema ACEIs
K.5.0mEq/L Aldosterone antagonists. K
sparing diuretics
65

66.  Labetalol
 Nicardipine
 Captopril
 Hydralizine
 Isosorbiddinitrate
Hypertensive Emergencies
66

67. Hypertensive Emergencies Mgt
67
Enalaprilat 1.25-5 mg IV every 6 hours
Hydralazine 12-20 mg IV;10-50 mg
intramuscular
Labetalol 20-80 mg IV bolus every 10
minutes;
0.5-2 mg/min IV infusion
Nicardipine 5-15 mg/h IV
Sodium
nitroprusside
0.25-10 mcg/kg/min IV infusion

68. Resistant hypertension
68
 Patients with resistant hypertension are those who
fail to achieve goal BP with the use of three or
more antihypertensive drugs.
 includes patients who are adhering to full doses of
an appropriate three-drug regimen that includes a
diuretic
 Mgt
(a) assuring adequate diuretic therapy,
(b) appropriate use of combination therapies, and
(c) using alternative antihypertensive agents when
needed.

69. Cases 1
 D.W . is a 50-year-old African American man being
discharged from the hospital after an acute MI. His
medical history is significant for HTN. He was taking
hydrochlorothiazide 25 mg/day before
hospitalization. An echocardiogram before discharge
showed an LVEF of more than 60%. His vital signs
include BP 150/94 mm Hg and HR 80 beats/minute.
Which is the best approach for managing his HTN?
 • A. Discontinue hydrochlorothiazide and add
diltiazem.
 • B. Continue hydrochlorothiazide and add
metoprolol.
 • C. Discontinue hydrochlorothiazide and add
losartan.
 • D. Continue hydrochlorothiazide and add losartan.
69

70. Case 2
 T.J. is a 45-year-old white woman with a history of type 2
diabetes mellitus treated with glyburide 5 mg/day. She
presents to the clinic for a routine follow-up of her
diabetes. Her vital signs today include BP (average of
two readings) 138/88 mm Hg and HR 70 beats/minute.
Her laboratory results are as follows: Na 140 mEq/L, K
4.0 mEq/L, chloride 102 mEq/L, bicarbonate 28 mEq/L,
BUN 14 mg/dL, SCr 1.0 mg/dL, 24-hour urine albumin 36
mg. Of note, at her last visit, her BP was 136/85 mm Hg.
Which is the best approach for managing her HTN at this
time?
 • A. Begin lifestyle modifications only.
 • B. Begin lifestyle modifications and add amlodipine 5
mg/day.
 • C. Begin lifestyle modifications and add lisinopril 2.5
mg/day.
70