Age and gender Related Blood Pressure changes

1
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• ????? ???????
• ?????
• ??????? ??? ??? ?? ??????, ??? ??? ?? ????
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• ?????? ???? ??? ??
• ?????? ???? ??? ?? ?????????? ???????

2
????? ???????
3
Age and gender- Related Blood Pressure changes
BP (mm Hg)
Systolic
Male
Female
Diastolic
Age (years)
4
Estimated prevalence of hypertension by gender
and age1988-1991
of population
Age (years)
5
Adults with ISH (SBP gt140 mm Hg, and DBP lt 90 mm
Hg)
Percentage
73
66
47
24
Age (years)
6
?????? ?? ????? ??? ??? ?? ?????? ?? ????? ??
????? 3 ?????? ????? ????? ?? ????.????? ???
????? ?? ??? ?????? ???? ??????, ????? ??????
???? ???? ????? ????? ?????? ????? ?? ???? ???
??? ???.
7
???? ????? ??? ??
8
Definition of systolic and diastolic blood
pressure
mm Hg
Cuff Pressure
140
120
100
80
60
40
Blood Pressure
Systolic
Diastolic
.
20
Ausc gap
Korotkoff
I
IV
V
9

• ?????? ????? ??????? ???? ?????.
• ?? ????? ????? ???? ??? ???? ?????. ??? ????
• ?????? ??? ??? ???? ??????, ???? ????? ??? ??
• ???? ????? ??????? ??? ???? ??????.
• ?? ????? ?? ??? ?? ???? ????? ????? ??? ????
  ?????,
• ?????? ? - 80 ????? ????? ?????? ? - 40
  ????? ?????. ????? ??? ?????? ??? ????? ??????
  ????? ??????.
• ?? ????? ?????? ?????? ??? 0 ???????? ????
  ?????.
• ????? ??? ???? ?????, ??? ??? ?? ??? ?? ?????.
• ???? ????? ???? ????? ???. ?? ????? ????? ????
  ?15- ?"?, ???? ????? ????? ?10- ?"? ????? ?????
  ?????? ?????, ?? ????? ?????, ??? ??? ??????
  ???? ???? ????? ???.

10

• ?? ????? ?????. ????? ????? ????? ?? ??? ?????
  ????? ?????? ?? 10???? ????????? ??????.
• ?????? ???? ?? ?????? ???? ??? ????? ????????
  ?????? 2.5 ?"? ??? ????? ?????? ?????. ????? ????
  ????? ?????? ??.
• ?? ?? ???? ?????? ?????, ?? ????? ??????? ??
  ?????? ??????? ??? ???? ??? ????? ????.
• ?? ????? ?? ??? ??? ???? ???????. ????? ???? ????
  ?? ?? 10 ?"? ????? ???? ??? ??? ???????. ????
  ????? ??? ?????, ?????? ?? ????? ??? ?? ????? ??.
  
• ?????? ??? ?? ???? ???? ???? ???? 30, ?? ????
  ???? ?????? ????? ??? ?? ???????.
• ???? ???? ????? ??? ?? ????? ???, ???? ??????
  ?????? ???? ?? ???????? ????? ?? ??? ??? ????.

11
Orthostatic Hypotension

• ????? ???? 5 ???? ?? ?????, ??? ???????? ??????
  ??????, ????? 3 ???? ?? ?????.
• ????? ?????? ?????? ???? ????? ?????? ????? ??
  ??? ??? ???????? ?????? ?? ???? ?????????.
• ????? ??????? ???? ????? ?? ???? ? 20 ?"? ?????
  ???? ??? ???????? ?/?? ????? ?? ???? ? - 10 ??
  ?????????.

12
??? ????? ?? ?????? ???????

• ??? ???? ?? ??? ??? ?? ???.
• ????? ??? ??? 65.
• ????? ????? ??????.
• ????? ??????? ?? ????? ?? ???????.
• ????? ????? ?????? ?????? ??? ??.

13
????? ??????? ??????? ?????? ??

• Pseudohypertenion
• White coat hypertension

14
????? ???? ??? ??

• ????? ??? ?? ??????.
• ????? ??? ?? ?????????? ?????.
• ????? ??? ?? ?????????? ???????? ???? 24 ????.

15
Home BP measurements

• Distinguishing sustained hypertension from white
  coat hypertension.
• Assessing response to antihypertensive
  medications.
• Improving patient adherence to treatment.
• Potentially reducing cost.
• Wrist and finger devices were not validated.
• Could not be used in patients with arrhythmia.
• Levels gt 135/85 should be considered as
  hypertension.
• Guidelines J Hypertension 200018493-508.
  Arch Intern Med 2000160 1251-1256

16
?????? ?????? ??????? ??? ??

• ????? ??? ?? ????? ???? ????? ?? ????? ??????
  ????? ??? ?? ???? ??? ??????? ??? ????? ??????
  ????.
• ????? ?? -white coat hypertension
• ????? ?? ?????? ?????? ??????.
• ????? ?? ?????? ??? ?? ?? ??? ????? (diurnal
  variation ).
• ????? ?? ?????? ???? ???.
• ????? ?? ???? ??? ?? ??? ?? ???????? ??????
  ??????? ????? ?????? ??? ??.

17
????? ??? ??? ?? ??? ISH/WHO

• ???????
• ????
• ??????
• ?????? ????
• ??? ??? ??
• ???? 1
• ??? ?????
• ???? 2
• ???? 3
• ISH
• Borderline ISH

?? ???????? 80 85 85-89 90-99 90-94 100-109 gt
110 lt90 lt90
?? ??????? 120 130 130-139 140-159 140-149 160-1
79 gt 180 gt 140 140-149
18
?????? ????? ??????? ??? ??

• ????? ??? ?? ???????, ???????? ????? ???? ?????,
  ????? ???? ??????.
• ???? ??????? ?????????. ( ?????? ????????? ???
  140 ???? ? - 120 ?????, ? - ?????? ??????????
  ??? 90 ???? ???? 80 ?????).
• ???? ?????? ??? ???? ?????.
• ????? ??? ?? ????? ????? ?????.

Use and interpretation of ABPM recommendations
of the BHS. BMJ 20003201128-34
19
?????? ????? ??????? ??? ??

• ???
• ????
• ???
• ????
• ????
• ????? ?? ????? ?????

???? lt130/80 lt 135/85 lt120/70 lt 20 gt 10
?? ???? gt135/85 gt140/90 gt125/75 gt 40 lt 10
????? ????? ?????? ???? ??????
Use and interpretation of ABPM recommendations
of the BHS. BMJ 20003201128-34
20

• ???? ??????? ????? ??? ?? ?????
• ????? ????? ?????? ??? ?? ??????
• ????? ??? ?? ? - 24 ????.
• ????? ??? ?? ????? .

21

• ?? ??????? ?????? ???? ??? ?? ????? ????? ??? ???
  ???? ????? ????? ????? ?? ??????? ??????? ?

22
Risk of Cardiovascular Events by Hypertensive
Status
Biennial age-adjusted rate per 1000
Normal Hypertension
60
Coronary disease
Peripheral vascular disease
Heart failure
Stroke
50
40
30
20
10
0
Risk ratio 2.0 2.2
3.8 2.6 2.0 3.7 4.0
3.0 Excess risk 23 12
9 4 5 5 10
4 Men Women Men Women Men Women
Men Women
Kannel (1993)
23
DBP, Stroke, and CHD
Stroke 7 prospective observational studies 843
events
CHD 9 prospective observational studies 4856
events
4.00
4.00
2.00
2.00
Relative risk of stroke
Relative risk of CHD
1.00
1.00
0.50
0.50
0.25
0.25
76 84 91 98 105
76 84 91 98 105
Approximate mean usual DBP (mm Hg)
n420,000 Mean follow up 10 yr MacMahon et al.
Lancet 1990335765
24
SBP, Stroke, and CHD
Stroke mortality (n1233)
CHD mortality (n11,149)
32
16
16
8
Relative risk of stroke mortality
Relative risk of CHD mortality
8
4
4
2
2
1
135
168
lt120
125
135
148
168
120
125
148
Approximate mean SBP (mm Hg)
Multiple Risk Factor Intervention Trial (MRFIT)
n347,978 men Neaton et al. In Laragh et al
(eds). Hypertension Pathophysiology, Diagnosis,
and Management.2 ed. NY Raven, 1995127
25
Impact of high normal BP on the risk of CV
disease (NEJM 20013451291-7)
Type of model and BP category
Hazard Ratio (95 CI)
men (n 2967)
Women (n 3892)

• Optimal (2880 subjects)
• Normal (2185 subjects)
• High normal (1784 subjects)

1.0 1.5 (0.9 - 2.5) 2.5 (1.6 - 4.1)
1.0 1.3 (1.0 - 1.9) 1.6 (1.1 - 2.2)
Adjusted for age, BMI, Total cholesterol, DM,
smoking
26
Relationship of SBP and DBP to Risk for CHD
3.0
2.5
2.0
SBP 170 mm Hg (Plt0.02)
SBP 150 mm Hg (Plt0.03)
CHD hazard ratio
1.5
SBP 130 mm Hg (Plt0.06)
1.0
SBP 110 mm Hg (Plt0.03)
0.5
0
60
70
80
90
100
110
DBP (mm Hg)
Franklin et al. Circulation 1999100354
27
Hypertension in Older Persons

• SBP is a better predictor of events than is DBP
• An elevated pulse pressure, is even a better
  marker of increased cardiovascular risk than
  either SBP or DBP alone

28
??????? ???? ??? ?? ??????
29
MAP CO TPR
SV HR
TPR
RAS
Blood volume
NO
SNS
ET
ANP
SNS
PG
SNS
RAS
BK
Vasopressin
Adrenomedullin
30
Pathophysiology

• Insulin resistance.
• Overactivity of the sympathetic nervous system.
• Overactivity of the renin-angiotensin system.
• Salt-sensitivity.
• Obesity
• Endothelial factors.
• Changes in cell membrane

31
Hypertension as an Insulin-Resistant state
Response of Plasma glucose and insulin to 75 g of
Glucose in patients with Hypertension and in
Normal Subjects
Plasma glucose mg/dL
Plasma insulin ?U/ml
Hypertensives
140
80
Hypertensives
120
60



80
40
Controls
40
20
Controls
Plt0.05
0
0
0
0
30
60
90
120
30
60
90
120
Time (min)
Ferrannini et al, NEJM 1987317,350
32
Effects of Insulin

• Enhances renal sodium reabsorption
• Stimulates SNS
• Increases pressor response to AII
• Increases AII mediated aldosterone production
• Increases sodium sensitivity
• Stimulates smooth muscle proliferation
• Increases intracellular calcium

33
Secondary Hypertension

• Renal Renovascular
• Renal parenchymal
• Endocrine Pheochromocytoma
• Hyperaldosteronism
• Thyroid diseases
• Acromegaly
• Congenital Adrenal Hyperplasia
• Cushing
• Parathyroid disease

34
Secondary Hypertension (cont)

• Coarctation of Aorta
• Neurogenic hypertension Brain tumors
• Quadriplegia
• Head trauma
• Guillian Barre
• Meningitis
• Pregnancy induced hypertension.
• Drugs and chemical induced hypertension.

35
Renal Artery Stenosis

• Renal artery stenosis can cause
• hypertension and renal failure.

36
Renal artery stenosis

• ??? ?????? ??????? ???? ??? ?? ??? ?????? ????
  ????? (RAS ) ??????? ? 1-3 ???????. ??????
  ????? ????? ?????? ????? ?????.
• ???? ????? RAS ?????? ?
• .????????? ?? ????? ??? ????? ??? ?? ????? ?? ???
  ??? ?? ??????.
• . ????? ??? ?????? ???? ??? ??????, ????? ??????
  ????? ???? ??? ??? ?? ?????.
• ????? ??? ?????? ???? ????? ?? ???? ????? ???
  ????? ?????.

37
Renal artery stenosis (cont)

• ???????
• ????? - 65 , ??? ?????, ???? ??????????, ?????
  ???? ?????, ????? ??? ????? ????? ? - 50
• ( fibromuscular dysplasia (FMD.
• Medial 80 , ???? ???????/??????????????. ????
  ??????? ????? ?????? ???? ?????? ? ??? ?????.
• ???????? ??? Takayasus disease ,
  ???????????????? ???????? ?? ???? ?????.

38
(No Transcript)
39
FMD
Atherosclerosis
40
???? ???? ? - RAS

• ??? ??? ?? ??? (????? ????????? ??? 120 ?"??).
• ??? ??? ?? ???? ?????? ?????? ????? ( ?????
  ????????? ??? 100 ?"?? ????? ????? ????? ? 3
  ??????).
• ????? ??????? ?? ??? ??? ?? ?????? ??????? ?? ???
  ???? ???? ? 20.
• ??? ??? ?? ?? ?????? ??????
• ????? ???? ?????? (PVD) ?? ????? ?? ???????.
• ????? ????? ??? ?? ????? ?????? ?? 24 ????.

41
(????)

• ??? ??? ?? ?? ???? ????????? ?????? ?? ???????.
• ??? ??? ?? ?????? ?? ??? ?? ???? ?? ???????? ??
  ?????? ????? ?????? ?????? ???? ???.
• ??? ??? ?? ?? ??????? ?????? ?? ???? ???? ??
  ??????.
• ????? ?????? ?????? ???? ????? ?????? ??????
  ?????.
• ??? ??? ?? ?????.

42
????? ????? ???? ??????????

• Captopril renal scan
• Duplex ultrasound
• Captopril test
• CT angiography
• MRA

43
???? ?????? ? - RAS

• ???? ??? ???? ?? ??? ??? ?? ?? ??? ??????.
• ????? ?? ????? ?????? ???.

44
?????? ? - RAS

• ?????? ?????? ????? ?????? ????? ????? ?? FMD
  ???? ?? ???? ???? RAS ????? ?????.
• ?????? ?????? ?? ???? ????? ?????? ????? ????
  ???? ?????? ???????? ???? ???? ?? ???? ????? ??
  ?????? ??? ?? ????? ??????? ?????.

45
(No Transcript)
46
????? ?????

• Chronic glomerulonephritis
• Chronic pyelonephritis
• Obstructive uropathy
• Polycystic kidney
• Chronic renal failure

47
Polycystic kidneys
48
????? ???????????

• Pheochromocytoma
• Hyperaldosteronism
• Thyroid diseases
• Acromegaly
• Congenital Adrenal Hyperplasia
• Cushing
• Parathyroid disease

49
(No Transcript)
50
Pheochromocytoma

• Pheochromocytomas are functional
• catecholamine secreting tumors of the
• paraganglionic chromaffin cells found in the
• adrenal medulla, the autonomic ganglia cells,
• and the extra-adrenal paraganglia cells
• originating from the neural crest cells.
• They are the cause of hypertension in 0.1
• to 0.2 of hypertensive patients

51
Pheochromocytoma

• Rough rule of 10
• 10 are extra-adrenal
• 10 are bilateral
• 10 are multifocal
• 10 are malignant
• 10 are found in children
• 10 are familial

52
Pheo - symptoms

• 95 of patients will have one or more of the
  followings.
• Headache
• Hyperhidrosis
• Palpitation

53
Pheochromocytoma

• Symptoms
• Hypertension - sustained
• Hypertension - paroxysmal
• Normotnesion
• Headache
• Fever
• Sweating
• Palpitations
• Nervousness

• Percent
• 50
• 40-50
• 5
• 70-90
• up to 65
• 60-70
• 51-73
• 35-40

54
Pheochromocytoma

• Symptoms
• Weight loss
• Fundoscopic changes
• Pallor
• Chest/abdominal pain
• Nausea or vomiting
• Weakness, fatigue

• Percent
• 40-70
• 50-70
• 28-60
• 22-48
• 26-43
• 15-38

55
Multiple Endocrine Neoplasia (MEN)

• MEN 2A
• Medullary carcinoma of thyroid
• Parathyroid hyperplasia or adenoma
• Bilateral adrenocortical hyperplasia
• Pheochromocytoma
• MEN 2B
• Mucosal neuromas, bumpy lips, skeletal defects

56
Pheochromocytoma -Biochemical diagnosisUrinary
excretion of catecholamine metabolites

• sensitivity specificity
• VMA 66 83-98
• Urine CA 75 80
• Metanephrine 83 89
• Free NE 100 98

57
Pheochromocytoma -Biochemical diagnosisPlasma
measurements

• sensitivity specificity
• NE, Epi, Dopa 66-82 83-98
• Normetanephrine 100 96
• and metanephrine
• NE gt1200 pg/ml, Epi gt 276 pg/ml,
• Dopa gt 7000 pg/ml

58
Pheochromocytoma -Biochemical diagnosisPharmacol
ogic tests

• sensitivity specificity
• Glucagon stimulation 81 100
• Clonidine suppression 87 93
• (plasma NE lt 500 pg/ml)
• Clonidine suppression 97 67
• (plasma NE lt 500 pg/ml
• or 50 decrease)

59
Pheochromocytoma

• ???? ????? ??????? ?? ???? ???? ?? ??????

60
Localization studies

• MRI - 98 sensitive
• CT scan - 89-95 sensitive
• US - no report of sensitivity
• MIBG scaning - 81 sensitivity
• MIBG is the most specific for pheo and is useful
• to detect metastasis and extraadrenal tumors.
• MRI and US are the methods of choice during
• pregnancy

61
(No Transcript)
62
Management of pheochromocytoma

• Pharmacologic management
• Treatment is based on alpha - blocked.
  Beta-blockers may increase blood pressure if
  given without alpha-blockers because of unopposed
  alpha stimulation.
• Surgical management
• Laparascopic removal of the tumor is possible in
  most patients. Patients should be well prepared
  for the operation with alpha blockers.

63
Primary hyperaldosteronism

• Adrenal adenoma - Conn syndrome
• Bilateral hyperplasia of aldosterone-secreting
  cells
• Glucocorticoid-suppressible hyperaldosteronism

64
Hyperaldosteronism

• Hypertension
• Hypokalemia
• Alkalosis
• (hypernatremia).

Hypokalemia may be absent mainly when the
patient keeps low sodium diet
65
Hypertension and hypokalemia
Exclude diuretic use, or other causes for
hypokalemia
Collect urine for 24 hours for electrolytes
measurement.
K gt 30 mmol/day
K lt 30 mmol/day
Suspected Hyperaldosteronism check PRA and Aldo
Look for other causes to hypokalemia
PRA Aldo
PRA Aldo
Primary hyperaldo
Secondary hyperaldo
66
Hyperaldosteronism - diagnosis

• Plasma aldosterone/Renin ratio
• (aldo - ng/dl, ratio gt 30 is highly
  suspicious).
• Nonsuppressible Aldosterone
• Saline infusion
• Captopril suppression

67
Hyperaldosteronism - diagnosisDefine the cause
and localize the mass

• Upright posture test (gt30 increase in plasma
  aldosterone suggest bilateral adrenal
  hyperplasia).
• CT (thin sections), or MRI
• Adrenal Scintigraphy
• Selective venous sampling

68
Hyperaldosteronism - Therapy

• Unilateral mass - surgery. (if the risk for
  surgery is high - spironolactone).
• Bilateral hyperplasia - Spironolactone.
• Glucocorticoid remediable aldosteronism -
  Dexamethasone

69
Coarctation of Aorta

• Infantile or adult type.
• Severe hypertension in the young.
• Decreased femoral pulses and low BP in the lower
  extremities.
• Diagnosis Echo, Spiral CT, MRI.
• Treatment surgery

70
(No Transcript)
71
CT angiography of patient with coarctation
72
Chemical induced hypertenion

• Steroids, Licorice, estrogen, progesterone.
• Narcotics and anesthetics Cocaine, ketamine etc.
• Sympathomimetic agents Nasal drops,
  metoclopramide, caffeine, antidepressants.
• Cyclosporine, erythropoietin, lithium, alcohol,
  nicotine
• NSAID

73
Pregnancy induced hypertension

• Chronic hypertension (before 20 weeks of
  pregnancy).
• Preeclampsia (after 20 weeks of pregnancy and
  associated with peripheral edema, proteinuria and
  sometimes HELLP syndrome - Hemolysis, Elevated
  Liver enzymes, Low Platelets).
• Preeclampsia on chronic hypertension
• Eclampsia
• Transient hypertension

74
??? ??? ?? ?????? ????? ?????
????? ????? ????
75
????? ????? ???? ??? ??

• TOD ?????? ?????
• ??
• LVH
• ???? ?? ???????
• ?? ????? ??
• ????? ????
• ???????? (????????????????)
• PVD
• ?????????

• ????? ?????
• ?????
• ???????????
• ?????
• ??? ??? 60
• ????? ?????? ?????
• ??????????? ???? (?)

?? ????? ???? ???? ??? ???? ? - 55 ??? ?? ????
????? ? - 65.
76
Target organ damage
Kidneys
Vascular
Brain
Heart
77
Target Organ Damage (TOD)

• Cerebrovascular disease
• Ischaemic Stroke
• Cerebral haemorrhage
• Transient ischaemic attack
• Heart Disease
• LVH
• Myocardial infarction
• Angina pectoris
• Coronary revascularisation
• Congestive heart failure

• Renal disease
• Diabetic nephropathy
• Renal failure (plasma creatinine concentration
  gt177 mmol/L) (gt2.0 mg/dl)
• Vascular disease
• Dissecting aneurysm
• Symptomatic arterial disease
• Advanced hypertensive retinopathy
• Haemorrhages or exudates
• Papilloedema

78
Cardiac hypertrophy
Concentric
Eccentric
Normal
Pressureoverload
Volumeoverload
? ? CSA
?CSA ? L
Adapted from Gerdes, M
79
(No Transcript)
80
????????????????

• ?????
• 30-300 ?? ??????? ? - 24 ????.
• 20-200 ?? ???????/?? ????????? ?????? ???.
• ??????
• ????? ????? , ?? ?? ????? ??? ??? ?? ??? ?????.
  ??????
• ????? ??????? ????????? ????? ????.

81
??????? ??????? ???? ??? ??

• ????
• ????
• ???? 1
• ???? 2
• ???? 3
• ???? 4

??? A-V 34 12 13 14 ????? ????????? ????
?????? ?????? ??? ??? ????? ???? (?????
A-V) ????? ???????, ???? ???? ???? ????? ????
?????. ??? ???? 3 ???? ?????
82
Changes in retinal vessels
A
V
A) Severe arteriolar vasoconstriction and
aneurysm - like lumen irregularities
B) Improvement in arteriolar irregularities
after treatment
Cristofori, 1991
a
83
(No Transcript)
84
?????? ?????

• ???? ???????
• ????? ??? ??? ?? ????.
• ???? ????? ????? ??????.
• ???? ???? ?????? ????? ?? ?????? ??????? ??????.

85
?????? ???? ??? ??
STROKE 40 CHD 15-20 CHF 50
86
Guidelines for hypertension treatment

• How to lower blood pressure

87
Guidelines for hypertension treatment
Lifestyle modifications for hypertension
management

• Weight reduction
• Reduced salt intake
• Dynamic exercise
• Reduced fat intake
• Increased fruit and vegetable consumption
• Limited alcohol consumption
• Stop smoking
• Reduced saturated and increased polyunsaturated
  fat

88
Guidelines for hypertension treatment

• If lifestyle modifications do not lower blood
  pressure to the desired levels, then drug
  treatment should be started

89
Antihypertensive Drugs

• Diuretics
• Sympatholytic agents
• b-blockers
• a-blockers
• ab-blockers
• Central acting agents Aldomin, Clonidine

90
Antihypertensive Drugs(cont.)

• Vasodilators
• Calcium antagonists DHP, NDHP
• Direct vasodilators hydralazine, minoxidil
• Blockers of the RAAS
• ACE inhibitors
• AT1 Receptor blockers (ARBs)

91
Diuretics
92
Principle sites of action of diuretic classes in
a nephron
93
Diuretics - mode of action

• Decrease in plasma and extracellular fluid volume
  thereby leading to decrease in cardiac output.
• With chronic use, plasma volume returns partially
  towards normal, but at the same time peripheral
  resistance decreases

94
Diuretics-cont

• ???? ?????? ????? ?????? (????????? lt 2.5 ??/??)
  ?? ?????? ???????. ?????? ?? ????? ????? ??
  ?????? ??????.
• ?? ?????? ?????? ???? ?? ?????? (12.5 ?? 25 ??,
  ???? ?????? ????? ????? ?????).
• ?? ?????? 2-4 ?????? ?? ????? ????? ?????.

95
Diuretics - advantages

• Reduce CV morbidity and mortality and total
  mortality in the elderly.
• Reduce SBP more than DBP in the elderly.
• Effective mainly in the elderly.
• Improve osteoporosis.
• Easy to use, cheap and convenient.
• Well combined with all antihypertensive agents.
• Remained the gold-standard treatment for
  hypertension.

96
Diuretics - disadvantages

• Cause hypokalemia, hyperuricemia, hyperglycemia,
  hypercholesterolemia, hypomagnesemia,
  hypercalcemia.
• Cause impotence.
• Less protection than ACEI and ARB on the kidneys.
  
• Cause hyponatremia mainly in elderly women.
• May aggravate nocturia in men with BPH.

97
Sympatholytic agents
98
b-blockers
99
Mode of action in hypertension

• b1 blockade is the important factor in
• lowering blood pressure
• Decrease cardiac output
• Suppression of renin
• CNS activity
• Inhibition of neuronal release of NE
• Stimulation of vasodilator prostaglandins
• Baroreceptor resetting
• Increase in ANP levels

100
?-blockers - advantages

• Effective in young patients with tachycardia.
• Effective in patients with IHD, and indicated for
  patients post MI.
• Effective in patients with hypertrophic CMP.
• Reduce morbidity and mortality in CHF.
• Effective in patients with migraine headache,
  anxiety and stress, intention tremor, MVP and
  hyperthyroidism

101
?-blockers - disadvantages

• Cause bronchoconstriction.
• May cause bradyarrhythmia.
• cause cold peripheries.
• Do not reduce CV mortality, IHD, and total
  mortality in the elderly.
• Cause metabolic abnormalities.

102
?-blockers - disadvantages (cont.)

• Fatigue and lethargy
• CNS effects sleep disturbances, depression ?
• GI tract indigestion, nausea, diarrhea
• Sexual Dysfunction
• Dry eyes and blurred vision
• Rebound phenomena
• Muscle cramps
• Skin worsening of psoriasis
• Hypersensitivity
• Worsening of myasthenia and myotonia

103
a-blockers
104
(No Transcript)
105
?-blockers - advantages

• Improve dyslipidemia.
• Improve glucose metabolism.
• Improve symptoms in patients with BPH.

106
?-blockers - disadvantages

• Less effective than diuretic in reducing BP and
  CV events (ALLHAT, JAMA 19.4.2000)
• Cause orthostasis.

107
a b blockers

• Labetalol - mainly for hypertension in pregnancy,
  and may be used in patients with pheochromocytoma
  and in patients with hypertensive emergency
  (intravenous).
• Carvedilol - Not approved for hypertension, but
  recommended for patients with CHF.

108
Central acting agents

• ?????? ?????? ?? ?????? ?????? ?????? ?????????
  ?? ??? ????? ??????? a2 ??????? ??? ??? ?? ??
  ????? ?????? ???, ??????? ???????? ???????? ?????
  ?????? ??.
• ??????? ???????? ?????? ??
• ??????? - ????? ?????? ???? ??? ?? ??????.
• ???????? (?????????)

109
Central acting agents- side effects

• ?????, ???????, ????????, ??????, ???? ???,
  ?????? ???????????.
• ???????? ????? ????? ??????? ???????? ??????
  ????????, ??????????????, ?????????,ANF ?????,
  ????? coombs ?????? (??- 20 ???????), ???
  ?????? ??????? ???, ???? ????? - ??? ?????.
• ?????? ????? ?????? ?????? ??????????, ????????
  ??????????????, ?????? ??????, ??????
  ????????????????, ????? ???????? ??????????.
• ????? ?????? ??????? ??? ?????? ??????? ???????.
• ?? ?????? ???? ?????? ??????? ?? ?????? ???????
  ??? ???? ?????? ??? ????.
• ????? ????????? ?????? ????? ??????? ??????.

110
Calcium antagonists
111
Interaction of calcium antagonists with the
calcium channel
Extracellular
Intracellular
Calcium antagonist Ca2
112
Actions of calcium antagonists on smooth muscle
and heart
Calcium antagonist
Slow Ca2 entry
Smooth muscle
Heart muscle

• Oesophagus
• Ureter
• Detrusor vesicae
• Uterus
• Intestine
• Bronchi

• Blood vessels

• Sinus rate
• AV conduction

• Contractility
• Cardioprotection

• Coronary flow
• Vasospasm
• Organ protection

Atherosclerosis
Blood pressure
113
Classification of calcium antagonists

• Group First Second generation Third
• Dihydropyridine Nifedipine Nifedipine Benidipine A
  mlodipine
• (artery gt cardiac) Nicardipine SR/GITS Isradipine
  Lacidipine
• Felodipine ER Manidipine Lercanidipine
• Nicardipine SR Nilvadipine
• Nimodipine
• Nisoldipine
• Nitrendipine
• Benzothiazepine Diltiazem Diltiazem SR
• (artery cardiac)
• Phenylalkylamine Verapamil Verapamil SR
• (artery lt cardiac) Gallopamil
• Abbreviations ER extended release GITS
  gastrointestinal therapeutic system SR
  sustained release

generation
generation
(specificity)
114
Calcium antagonists (DHP)

• Very effective in lowering BP.
• Reduce morbidity and mortality in elderly
  patients with ISH (Syst-Eur, Lancet 1997).
• Reduce morbidity and mortality in elderly
  diabetic patients with ISH ( Syst-Eur, NEJM
  1999).
• Anti-anginal effect.
• Long-term treatment reduce morbidity/mortality as
  the conventional treatment (STOP II, INSIGHT).

115
Calcium antagonists (NON-DHP)

• ?????? ?? ???? ????????? ???? ??? ????? ??????
  ????? ????, ???? ?????? ??????? ?????? ?????? ??
  ??????, ????? ?????? ??????? ????????, ??????
  ???? ????? ???????? ???.
• ?? ?????? ?????? ?????? ?? ?? ????? ?? ?? ???
  ????? ???????? ??? ????? ?????? ???.
• ???? ?????? ?????? ?? ??? ???? ????? 2 ?????.
• ?? ?????? ?????? ?? ????? ?.

116
Calcium antagonists (NON-DHP)

• ???????
• ?????? ???? ??? ???? ?? ????? ??????? ??? (EF gt
  40), ????? ?????? ???? ????? ?, ?????? ???
  ?????? ???? ?????? ???????.
• ?????? ??? ?????? ?????? ?? ?? ????? ?? ?? ???
  ????? ?????? ?????????.

117
Calcium antagonists - disadvantages

• Side effects - Ankle edema, Flushing, Headache,
  constipation, gingival hypertrophy, negative
  inotropic effect, may worsen CHF.
• Activate the SNS and may increase heart rate
  (DHP).
• Less protection to the kidney than ACEI.
• Price (DHP).

118
Direct vasodilators

• ??? ?? ?????? ??????? ?????? ??? ?? ??????? ?????
  ????? ?? ????? ???? ??????????.
• ??????? ?????? ??
• ???????? - ????? ?????? ???? ??? ?? ??????.
• ?????????? - ???? ?????? ??????? ?? ??? ??? ??
  ???? ??????.
• ????? ?????? ?????? ? ??????? ?????? ??????
  ??????? ??? ???? ????? ?? ????? ?????????? ??????
  ??????? ??????? ?????? ??????? ??? ??.

119
Direct vasodilators -side effects

• ????? ??????
• ???? ?????
• ?????????? - ?????? ???????????? ?????? ????
• ??????????? ?????? ????? ?? ????? ??? ??????
  ????? ??????? ???????????.

120
ACE Inhibitors
121
The renin-angiotensin system
LIVER
Angiotensinogen
KIDNEY
Renin
Negative feedback
Alternativepathways(t-PA,chymasecathepsin G)
Angiotensin I
Increased blood pressure
Bradykinin
ACE
Inactivefragments
Sodiumretention
Angiotensin II
AT1 RECEPTORS IN BLOOD VESSELS
Aldosterone
AT1 RECEPTORS IN ADRENAL GLAND
VASOCONSTRICTION
122
ACEI - advantages

• Effective in patients with CHF.
• Protect the kidney in diabetic nephropathy.
• Protect the kidney in nondiabetic renal failure.
• Reduce LVM.
• Protect the vascular tree.
• Reduce morbidity and mortality in normotensive
  patients with high CV risk (HOPE study).

123
ACEI - Side effects

• Cough (13-25 incidence).
• Angioedema (rare, but life threatening).
• First dose hypotension, particularly in
  combination with diuretics (e.g. the elderly).
• Deterioration in renal function (in bilateral
  RAS).
• Hyperkalemia mainly in diabetic patients and in
  patients with renal failure, or when given with
  potassium sparing diuretic.
• Rash, taste disturbances, cholestatic jaundice,
  leukopenia.

124
Mechanism of Action ofAngiotensin II Receptor
Antagonists
Angiotensinogen
Alternate pathways
Bradykinin
Angiotensin I
ACE
Angiotensin II
Inactive peptides
?
AT1 receptor
Other AT receptors
AT2 receptor
Vasodilation Attenuate growth and disease
progression
?
125
Alternative way to block the RAAS

• AT1 receptors blockers
• Block completely the effect of AII at the
  receptor level
• Does not inhibit the degradation of bradykinin

126
AT1 receptors blockers - advantages

• Equal efficacy as ACEI.
• Low rate of side effects.
• Once daily.
• Reduce LVM.
• Effective in CHF (losartan).
• Protect the kidney in diabetic patients.
• Metabolically neutral.

127
AT1 receptors blockers

• ?????? ?????? ?? ???? ?????? ??????, ???? ?? ????
  ?????? ????? ?-AT1 receptor antagonist ??????
  ??????? ??????? ????? ?????? ACE.
• ??? ??? ?????? ?????? ?? ?????? ?? ??????
  ??-????? ?? ????? ?????, ?? ?????? ?? ?????? ??
  ???? ???? ?????.
• ??? ??? ?????? ?????? ?? ????? ??????.
• ?????? ?????? ?? ?????? ???? ?????? ?? ??????.

128
AT1 receptors blockers -side effects

• ???? ???
• ??????, ???????
• ?????????
• ?????????
• ????? ????? ??????? ???

129
AT1 receptors blockers - disadvantages

• Expensive.

130
Combination therapy

• ACEI Diuretics
• ACEI CCB
• BB DHP CCB
• Diuretic with any drug
• Not recommended
• BB NDHP CCB
• Potassium sparing ACEI

131
Tailored therapy
Make choice based on patient profile
-
132
How to start antihypertensive treatment
depends on

• Demographic consideration.
• Associated risk factors.
• Concomitant disease.

133
Response rate to monotherapy

• Response rate to monotherapy is less than 50.
• With the exception of age and race, in the
  majority of patients there are no predictors of
  drug response.

134
What to do when a given antihypertensive agent
fails to normalize blood pressure ?
Switch to another agent
Wait 4 to 6 weeks
Increase the dose
Combine with another agent
135
Is it worthwhile to increase the dose

• Dose escalation in hypertension is often
  associated with dose-related side effects, but
  not necessarily with a significant increase in
  anti-hypertensive effects.

136
The effect of dose escalation
Blood Pressure
Side effects
Low dose
Medium dose
High dose
137
The effect of dose escalation
Angiotensinogen
PRA
CCB (DHP)
Vasodilation
Angiotensin I
Sympathetic activation
Alternate pathway
ACE
Angiotensin II
BP
138
The effect of dose escalation
Angiotensinogen
Diuretics
Volume depletion
PRA
Angiotensin I
Alternate pathway
ACE
Angiotensin II
BP
139
The advantage of combination therapy

• Combining drugs that work on different
  physiologic systems increase the level of BP
  control.

140
Combination of ACEI or ARB with diuretic
K
ACEI or ARB
Diuretic
RAAS
BP
Combination
141
Combination of CCB with ?-blocker
Heart rate
?-blocker
CCB
Vasodilaion
BP
Combination
142
The advantage of combination therapy

• It may be preferable, therefore, to combine low
  doses of 2 agents to improve blood pressure
  control while at the same time minimizing the
  rate of adverse response.

143
Guidelines for hypertension treatment

• Heterogeneity of hypertension with respect to
  etiology and pathogenesis.
• Marked individual differences in response to
  different classes of drugs, therefore choose the
  best class of drugs for the individual patient.
• Combining drugs that work on different
  physiologic systems increases the level of BP
  control.

144
Guidelines for hypertension treatment

• What should be the goal of antihypertenive
  treatment

145
Guidelines for hypertension treatment
What should be the goal BP

• All patients lt140/90 and lower if tolerated.
• Diabetic patients lt 130/80, the lower the better.
  
• Nephropathy lt 120/75
• Elderly lt140/90 and lt160/90 acceptable
• Control all other risk factors.

146
Guidelines for hypertension treatment

• Special patients groups
• Elderly
• Diabetics

147
Blood pressure measurements in Older Persons

• Pseudohypertension (falsely high sphygmomanometer
  readings)
• White-coat hypertension and excessive variability
  in SBP
• Auscultatory gap
• Orthostasis, postprandial hypotension

148
Hypertension in Older Persons

• Those with borderline (stage 1) isolated
  systolic hypertension (140-159/lt90) are at
  significantly increased cardiovascular risk, but
  the benefits of treatment in those individuals
  have not yet been demonstrated in a controlled
  trial.

149
Benefit of lowering BP in the elderly

• Stroke reduction
• Cardiac events
• Total mortality

36 25 12
150
Treatment of Hypertension in Older Persons

• pharmacologic treatment is indicated. Treatment
  of hypertension in older persons has demonstrated
  major benefits.
• Hypertension therapy should begin with lifestyle
  modifications.
• Older patients will respond to modest salt
  reduction and weight loss.
• If goal blood pressure is not achieved, then use
  drug therapy

151
Treatment of Hypertension in Older Persons

• The starting dose in older patients should be
  about half of that used in younger patients.

152
The Goal of Treatment in Older Persons

• The goal of treatment in older patients should
  be the same as in younger patients (to lt140/90 mm
  Hg if at all possible), although an interim goal
  of SBP below 160 mm Hg may be necessary in those
  patients with marked systolic hypertension.

153
The Goal of Treatment in Older Persons

• Any reduction in blood pressure appears to
  confer benefitthe closer to normal, the greater
  the benefit.

154
Hypertension in the elderly

• Hypertension in the elderly should be treated.
• Isolated systolic hypertension in the elderly
  should be treated.
• Diuretic is more beneficial than beta-blockers in
  the elderly.
• Long-acting CCB is an alternative treatment in
  elderly patients with ISH.

155
Summary Diabetic patients

• The risk of CV disease is almost double in
  diabetic hypertensive patients.
• BP should be lowered to less than 130/80 mm Hg.
• To achieve target BP combination therapy is often
  required.
• Lowering BP seems to be more important than
  strict control of glucose levels.
• ACE inhibitors (or ARB) are recommended in all
  diabetic patients.
• CCB are effective in reducing morbidity and
  mortality in elderly diabetic hypertensive
  patients and frequently required to achieve goal
  BP.