SYSTEMIC HYPERTENSION

MECHANISMS, DIAGNOSIS,
THERAPY

CRISTIAN DINA
 Systemic Hypertension
• definition
• prevalence
• assessment of individual risk
• mechanisms of primary hypertension
• association of hypertension with other conditions
• hypertension in special groups
• secondary forms of hypertension
• hypertensive crises
• therapy
 U.S. National Health and
Nutrition Examination Survey
70

60

50

40 Diagnosed
Treated
30
Controlled
20

10

0
1976-1980 1988-1991
Systemic Hypertension: Definition
30 30

25 25

20 20

15 15
SBP, mmHg DBP, mmHg
Relative Risk Relative Risk
10 10

5
5

0
0
<1
11
12 19
13 29
14 39
15 49
16 59

<7

70

75

80

85

90

95

10
0-
0-
0-
0-
0-
0+
10

1
1
1
1
1

-7

-7

-8

-8

-9

-9

0+
4

9
Systemic Hypertension: Initial Attitude
Persistently raised
clinic blood pressure

yes
Target organ damage?

high Start treatment

Home blood pressure

24-hour ambulatory high

blood pressure

Continue to monitor
clinic/home blood pressure
Systemic Hypertension: Guidelines in
Measuring Blood Pressure
• Conditions for the patient
 posture
 circumstances

• Equipment
 cuff size
 manometer
 ultrasound equipment for infants

• Technique
 number of readings
 performance
 recordings
 Documentation of Systemic
Hypertension
• marked variability
• borderline hypertension
• white-coat hypertension
• hypertension in children and adolescents
 Classification of BP: Adults Aged
18Years and Older
CATEGORY SYSTOLIC DIASTOLIC

Normal <130 <85

High normal 130-139 85-89

Hypertension
Stage 1 (mild) 140-159 90-99
Stage 2 (moderate) 160-179 100-109
Stage 3 (severe) 180-209 110-119
Stage 4 (very severe) >210 >120
Systemic Hypertension: Prevalence
70 64
60
60
53
48
50
41
40
33 '76-'80
30 24 '88-'91
20 14 15
9 8
10 4
0
18-24 25-34 35-44 45-54 55-64 65-74
 Types of Hypertension
• Systolic and diastolic hypertension
 Primary, essential, or idiopathic
 Secondary
• renal
• endocrine
• coarctation of the aorta
• pregnancy-induced hypertension
• neurological disorders
• acute stress, including surgery
• increased intravascular volume
• alcohol and drug use
 Systolic hypertension
• increased cardiac output
• rigidity of the aorta
 Frequency of Various Diagnoses
in Hypertensive Subjects
DIAGNOSIS RUDNICK SINCLAIR ANDERSON
Essential hypertension 94% 92.1%
89.5%
Chronic renal disease 5% 5.6% 1.8%
Renovascular disease 0.2% 0.7% 3.3%
Coarctation of the aorta 0.2%
Primary aldosteronism 0.3%
1.5%
Cushing’s syndrome 0.2% 0.1%
0.6%
Pheochromocytoma 0.1%
0.3%
Oral contraceptive-induced 0.2%
1.0%
Features of “Inappropriate” Hypertension
• Onset before age 20 or after age 50
• Level of blood pressure >180/110 mmHg
• Organ damage
 funduscopic findings of grade 2 or higher
 serum creatinine >1.5mg/100ml
 cardiomegaly(x-ray) / left ventricular
hypertrophy(ecg)
• Features indicative of secondary causes
 unprovoked hypokalemia
 abdominal bruit
 variable pressures with tachycardia, sweating,
tremor
 family history of renal disease
• Poor response to therapy that is usually effective
Natural History of Untreated Hypertension

• Meta-analysis of 9 major studies, 420,000 individuals,

follow-up of 6-25y: direct, continuous and apparently
independent association” of DBP with both stroke and
CHD”
• symptoms and signs
• course of untreated hypertension
 Complications of Hypertension
Vascular complications of hypertension

HYPERTENSIVE
Accelerated-malignant phase
Hemorrhagic stroke
Congestive heart failure
Nephrosclerosis
Aortic dissection
ATHEROSCLEROTIC
Coronary heart disease
Sudden death
Other arrhytmias
Atherothrombotic stroke
Periph.vascular disease
 Target Organ Damage
• Retinopathy
 hypertensive
 atherosclerotic

• cardiac involvment
 abnormalities of LV function
 LV hypertrophy
 Coronary artery disease

• renal function
• cerebral involvment
 Target Organ Damage:
Funduscopic Examination
• Grade 1: narrowing of the arteriolar lumen
• Grade 2: sclerosis of the adventitia/thickening of the
arteriolar wall: arteriovenous nicking
• Grade 3: rupture of small vessels: hemorrhages
and exudates
• Grade 4: papilledema
 Target Organ Damage: Cardiac
Involvement
BP
Systolic Diastolic
dysfunction LVH dysfunction

EF ↓ EF → or ↑
Ventricular
EDV ↑ EDV → or ↓
arrhytmias
LV dilation LV size normal

LV filling pressure ↑
Low CO
syndrome Pulmonary venous
congestion
Dyspneea
 Mechanisms of Primary Hypertension
Autoregulation
BLOOD PRESSURE= CARDIAC OUTPUT x PERIPHERAL RESISTANCE
Hypertension = Increased CO and/or Increased PVR

↑ Preload ↑ Contractility Functional Structural

constriction hypertrophy

↑ Fluid Venous
volume constriction

Renal Decreased Sympathetic Renin- Cell Hyper-

sodium filtrration nervous angiotensin membrane insulinemia
retention surfacee overactivity excess alteration

Excess Endothelium-
sodium Genetic Genetic Obesity derived
Stress
intake alteration alteration factors
Mechanisms of Primary Hypertension

• hemodynamic patterns
• genetic predisposion
• the fetal environment
• renal retention of excess sodium
• defects in cell transport or binding
• vascular hypertrophy
• sympathetic nervous hyperactivity
• the renin-angiotensin system
• hyperinsulinemia/insulin resistance
• endothelial cell disfunction
 Hypertension in Special Groups
• african americans
• women
• children and adolescents
• elderly
• diabetes mellitus
Secondary forms of Hypertension
• Oral contraceptive and postmenopausal estrogen use
• Renal parenchymal disease
• Renovascular hypertension
• Adrenal causes of hypertension
• Hypertension after heart surgery
• Hypertension during pregnancy
 Hypertensive Crises
• Definitions
 emergencies
 urgencies
 accelerated-malignant hypertension
 hypertensive encephalopathy

• Incidence
 <1%
 any hypertensive disease can initiate a crisis!
Circumstances requiring rapid treatment of hypertension
• Accelerated-malignant hypertension with papilledema
• Cerebrovascular
 hypertensive encephalopathy  atherohrombotic brain infarction
 intracerebral hemorrhage w.severe hypertension
• Cardiac
 acute aortic dissection  acute myocardial infarction
 acute left ventricular failure  after coronary bypass surgery
• Renal
 acute glomerulonephritis
 renal crises from collagen-vascular diseases
 severe hypertension after kidney transplantation
• Excessive circulating catecholamines
 pheochromocytoma crisis
 food/drug interactions w.monoamine-oxidase inhibitors
 sympathomimetic drug use (cocaine)
 rebound hypertension after sudden cessation of antihypertensive drugs
• Eclampsia
• Surgical
 severe hypertension in patients requiring immediate surgery
 postop.hypertension, postop.bleeding from vascular suture lines
• Severe body burns
• Severe epistaxis
A scheme for the initiation and progression of malygnant
hypertension
Critical degree of hypertension
Local effects Systemic effects
(Prostaglandins, free (Renin-angiotensin,
radicals, etc.) catechol, vasopressin)

Endothelial damage Pressure natriuresis

Platelet deposition Hypovolemia

Mitogenic and Further increase

migration factors in vasopressors

Myointimal proliferation

Further rise in blood pressure

and vascular damage

Tissue ischemia
 Hypertensive Crises: Clinical
Characteristics
• Blood pressure: ussualy >140mm Hg diastolic
• Funduscopic findings: hemorrhages, exudates,papilledema
• Neurological status: headache, confusion, somnolence,
stupor, visual loss, focal deficits, seizures, coma
• Cardiac findings: prominent apical impulse, cardiac
enlargement, congestive failure
• Renal: oliguria, azotemia
• Gastrointestinal: nausea, vomiting
 Hypertensive Crises: Differential
Diagnosis
• Acute left ventricular failure
• Uremia from any cause, particularly with volume overload
• Cerebrovascular accident
• Subarachnoid hemorrhage
• Brain tumor
• Head injury
• Epilepsy(postictal)
• Collagen diseases, partic. lupus, with cerebral vasculitis
• Encephalitis
• Overdose / withdrawal from narcotics, amphetamines, etc
• Hypercalcemia
• Acute anxiety with hyperventilation syndrome
 Systemic Hypertension: Therapy
• Benefits of therapy
• Threshold for therapy
• Goal of therapy
• Life style modifications
• Antihypertensive drug therapy
• Special considerations
• Therapy for hypertensive crises
 Benefits of Therapy
• reduction of blood pressure
• prevention of cardiovascular complications
 stroke 40%
 CHD 16%

• different benefits for different degrees of hypertension

 Threshold for Therapy
• U.S.Joint national Committee vs. British and
Canadian expert committees: DBP: 90 or 100mmHg?

• WHO & International Society of Hypertension:

 DBP>95mmHg after 3-6 month of observation

• New Zealand experts:

 10 y risk>20% and SBP>150mmHg or
DBP>90mmHg
 all patients >170/100mmHg
 Absolute rate of cardiac events and
stroke related to diastolic blood pressure
during antihypertensive treatment
60

50
Stroke
Rate/1000 years

40

30

20
Cardiac events
10

0
70 80 85 90 95 100 105 110
Mean in-study diastolic blood pressure (mmHg)
• Features considered in the decision to treat
 Other risk factors
• cigarette smoking
• total cholesterol/HDL cholesterol ratio>6
• diabetes
• obesity (body mass index>30)
• family history of premature cardiovascular disease (in parent
or sibling before age 55)
 Symptomatic cardiovascular disease
• angina or silent ischemia
• myocardial infarction
• coronary angioplasty or bypass surgery
• heart failure
• left ventricular hypertrophy (ECG or echocardiography)
• transient ischemic attacks
• stroke
• peripheral vascular disease
• familial hyperlipidemia
• other target organ damage such as renal disease
Absolute risk of having a cardiovascular event in 10 years
according to age, blood pressure, and other risk fators
Men Women
Blood pressure Systolic 150 160 170 150 160 170
(mmHg): Diastolic 90 95 100 90 95 100
Age Risk
(years): factor:
None
One
40 Two
Three
Major
None
One
50 Two
Three
Major
None
One
60 Two
Three
Major
None
70 One
Two
Three
Major
<10% 20-40%
10-20% >40%
 Goal of Therapy
Risk of cardiovascular disease C B

Blood pressure

Hypothetical relationships between levels of blood

pressure and risk of cardiovascular disease.
 Life Style Modifications
• avoidance of tobacco
• weight reduction
• diet
 sodium restriction
 magnesium supplementation
 calcium supplementation
 moderation of alcohol

• physical exercise
• relaxation techniques
• combined therapies
 Antihypertensive Drug Therapy
• General guidelines
• Diuretics
• Adrenergic inhibitors
• Vasodilators
• Special considerations in therapy
• Therapy for Hypertensive Crises
 Therapy: General Guidelines
to improve patient adherence to antihypertensive therapy

1. Be aware of the problem of nonadherence and be alert to

signs of patient nonadherence.
2. Establish the goal of therapy: to reduce blood pressure to
normotensive levels with minimal or no side effects.
3. Educate the patient about the disease and its treatment
a. involve the patient in decision making
b. encourage family support
4. Maintain contact with the patient.
a. encourage visits and calls to allied health personnel
b. allow the pharmacist to monitor therapy
c. give feedback to the patient home BP readings
d. make contact with patients who do not return
5. Keep care inexpensive and simple
 Therapy: General Guidelines
to improve patient adherence to antihypertensive therapy

6. Prescribe according to pharmacological principles.

a. add one drug at a time
b. start with small doses(5-10 mmHg reductions each step)
c. prevent volume overload (diuretic and sodium restriction)
d. medication on awakening /after 4 AM(awakenings to void)
e. ensure 24-hours effectiveness by home/ambulatory
monitoring
f. continue to add effective and tolerated drugs, stepwise, in
sufficient doses to achieve the goal of therapy
g. stop unsuccessful therapy and try a different approach
h. adjust therapy to ameliorate side effects that do not
 Therapy: General Guidelines
• Drug combinations:
 efficacy of therapy beyond that of each component
 no more side-effects than seen with each
separately
• Complete coverage with once daily dosing
• The initial choice
• Individualized therapy
• Substitution
• The place of guidelines
 Therapy: General Guidelines
COEXISTING DIURETIC b-BLOCKER a-BLOCKER CaBLOCKER ACEI
CONDITION
Older age(>65) ++ +/- + + +
Black race ++ +/- + + +/-
Angina +/- ++ + ++ +
Post-myocardial inf. + ++ + +/- ++
Congestive failure ++ +/- + - ++
Cerebrovasc.disease + + +/- ++ +
Renal insufficiency ++ +/- + ++ ++
Diabetes +/- - ++ + ++
Dyslipidemia - - ++ + +
Asthma or COPD + - + + +
Benign prostatic ++
hypertrophy

++ =preffered, + =suitable, +/- =usually not preffered, - =usually contraindicated

 Therapy: Diuretics
• Major groups
 carbonic anhydrase inhibitors: acetazolamide
 loop diuretics: furosemide, bumetanide, torsemide,
ethacrynic acid
 thiazides and related sulfonamide compounds:
hydrochlorothiazide, chlorthalidone,
metolazone, indapamide, xipamide
 potassium-sparing agents: amiloride, triamterene,
spironolactone
• Mechanism of action
 ↑ urinary sodium excretion, ↓plasma volume, ↓CO
 ↓ peripheral resistance
 Therapy: Diuretics. Complications
Diuretic therapy

Renal reabsorption of Na(and Mg) Hypomagnesemia

Hyponatremia Saluresis and diuresis
↓ Plasma volume

↓Cardiac output ↓ Renal blood flow ↑PRA

Postural ↓GFR ↑Aldosterone

hypotension Kaliuresis
Pre-renal Proximal Distal Ca
azotemia reabsorption reabsorption Hypokalemia
↓ Cluric acid ↓ Clcalcium

HyperuricemiaHypercalcemia Glucose Hyper-

tolerance cholesterolemia
 Therapy: Adrenergic Inhibitors
1. Peripheral neuronal inhibitors 4. β-receptor blockers
a. reserpine a. acebutolol
b. guanethidine b. atenolol
c. guanadrel c. betaxolol
d. bethanidine d. bisoprolol
2. Central adrenergic inhibitors e. carteolol
a. methyldopa f. metoprolol
b. clonidine g. nadolol
c. guanabenz h. penbutolol
d. guanfacine i. pindolol
3. α-receptor blockers j. propranolol
a. α1 & α2-receptor -phenoxybenzamine k. timolol
-phentolamine 5. α and β-rec.blocker
b. α1-receptor -doxazosin labetalol
-prazosin
-terazosin
 Therapy: Vasodilators
DRUG RELATIVE ACTION ON
ARTERIES OR VEINS
Direct vasodilators
Hydralazine A >> V
Minoxidil A >> V
Nitroprusside A = V
Diazoxide A > V
Nitroglycerin V > A
Calcium entry blockers A >> V
Converting enzyme inhibitors A > V
Alpha blockers A = V
 Therapy for Hypertensive Crises
DRUG DOSAGE ONSET OF ADVERSE
ACTION EFFECTS
Nitroprusside .25-10µg/kg/min instantaneous Nausea, vomiting, sweating,
thiocyanate intoxication
Nytroglicerin 5-100 µg/min 2-5 min Tachycardia, flushing,
headache, vomiting
Diazoxide 50-100mg i.v. 2-4 min Nausea, hypotension, flushing
repeated bolus tachycardia, chest pain
Nicardipine 2-10 mg/hr, i.v. 5-10 min Tachycardia, headache,
flushing, local phlebitis
Hydralazine 10-20 mg i.v. 10-20 min Tachycardia, headache,
10-50 mg i.m. 20-30 min flushing, vomiting, angina
Enalapril 1.25-5 mg q 6h 15 min Precipitous fall in BP in high
renin states; response varies
Phentolamine 5-10 mg i.v. 1-2 min Tachycardia, flushing
Esmolol 500 µg/kg/min 4’ 1-2 min Hypotension
then 150-300 µg/kg/min
Labetalol 20-80mg i.v. bolus 5-10 min Vomiting,scalp tingling,nausea
2mg/min i.v. infusion postural hypotension, dizzines