Pharmacotherapy

Hypertension
Defined as:

Condition where blood pressure is elevated to an extent that

clinical benefit is obtained from blood pressure lowering

&

140/90 mmHg is considered the upper limit of normal

(treatment threshold or targets)
• Hypertension is largely a condition of older individuals

• Diastolic pressure peaks at age of 50

• Systolic pressure continues to increase with advancing age

• Risk of cardiovascular disease double for every 20/10mmHg rise in

blood pressure
 Most common and important cardiovascular complications associated
with hypertension are stroke and myocardial infarction

↑5mmHg in usual diastolic blood pressure is associated with 35-40%

↑ risk of stoke

Risk of heart failure is increased with six fold in hypertensive subjects

↓ blood pressure of 10/6mmHg associated with 38% ↓ stoke and 16%

↓ coronary events

↓5 mmHg blood pressure is associated with 25% ↓ renal failure

 Introduction
Chronic sustained elevation of systemic arterial blood pressure.

JNC 8 Recommendation

• Definitions of HTN and prehypertension not addressed, but thresholds for

pharmacologic treatment are defined.
Strategies to Dose Antihypertensive Drugs (JNC8)

Strategy Description
A Start one drug, to maximum dose, and then
add a second drug.
B Start one drug, then add a second drug
before achieving max dose of first.
C Begin 2 drugs at same time, as separate pills
or combination pill. Initial combination
therapy is recommended if BP is greater
than 20/10mm Hg above goal.
JNC 8 Hypertension Guideline Algorithm
Complications of hypertension:
Myocardial infarction
Stroke
Cerebral/brainstem infarction
Cerebral haemorrhage
Lacunar syndromes
Multi infarct disease
Hypertensive encephalopathy/ malignant hypertension
Dissection aortic aneurysm
Hypertensive nephroscelrosis
Peripheral vascular disease
Epidemiology
10-25% population are expected to benefit from the drug treatment

90-95% of cases of hypertension , there is no underlying medical illness to

cause high blood pressure= essential hypertension

Essential = compensation mechanism to maintain adequate circulation

Genetic factors also clearly plays a role, but not a single gene is responsible
for hypertension except in Polycystic kidney disease /Liddle’s syndrome

More common in black people of African (Caribbean origin)

Causes of hypertension

PRIMARY HYPERTENSION : Essential hypertension

• Over 90% of hypertensive individuals are classified under

essential hypertension.
• Genetic factors affect sodium balanced and other BP
regulating pathways.
Causes of hypertension
SECONDARY HYPERTENSION
• Approx. 10% of hypertensive patients
• Maybe secondary to other diseases like CKD or renovascular disease.
• Also may be secondary to certain drugs
Renal diseases Drugs:
Endocrine disease Sympathomimetic amines
Steroid excess: hyperaldosteronism, hypercorticoidism Oestrogens (?)
Growth hormone excess Ciclosporin
Catecholamine excess Erthyropoietin
Pre clampsia NSAIDS
Steroids
Vascular causes: Renal artery stenosis: fibromuscular High salt
hyperplasia, renal artery atheroma Alcohol intake
Obesity
 Pathophysiology of HPN
Regulation of Blood pressure
Mean blood pressure is the product of Cardiac output and total
peripheral resistance

In most hypertensive individuals no change in cardiac output but

increase in peripheral resistance (?)

Control of blood pressure is important and number of homeostatic

reflexes are evolved to provide the BP homeostatis
 Pathophysiology of HPN
Factors Affecting Control of BP

1. Humoral (RAAS) or Vasodepressor mechanisms

2. Abnormal Neuronal Mechanisms
3. Defects on Peripheral Auto regulation
4. Disturbances in sodium, calcium and natriuretic hormones
***RAAS ultimately regulates arterial BP
Minute to minute increase in BP – baroreceptor reflex
Longer term regulation – renin-angiotensin- aldosterone system(salt,
water and blood pressure control)
Long term increase in shear stress also causes the vascular remodeling
Nitric oxide overcome by increased sensitivity to vasoconstrictor
endothelin (increases peripheral resistance)
Atrial natriuretic peptide
Bradykinin
Antidiuretic hormone
Clinical presentation
• Severe cases may present – Headache, visual disturbance or evidence
of target organ damage ( stroke, ischaemic heart disease or renal
failure)

• Malignant hypertension : accelerated/uncommon/ emergency, usually

>220/120mmHg evidence of Small vessel damage
 • Fundoscopy: papilloedema (optic disc swelling), haemorrhages and
exudates

• Renal damage: haematuria, proteinuria and impaired renal function

• Hypertensive encephalopathy: small vessel damage in brain/ cerebral

oedema- confusion, headache, visual loss, seizures and coma

• MRI shows extensive white matter changes

• Requires hospital admission and rapid control of blood pressure over

12-24h towards normal levels
Natural Course of the Disease
• Essential Hypertension – preceded by elevated BP that are in the pre-
hypertension category
• Fluctuation of BP may occur between normal and elevated values
• Progression of disease may lead to increase of PVR and BP
 Hypertension-Associated Complications
• CV events (MI, CVA) – Probability of CV events and CV morbidity
and mortality are directly correlated with severity of HPN
• HPN accelerates atherosclerosis leading to ventricular and vascular
dysfunction
• CVA is a consequence of HPN
• Retinophaties can be developed
• Accelerated artheriosclerosis
• Kidney damage characterized by pathologically increased hyaline
arterioscelorosis, hyperplastic arterioscelorosis arteriolar hypertrophy,
fibrinoid necrosis and atheroma of the major renal arteries;
Albuminuria follows leading to ESKD
• Peripheral vasculature is a target organ leading PAD
Management of hypertension
Diagnosis of hypertension:
All adults have their blood pressure check for every 5 years
Those with high blood pressure 130-139mmHg systolic and 85-89 mmHg
diastolic should have annual measurement
Measurement of blood pressure:
Well maintained sphygmomanometer of validated accuracy
Measured in both arms
In sitting and standing positions
In relaxed condition
Accurate sized cuff should be used
White coat hypertension (?)
Assessment of hypertensive patient
Secondary causes

Contributing factors:

Evidence of end organ damage

Determination of cardiovascular risk

 Secondary causes
Renal damage (haematuria, polyuria)
Phaeochromocytoma (headache, postural dizziness, syncope)
Physical examination: abdominal bruits (renal artery stenosis)
Radiofemoral delay (coarctation of aorta)
Palpable kidneys (polycystic kidney disease)
Laboratory analysis (full blood count, electrolytes , urea , creatinine
and urinalysis)
Ultrasound of abdomen
Isotope regimen for suspected renal disease
• Renin levels suppressed by Beta blockers

• Aldosterone by ACE inhibiotors and receptor antagonists

• Very high aldosterone /renin ratio- conn’s syndrome or primary

hyperaldosteronism, cause by benign adenoma/ simple hyperphlasia

• CT/ MRI scanning shows images of tumours

Contributing factors:
Should be assessed for possible contributing factors and possible
factors such as obesity, excess alcohol or excess salt intake and lack of
exercise

Provoked by use of drugs (OTC drugs cold and flu remedies)

Smoking, diabetes and hyperlipidaemia

Family history of cardiovascular disease

Evidence of end organ damage:

Optic fundi- retinal damage

ECG – detect left ventricular hypertrophy/ ischaemic heart disease

Urine analysis for microalbuminaria (indicator of higher risk of future

end stage renal disease and overall vascular risk)
Determination of cardiovascular risk:

Patients with documented atheromatous vascular disease

(MI/Stroke/angina/ peripheral vascular disease)

Type 2 Diabetes over 40 years of age = coronary equivalent

Non diabetic patients with MI

Non diabetic patients without cardiovascular disease necessary to

estimate the cardiovascular risk (microalbuminuria increase 2-3 folds
cardiovascular risk)
Treatment
Non pharmacological approaches

Pharmacological approaches

Ancillary drug treatment

Non pharmacological treatment
• Patients with mild hypertension in the range of 140-159/90-100mmHg
offered lifestyle advice

• Over weight- weight loss reduces BP about 2.5/1.5mmHg/kg

• DASH (dietary approaches to stop hypertension) found to lower BP

significantly 4.5/2.7mmHg

• DASH- fruit, vegetables, low fat dairy products, fish, low fat poultry
and whole grains, minimizing red meat, confectionary and sweetened
drinks
• Subjects should reduce their salt intake (6g NaCl)

• Significant hidden salt in the processed meat, ready meals, cheese and even
bread

• Control intake of calories and saturated fat

• Regular aerobic exercise (min 30mins)

• Alcohol intake 2 units for females and 3 units for male

• Smoking should be quit, or else reduce the units

Pharmacological approaches
Treatment thresholds:
S.NO Blood pressure threshold Approach
01 >220/120mmHg Treated immediately, dual therapy suggested for
>20mmHg increase then target

02 >160-220/100-120mmHg Monitored over several weeks, treated if BP remains

(severity and end organ damage) in this stage

03 >140-159/90-99mmHg Monitored annually unless evidence of target organ

(severity and end organ damage) damage, CVD, DM

04 >135-139/85-89mmHg Monitored annually/reassessed annually

05 Less then 135/89mmHg Rechecked every 5 years
Refer to Table 13-5 of your book.
Other agents:
Minoxidil: powerful antihypertensive drug, indicated in severe
peripheral oedema and reflex tachycardia (* women ?)
Hydralazine: add on for resistant hypertension therapy
Sodium nitroprusside: direct acting arterial and venous dilator /
intravenous infusion/ blood pressure during anaesthesia
Aliskiren: ? antagonist
Darusentan: endothelin antagonist undergoing clinical trials in
resistant hypertension.
 Thiazide in HPN
• SHEP study and STOP Hypertension study and the MRC study all showed
significant REDUCTION in incidence of stroke, MI, all-cause CV disease
and mortality with thiazide-based therapy vs placebo

• The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack

Trial (ALLHAT)
• Showed evidence to justify thiazide used as first-line therapy
• Largest prospective HPN trial ever conducted in patients 55 years and
older with HPN and 1 addition CV risk factors (42,418 patients
• JNC7 recommends a thiazide as first-line therapy for most patients, and
are consistent with the historical treatment of HPN
 ACEI, ARB and CCB as first-line Agents
• Clinical trial data cumulatively demonstrate that ACEi, CCB or ARB based
antihypertensive therapy reduces CV events.
• May be used for patients without compelling indications as a first-line
therapy
• The Blood Pressure Lowering Treatment Trialist’s Collaboration involving
29 major randomized trials showed the ff:
• Significantly lower major CV events with ACEi and CCB based regimens
• Meta-analyses including ALLHAT the following are the findings:
adequate data to support the usefulness of using ACEi, CCB or ARB for
HPN as first-line anti-HPN agents
Beta-Blocker VS First Line Agents in HPN
• B blockers may not reduced CV events to the extent that an ACEi, ARB,
CCB or thiazide does
• Possible that atenolol is inferior and is the only B blocker that can
reduced CV events less than the other first-line anti-HPN drug classes
• B blocker for patients without compelling indications still has a role in the
management of HPN
• B blocker as first-line in HPN reduces CV events compared to NO anti-
HPN therapy
• B blockers can be used as first line drug when ACEi, ARB, CCB, or
thiazide cannot be used.
Patients with Compelling Indications
A. Heart Failure with Reduced Ejections Fraction
• The following can be used: ACEi or ARB plus diuretic, B blocker may
be added (bisoprolol, carvedilol or metoprolol) and aldosterone
receptor antagonist may be added
B. Coronary Artery Disease
• B blockers as first line therapy chronic stable angina, reduced BP and
improved ischemic symptoms by decreasing myocardial oxygen
consumption and demand
• Most effective in CV events in patients with recent MI and/or
ischemic symptoms
• Long acting CCBs (verapamil and diltiazel) may be useful alternatives
to B blocker
Patients with Compelling Indications
C. Diabetes
• Ideally treated with ACEi or ARB; both provide nephroprotection due
to vasodilation of the efferent arteriol of the kidneys; ACEi has
overwhelming data demonstrating such CV risk reduction
• CCBs most appropriate as add on agents for patients with diabetes
• Thiazides are recommended as add on therapy to lower BP and
provide additional CV risk reduction
Patients with Compelling Indications
D. CKD
• ACEi and ARB are usually indicated with patients with CKD and
HPN; there is lowering of BP and intraglomerular pressure reduced
which are beneficial for such patients; they slow progression of CKD
in diabetes
E. Recurrent Stroke Prevention
• Thiazide alone or combined with ACEi are considered as evidence
based effective anti-HPN drugs in patients with history of stroke and
TIA
Treatment of HPN in Special Populations
A. HPN in older people
• Morbidity and mortality in the elderly are more directly correlated
to SBP than to VBP
• SHEP trial (chlorthalidone based therapy with athenolol or
reserpine as add on therapy – significant reduction in the incidence
of stroke, CAD and Heart Failure
• Systolic HPN in Europe study (long acting dihydropyridine CCB)
revealed significant reduction in stroke, CAD and Heart failure
Treatment of HPN in Special Populations
B. HPN in children and adolescence
• ACEi, ARB, B blocker, CCB and thiazide are all acceptable choices
for children and are all supported with data regarding their used.
• ACEi, ARB or direct renin inhibitor should be avoided in sexually
active girls with HPN due to potential teratogenic effects
Treatment of HPN in Special Populations
C. HPN in pregnancy is categorized as follows:
1. Preeclampsia-eclampsia
2. Chronic HPN of any cause
3. Chronic superimposed preeclampsia
4. Gestational HPN
• Definitive treatment for preeclampsia is delivery
• salt restriction or any measures that contract blood volume
SHOULD NOT be employed
• The following drugs may be used: HYDRALAZINE,
LABETALOL, NIFEDIPINE
Treatment of HPN in Special Populations
C. HPN in pregnancy
Treatment of HPN in Special Populations
D. Pulmonary Disease and Peripheral Arterial Disease
• B blockers especially nonselective should be avoided in patients
with HPN and reactive airway disease, COPD
• Cardioselective B blockers can be safely used in asthma or COPD;
monitoring should be done
• B blockers can be problematic for patient with PAD (decreased
peripheral blood flow secondary to stimulation of alpha 1 receptors
unopposed)
• B blockers with alpha 1 blocking properties like carvedilol can be
used
Treatment of HPN in Special Populations
E. Metabolic Syndrome
• Using ACEi or ARB results to lower incidence of new onset
diabetes in patients with HPN
• ALLHAT showed a reduced incidence of CV events in patients
with impaired fasting glucose among patients using
CHLORTHALIDONE vs lisinopril
• Thiazide can be used as first line agent with metabolic syndrome
similar ACEi, ARB, and CCB
Treatment of HPN in Special Populations
F. HPN with Erectile Dysfunction
• TOMHS and Veterans Administration Cooperative Trials show NO
difference in the incidence of erectile dysfunction between thiazide
and B blockers vs ACEi and CCB
• Centrally acting agents – higher rates of sexual dysfunction; avoid
in men with erectile dysfunction
Individual Antihypertensive Agents
See your book and review the drugs’
pharmacologic profiles
Hypertensive Urgencies and Emergencies
Hypertensive Urgencies and Emergencies
Hypertensive Urgencies and Emergencies
• Characterized by BP =/< 180/120 mmHg
• Urgencies not associated with acute or immediate end-organ injury
• Emergencies are associated with acute end-organ injury like: encephalopathy,
intracranial hemorrhage, acute left ventricular failure with pulmonary edema,
dissecting aortic, aneurysm, unstable angina and eclampsia or severe hypertension
during pregnancy
A. Hypertensive Urgencies
• Ideally managed by the following:
1. adding new antihypertensive
2. increasing the dose of a present drug
• Rapid BP reduction should not be done; inherent risk to precipitate CVA, MI and
Acute Kidney Failure
• Short acting oral antihypertensive can be used (captopril, clonidine, labetalol)
• Nifedipine immediate released oral or sublingual is discouraged and is dangerous
Hypertensive Urgencies and Emergencies
B. Hypertensive Emergencies
• Generally requires parenteral antihypertensive therapy
• Goal: reduction in MAP up to 25% within minutes to hours
• Do not lower BP to less than 140/90
• Precipitous drop in BP may lead to ischemia and infraction
Ancillary treatment
ASPIRIN:
• Use reduces CV events at the expense of an increase in GIT complications
• Blood pressure should be controlled (<150/90mmHg) before aspirin.
• It should be restricted to the patients who have no contraindication and
either :
Evidence of established vascular disease
No evident of CVD but who are over 50 yrs of age
No evident of target organ damage
10 year CVD risk >20%
Lipid lowering therapy:

• Increasing evidence from the clinical trials of the benefit of lipid

lowering drug treatment in patients with hypertension
• Atorvastatin 10mg reduction in CHD and stroke
• LLT with statins should be prescribed to patients
Under 80 years of age
With cholesterol >3.5mmol/L,
Pre existing vascular disease,
10 years CV risk of >20%
Drug selection:
Drugs should be chosen on the basis of efficacy, safety, convenience and
cost
Efficacy:
Evidence from the large scale clinical trials
Short term studies only generates hypothesis and should be used to change
current strategies
Safety:
Drugs need to take on long term, so should be with long established safety
records
Recognize the importance of symptomatic adverse effects since these may
reduce adherance
Convenience:

Once daily preparation is more adherence than more frequent regimens

Conscious of the cost of individual preparations
Combination of low doses of anti hypertensive drugs are often better
tolerated than single drugs taken in large doses
 Algorithm for antihypertensive therapy
< 55 yrs and non blacks > 55 yrs and non blacks

Calcium channel blockers (nifedipine, amlodipine,

ACE Inhibitors verapamil, diltiazem)
(capto/enala/lisino/perindo/rami-PRIL) +
Diuretics (thiazides, loop diuretics)

A+C or A+D

A+C+D

Consider adding alpha/beta blocker, spironolactone

Seek specialist advice

Thank you