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Hypertension. Hypertension is not a diseaseIt is an arbitrarily defined disorder to which both environmental and genetic factors contribute Major risk factor for:cerebrovascular diseasemyocardial infarctionheart failureperipheral vascular diseaserenal failure. Definition. Elevation of arteria

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  • Hypertension is not a disease
  • It is an arbitrarily defined disorder to which both environmental and genetic factors contribute
  • Major risk factor for:
    • cerebrovascular disease
    • myocardial infarction
    • heart failure
    • peripheral vascular disease
    • renal failure
  • Elevation of arterial blood pressure above 140/90 mm Hg. Can be caused by:
    • an underlying disease process:In 5-10% a cause can be found
  • (secondary hypertension)
      • Renal artery stenosis
      • Hyperaldosteronism
      • pheochromocytoma
    • idiopathic process (primary or essential hypertension) In 95% of cases
The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. The myocardial fibers have undergone hypertrophy.
This left ventricle is very thickened (slightly over 2 cm in thickness), but the rest of the heart is not greatly enlarged. This is typical for hypertensive heart disease. The hypertension creates a greater pressure load on the heart to induce the hypertrophy.
major risk factors that increase mortality in hypertension
Major Risk Factors That Increase Mortality in Hypertension
  • Smoking
  • Dyslipidemias
  • Diabetes Mellitus
  • Age >60
  • Gender: men, postmenopausal women
  • Family history
  • The hypertension prevalence in the big cities, small to medium cities and class 1 to class 4 rural areas in China was 20.4%, 18.8%, 21.0%, 19.0%, 20.2% and 12.6% respectively
  • Pakistan (NHSP):the prevalence of hypertension is 17.9%
  • 24% of the USA adult population representing 43,186,000 persons had hypertension.
  • Diagnosis is generally based on repeated, reproducible measurements of elevated blood pressure and not on patient symptoms. Patient compliance is a major obstacle to therapy
stages of hypertension

Diastolic Range (mm Hg)

Systolic Range (mm Hg)

High Normal



Stage 1



Stage 2



Stage 3

> 109


Stages of Hypertension
treatment rationale
Treatment Rationale

Long-term goal of antihypertensive therapy:

Reduce mortality due to hypertension-induced disease

  • Stroke
  • Congestive heart failure
  • Coronary artery disease
  • Nephropathy
  • Peripheral artery disease
  • Retinopathy
ways of lowering blood pressure
Ways of Lowering Blood Pressure
  • Reduce cardiac output (ß-blockers, Ca2+ channel blockers)
  • Reduce plasma volume (diuretics)
  • Reduce peripheral vascular resistance (vasodilators)


individualized care
"Individualized Care"
  • Risk factors considered
  • Monotherapy is instituted
  • Non pharmacological therapy tried first
  • Considerations for choice of initial monotherapy:
    • Renin status
    • Coexisting cardiovascular conditions
    • Other conditions
determinants of arterial pressure
Determinants of arterial pressure

Blood pressure is controlled by an integrated system

  • Prime contributors to blood pressure are:
    • Cardiac output
      • Stroke volume
      • Heart rate
    • Peripheral vascular resistance


  • Each of these factors can be manipulated by drug therapy

Treatment of hypertension seeks to lower CO and/or TPR.

for short term neural control
For Short-Term Neural Control

Baroreceptor reflex

Sit or stand up quickly, BP fallsneural responses reestablish normal BP or Sudden increase in stroke volume, BP rises, neural responses reestablish normal BP

long term renal control of bp direct
Long-term Renal Control of BP: Direct

Pressure Diuresis

Blood volume too high, RenalSympathetic vasoconstriction reducedMore fluid enters kidney, more urine formed Lowers BP via lower blood volume

Blood pressure too low, Renal

Sympathetic vasoconstriction risesLess fluid enters kidney, less urine formedRaises BP by higher blood volume

renal control of bp indirect
Renal Control of BP: Indirect

If BP too low, increase BP by increasing __________

Kidney cells secrete _______Converts angiotensinogen to angiotensin I_______________________in lung converts angiotensin I to angiotensin II….

summary of long term renal control of bp
Summary of Long Term Renal Control of BP

Regulates BP by Changing:


Directly – by allowing more or less fluid

to enter kidney tubules

Indirectly – Reabsorbing more fluid that

was already destined to be urine


Vasoconstriction / vasodilation

major antihypertensive drugs

1) Diuretics

- Thiazides and congeners.

- Loop diuretics.

- Potassium-sparing diuretics.

2) Sympatholytic drugs

- Centrally acting antiadrenergic agents.

- Adrenergic neuron blocking agents.

- Alpha adrenergic blockers.

- Beta adrenergic blockers.

- Alpha-beta adrenergic blockers.

3) Vasodilators

- Nitric oxide releasers.

- Potassium channel openers.

- Calcium channel blockers.

4) Angiotensin inhibitors and antagonists.

- Angiotensin Converting Enzyme (ACE) inhibitors.

- Angiotensin receptor antagonists.

  • First -line drug
  • Low dose diuretic therapy is safe and effective in preventing HTN complications
  • hydrochlorothiazide (Hydrodiuril), chlorthalidone (Hygroton
  • furosemide
  • spironolactone
1 thiazide diuretics
1.Thiazide diuretics
  • Thiazides are the most effective diuretics to reduce blood pressure in patients with normal renal function. The antihypertensives doses are lower that those required for diuretic effect.
  • MOA:The initial hypotensive effects of diuretics is associated with a reduction in blood volume and cardiac output. Peripheral vascular resistance is unaffected.
After 6-8 weeks of continuous therapy intravascular volume and cardiac output return towards normal while peripheral vascular resistance decreases.

- Mechanisms of this decrease are probably related to

a depletion of body Na+ stores which leads to:

a) a decrease of interstitial fluid volume

b) a fall in smooth muscle Na+ concentration that in turn decreases intracellular Ca++ concentration

c) a change in response of cell surface receptors to vasoconstrictor hormones

thiazide diuretics clinical use
Thiazide diuretics: clinical use
  • Used for monotherapy of mild hypertension and for polydrug therapy of more severe cases.
  • Therapeutic expectation with monotherapy: 20/10 mmHg drop in 60% of patients.
  • Use low doses (ceiling effect) to minimize side-effects (K loss).
  • Low-dose thiazide/low dose beta-blocker combo
  • Can be used in conjunction with sympatholytics, ACEI, Ca-channel blockers
thiazide diuretics side effects
Thiazide Diuretics: side-effects.
  • Major Side-effects: a) K loss(minimized by using low doses, diet, use of combos with K-sparing diuretics). b) hyperuricemia(bad for gout) c) hyperglycemia, glucose intolerance (bad for diabetes) d)increase LDL & VLDL (bad for atherosclerosis)
  • Beneficial effect: Ca-sparing (good for osteoporosis)
furosemide and high ceiling diuretics
Furosemide and high ceiling diuretics
  • Use in hypertension is limited . On their own they are not very effective at lowering BP
  • Main indications are:
  • a) severe hypertension when several drugs with Na-retaining properties are used (e.g. hydralazine, major sympatholytics). Usually a beta-blocker is also required . b) when GFR is < 30-40 ml/min
  • c) in CHF or cirrhosis.
beta adrenergic antagonists
Beta-adrenergic antagonists
  • Propranolol
  • Nadolol"nonselective"
  • Pindolol - "nonselective";partial agonist (some intrinsic sympathomimetic activity); less bradycardia than other beta-blockers
  • Metoprolol - beta1 "selective"
  • Labetolol- ""beta / alpha";higher instance of side effects (orthostatic hypotension; sexual dysfunction);
  • useful in hypertension of pheochromocytomas
beta adrenergic antagonists36
Beta-adrenergic antagonists
  • Mechanism of action: beta-1 blockade a) in heart (they reduce cardiac contractility and CO). b) in kidney (they reduce renin release by sympathetic nerves). Drop in AII produces: - Na loss by kidney (leading to BV reduction) - vascular relaxation in some vascular beds. c) in the CNS (controversial)
beta adrenergic antagonists side effects 1
Beta-adrenergic antagonists: side-effects/1
  • Bronchoconstriction (minimized by using beta-1 selective drug; bad for asthmatics)
  • Increase in LDL/HDL ratio (bad for atherosclerosis)
  • Depression, loss of energy (CNS effect)
  • Increase AV node refractoriness (good for SVTs but could be bad if abnormal SA or AV nodes)
  • Decreased cardiac contractility (good for angina, good or bad for CHF)
beta adrenergic antagonists side effects 2
Beta-adrenergic antagonists: side-effects/2
  • Block prodromal signs of hypoglycemia in insulin-dependant diabetics.
  • Withdrawal: Rebound hypertension and cardiac ischemia
  • Cold extremities. May precipitate or worsen Raynaud’s disease (vasospasm of extremities due to beta-blockade of AV shunts). Labetatol (alpha + beta blocker) or blocker with ISA may be prefered in this case.
  • Adverse effect in patients with occlusive peripheral vascular disease (Production or aggravation of intermittent claudication. IC is due to low calf blood flow)
beta blockers clinical use in hypertension
Beta-blockers: clinical use in hypertension
  • Can be used alone for monotherapy .
  • combined with low dose thiazide
  • Should not be combined with verapamil or diltiazem to avoid excessive cardiac depression
  • Non-selective, beta-1 selective and blockers with ISA work equally well.
  • Can be combined with ACEI, dihydropyridines (cautiously), other vasodilators.
ace inhibitors mechanism of antihypertensive action
ACE inhibitors: mechanism of antihypertensive action
  • ACEIs  AII and  bradykinin (vasodilator).
  • In the context of hypertension ACEIs work: by  preload and  afterload via: a)  arteriolar dilation ( TPR).

b) Na reabsorption by kidney (hemodynamic effect on kidney and drop in aldosterone secretion). This reduces blood volume and preload c)  release of NE (which lowers TPR and CO) d)  cardiac contractility

aceis side effects drug interactions
ACEIs: side-effects/drug interactions
  • SAFE, effective and well-tolerated. Few side-effects but some potentially serious.
  • Common side-effects are due to bradykinin accumulation : cough, skin rashes, angioedema
  • Hyperkalemia (bad in presence of K-sparing diuretic, good in presence of thiazide)
  • First dose orthostatic hypotension (can be severe in hypovolemic patient e.g. using diuretics)
  • Risk of severe foetal pbs.
  • Acute Renal failure in patient with high grade renal artery stenosis.
use of aceis in hypertension
Use of ACEIs in hypertension
  • Excellent first line agent for monotherapy in absence of renal ischemia.
  • Can be combined with beta-blockers or thiazides diuretics (NOT with K-sparing diuretics) or alpha-1 blockers for enhanced effectiveness.
  • Notfor pregnant women.
  • Other major uses of ACEIs: diabetic nephropathy, CHF and post MI treatment.
aceis differences between agents
ACEIs differences between agents
  • Little difference except:
  • T1/2. a) short (2 hrs) e.g. captopril b) long (~ 10-12 hrs) e.g. enalapril, linosipril, fosinopril, several others.
  • Excretion: a) renal (most drugs). Doses should be reduced in patients with renal insufficiency. b) some liver metabolism (fosinopril)
angiotensin receptor antagonists
Angiotensin receptor antagonists
  • Prototype: Losartan.
  • Block AT1 not AT2 receptors, no effect on bradykinin.
  • Less efficacious than ACEIs (??)
  • Effect potentiated by thiazide.
  • Produces neither cough nor angiodema (bradykinin effects) but other side-effects are the same as those of ACEIs.
difference between aceis at1 blockers
Difference between ACEIs & AT1 blockers

AT1 R antagonists


AngII Bradykinin



AngII Bradykinin



Normal Reduced Increased

dhps mechanism of action
DHPs:mechanism of action

SNA  is


with long-

lasting DHPs

dihydropyridine ca channel blockers
Dihydropyridine Ca channel blockers
  • Mechanism of antihypertensive action: arteriolar vasodilation, TPR drop.
  • DHPs are slightly more potent antihypertensives than verapamil or diltiazem
  • Side-effects:
  • a) orthostatic hypotension
  • b) reflex tachycardia may lead to cardiac ischemia and/or arrhythmias
  • (minimized by using slow-onset and long-lasting preps)
  • c) headache, flushing, dizziness d) pedal oedema.
non selective ca channel blockers side effects
Non-selective Ca channel blockers: side-effects
  • Side-effects:
  • a) SA node inhibition: probably good as it prevents the baroreflex mediated tachycardia b) increase in AV node refractoriness. Good for SVTs but can produce AV block in patients with cardiac conduction problems.
  • c) decrease cardiac contractility
centrally acting drugs
Centrally Acting Drugs
  • Clonidine activates alpha2 and imidazoline receptors in the

vasomotor center of the medulla which inhibits the sympathetic

nervous system.

  • A reduced heart rate and cardiac output account for reduction

in blood pressure.

  • Considered a second-line drug or for special cases

(ie methyldopa in pregnant hypertensive patients).

alpha 2 adrenergic agonists
Alpha-2 adrenergic agonists
  • Clonidine, guanabenz, guanfacine, alpha-methyl dopa (the latter is a prodrug converted into alpha-methyl NE).
  • Mechanisms of action: sympatholytics; reduce CO & TPR a) Major site: CNS. Reduce activity of sympathetic nerves by action on vasomotor center b) peripheral site: reduce release of NE from sympathetic terminals
centrally acting drugs55
Centrally Acting Drugs
  • Antihypertensive effect results from action in the CNS causing

a reduced sympathetic nerve firing rate.

  • Prototype: clonidine
mechanism of action of clonidine
Mechanism of action of clonidine

Central effect


alpha 2 adrenergic agonists side effects
Alpha-2 adrenergic agonists: side-effects
  • Sedation
  • Depression
  • Dry mouth, constipation.
  • Rebound hypertension (clonidine but not alphamethyl-dopa)
  • Impairment of sexual function
  • Na retention (improved by use of diuretics)
alpha 2 adrenergic agonists therapeutic status
Alpha-2 adrenergic agonists: therapeutic status
  • Second-line drugs in hypertension, not used for monotherapy.
  • Use of slow-release patch (clonidine) improves side-effects)
  • Methyl-dopa is safe in pregnancy.
  • Note: alpha-2 adrenergic agonists are used to treat glaucoma, pain, spasticity and opiate withdrawal.
ganglionic blockers
Ganglionic blockers
  • Historical interest only. These drugs produce intolerable side-effects (orthostasis, Na retention, GI and sexual dysfunction)
  • trimethaphan was withdrawn in 1996
  • mecamylamine still available but never used.
  • Depletes NE from storage vesicles
  • Major action is in CNS. Reduces sympathetic outflow. Reasonably effective, especially with thiazide.
  • Side-effects: depression, sedation, GI hyperactivity.
  • Cheap, its only virtue.
  • Little used at present.
  • Peripheral sympatholytic drug.
  • Rides the NE transporter, dislodges NE from vesicles and prevents exocytosis.
  • Lots of side-effects: postural hypotension cerebral ischemia, GI hyperactivity, sexual dysfunction
  • Potentially very serious drug interactions (tricyclics, indirectly acting sympathomimetics e.g. cold medicines)
  • Use in hypertension restricted to severe cases. Must be combined with diuretic
  • Hydralazine & Minoxidil
  • Oral vasodilators used are used for long-term outpatient treatment of severe hypertension in the context of a polydrug therapy.
  • Work by reducing afterload (TPR).
  • Cause marked Na retention and rapidly increase BV (pseudotolerance) i.e. must be used in conjunction with diuretics.
  • Cause marked reflex tachycardia and increased contractility (beta -mediated) ergo must be used with beta-blockers.
  • Minoxidil causes hypertrichosis(growth of body hair).
alpha 1 adrenergic antagonists
Alpha-1 adrenergic antagonists
  • Mechanism of action:
  • a) antagonize effect of sympathetic tone in arteries and veins (reduce TPR and preload) b) reduce baroreflex via central action (thus produce very little reflex tachycardia).
  • Side-effects: few
  • a) first-dose hypotension (Pb with older patients)
  • b) retention of salt and water
alpha 1 adrenergic antagonists therapeutic use
Alpha-1 adrenergic antagonists: therapeutic use
  • Can be used for monotherapy of mild hypertension
  • May improve LDL/HDL ratio
  • Effects additive with thiazide diuretics and ACEI.
  • Should not be combined with vasodilators (e.g. dihydropyridines): tachycardia.
  • Good for patients with benign prostatic hyperplasia.
alpha 1 adrenergic antagonists difference between agents
Alpha-1 adrenergic antagonists: difference between agents
  • Prototype: prazosin
  • Newer agents (terazosin, doxazosin) have longer T1/2 .
  • Newer agents can be given once a day.
treatment of mild hypertension
Treatment of mild hypertension
  • Nonpharmacological (salt restriction , exercise, weight loss)
  • Pharmacological: alternatives for initial treatment include: a) monotherapy with thiazide, ACEI, beta-blocker or alpha-1 blocker or calcium-channel blocker. Drug is selected on the basis of efficacy,concurrent pathologies and individual sensitivity to side-effects. b) low thiazide/low beta-blocker combo c) thiazide/ K sparing combo.
principles of polydrug therapy
Principles of polydrug therapy
  • Monotherapy is sufficient in only 55% of cases.
  • In more severe cases 2 or 3 drugs have to be used.
  • Each drug must belong to a different class
  • The combination of 2 first-line drugs is tried first. One of the drugs is likely to be an ACEI.
  • Vasodilators if used must be given with a diuretic and a beta-blocker.
treatment of hypertensive emergencies
Treatment of hypertensive emergencies
  • Goal: produce a rapid but well controlled fall in BP.
  • Context: hypertensive encephalopathy, eclampsia, pheo, hypertension with pulmonary oedema, aneurism, subarachnoid hemorrhage etc..
  • Labetalol iv (alpha & beta blocker)
  • I.v nitroprusside
  • I.v. nitroglycerine
  • hydralazine iv or im (eclampsia)
  • iv phentolamine or phenoxybenzamine po (pheo)