hypertension - causes and treatments

7/31/2019 Hypertension - Causes and Treatments

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Hypertension: I and IIRJ Prince


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Cardiovascular disorders:a complex web

Lifestyle Genetics

Hypertension Hyperlipidaemia

Atherosclerosis

Heart AttackStroke

Angina

Heart failure

Dysrhythmias Thrombosis

Coronary artery disease


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Blood Pressure:Basic Definitions

120 over 80 = systolic over diastolic

Systolic - pressure while heart is contracting(maximum pressure)

Diastolic - pressure while heart is filling(minimum pressure)

Pulse pressure - difference between the two

Hypertension Increased diastolic pressure

Increased systolic pressure

Increased pulse pressure

Hypotension - decreased BP


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Quantifying hypertension

Diastolic B.P.

Severe >120 mm Hg

Moderate 105-120 mm Hg

Mild 90-105 mm Hg


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60% hypertensive patientsadequately controlled

10% at optimal blood pressure

estimated 70 millionuntreated hypertensive

patients in World

sTop 7 countries


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Classification of hypertension by aetiology1. Primary (essential or idiopathic) hypertension

Cause unknown2. Secondary hypertension

Identified cause e.g. :-

Polycystic renaldisease Renal arterystenosis *Phaeochromocytoma(CT scan)

From:A Colour Atlas of Hypertension 2nd edn.

By Shapiro L.M. & Buchalter M.

1989 WolfePublishing Ltd. With permission

* From:Colour Atlas & Text of Clinical MedicineBy Forbes CD & Jackson WF.

Mosby-Wolf 1993 Harcourt HealthScience. With permission


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Consequences of hypertensionHigh sustained arterial BP increases mortality from:

1. Coronary artery disease (myocardial infarction)2. Stroke

- cerebral haemorrhage- thrombosis and thromboembolism

From: A Colour Atlas of Hypertension 2nd

edn. By Shapiro L.M. & Buchalter M.1989Wolfe Publishing Ltd. With permission


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Care pathway

CBPM 160/100 mmHg &

ABPM/HBPM 150/95 mmHg

Stage 2 hypertension

Consider specialistreferral

Offer antihypertensive drugtreatment

Offer lifestyle interventions

If younger than 40 years

If target organ damage present or 10-year cardiovascular risk > 20%

Offer annual review of care to monitor blood pressure, provide support anddiscuss lifestyle, symptoms and medication

Offer patient education and interventions to support adherence to treatment

CBPM 140/90 mmHg &

ABPM/HBPM 135/85 mmHg

Stage 1 hypertension


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Blood pressure control by drugs

Blood pressure = cardiac output x peripheral resistance

Basic principle : interfere with control mechanisms

but.....do not compromise cardiovascular reflexes

1. Principles of treatment


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Antihypertensive PrescriptionsUSA : 2005

ACE inhibitors 149,479,476

73,733,419AII antagonistsCa2+ antagonists

Others

-blockers

88,965,585

150,138,101

(Diuretics, etc)65,043,697

1.

2.3.

5.


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Typical resistance arteriole

endothelium

myocyte

post-ganglionicsympatheticneurone

internalelastic

lamina

10 m


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norepinephrine

phospholipase C activation

Norepinephrineand vascular tone

1-adrenoceptor

[Ca2+]i

Ca-store

inositol trisphosphate (InsP3) release

Ca-sensitive Cl- channels open

Cl- efflux

membrane depolarisation


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Opening of L-type Ca channels

Depolarisation

Ca2+ influx

[Ca2+]i

Consequences of depolarisation

Contraction(Ca-calmodulin

Ca2+

release)


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Calcium antagonists : L-type channel

diltiazem(a benzothiazepine) nifedipine

(a dihydropyridine)

verapamil

(a phenylalkylamine)


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ASCOT Trial(Anglo-Scandanavian Cardiac Outcomes Trial)

Compared amlodipine (+ perindopril)withatenolol (+ bendroflumethiazide)

1. Blood pressure controlledResults

2. Reduced incidence of associated CV disease

3. Conclusion : Calcium-antagonist (+ACEinhibitor) should replace older treatments


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Calcium antagonists : summary

4. Heart : reduced contractility and A-V conduction

1. Reduce the opening of L-type calcium channels

2. Target organs : vasculature (and heart)

5. Side-effects : headache, constipation

3. Vessels : inhibit ligand-gated Ca2+ entry


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Diuretic Mechanisms In Hypertension

Diuresis: increased urine output

Intravascular salt and water depletionshort term effect

renal failureside effects of other therapy

Longer term effects due to arterial dilation? reduced Ca2+ entry due to decreased Na+

Also used to treat oedema

pulmonary oedema due to heart failure


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Osmotic Diuretics

Main example: MANNITOL

Filtered at glomerulus but not reabsorbed

Increases urine osmolality

Decreases water reabsorption

Only diuretic acting outside nephron lumen

Given IV (orally osmotic diarrhoea)

Uses: treatment of renal failure

reducing intracranial, intraoccular pressure(nb not a renal mechanism)


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Loop Diuretics (i)

Main examples: frusemide (furosemide), bumetanideAct by inhibiting Na+/K+/2Cl- cotransporter in

ascending loop

Na+

K+

Cl-

Na+

K+

Cl-

Na+K+

2Cl-

Lumen

X


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Consequence:water cannot be absorbed from the descending loop

NaCl

H2O

Descending LimbNo active transport

Water permeable

Ascending LimbActive transport Na+Passive transport Cl-

Water impermeable

Loop Diuretics (ii)


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Loop Diuretics (iii)

Clinical Uses: heart failure pulmonary oedema renal failure

(all involve salt and water overload)

hypertension with renal failureAlso get vascular effects (not well understood)

Most powerful diuretics (up to 10 litres urine/day!)(high ceiling diuretics)


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Thiazide Diuretics (i)

Main examples: Bendroflumethiazide,

Chlortalidone (thiazide related)

Act by inhibiting Na+/Cl- cotransport in distalconvoluted tubule

Na+

K+

Ca2+

Na+

K+

Ca2+

Na+

Cl-

Lumen X

Ca2+


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Thiazide Diuretics (ii)

NaCl

x

NaCl

Increased NaCl

passed to moredistal segments

Less differencein osmolalitybetween urine

and plasma

Lesser ability toreabsorb waterin more distal

portions

Decrease abilityto dilute urine


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Thiazide Diuretics (iii)

Clinical uses: Oedema due to heart failure Hypertension (lower doses) Initial effects due to diuresis Later, get vascular effect

Mild diuretics

Hypokalaemia (low potassium levels)


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Hypokalaemia (low potassium levels)

Major problem with loop diuretics, thiazides

Increased NaCl passed on to collecting duct increasestransport across PRINCIPAL cells

Increases lumenve potential leading to K+ loss

Increased volume of urine: increased flushing of K+

Na+

K+

Na+

K+

Lumen

Na+

K+

-30 mV


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Na+

K+

Na+

K+

LumenNa+

K+-30 mV

Potassium Sparing Diuretics

General mechanism: decrease trans-principal cellNa+ movement, decreaseve lumen potential

Main examples: Spironolactone, amiloride, triamterene


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Spironolactone

Aldosterone antagonist

Aldosterone increases sodium absorption byincreasing number of Na+/K+ ATPasesstimulating Na+ channels via protein mediator

Na+

K+

Na+

K+

LumenNa+

K+-30 mV

+

+


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Amiloride, Triamterene

Na+

K+

Na+

K+Lumen

Na+

K+-30 mV

Block sodium channels in lumenal membrane

x


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Potassium Sparing Diuretics

Weak diuretic action on their own

Usually used in combination with other diuretics

Spironolactone used in hyperaldosteronismcirrhosis (failure to metabolize ALD)

Conn s syndrome (adrenal tumor)


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Physiological Control of Blood Pressure

2) Slow compensatory control

Renin

Angiotensin

Aldosterone

Salt and water retention

Increased BP

Vasoconstriction


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Physiological Role of Aldosterone

Acts on specific receptors in collecting duct/tubuleAldosterone (mineralocorticoid) increases sodium absorption by

genomic effects - increasing number of Na+/K+ ATPases- increasing number of Na+ channels

non-genomic effects -stimulating Na+ channels via

protein mediator

Na+

K+

Na+

K+

LumenNa+

K+-30 mV

+

+

G ti f A i t i H


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Angiotensinogen(plasma globulin)

Angiotensin III (7mer)Active

Renin

Angiotensin I (10mer)Inactive

ACEAngiotensin II (8mer)Active

Aminopeptidase

Generation of Angiotensin Hormones

Binds to AT1RAldosterone

Secretion(adrenal cortex)Vasoconstriction

Angiotensin IV (6mer)

Active


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Physiological Control of Renin Secretion

Secreted by cells

ofjuxtaglomerularapparatus

Adrenaline ( -adrenoceptors)ProstacyclinsDecreased Na+ in distal tubuleDecreased in blood pressure in kidneyActions of other hormones

+


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Tissue Distributions of Renin and ACE

Renin discrete (juxtaglomerular appartus)global control secreted into circulation

ACE - found in many tissuesseveral subtypeslocal production of Angiotensins


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Renin

Angiotensin

Aldosterone

Salt and water retention

Increased BP

Spironolactone

Pharmacological Intervention in RAA System

Renin InhibitorsEg AliskirenOthersIn development

ACE Inhibitors

Angiotensin II Antagonists

Vasoconstriction

ACE Inhibitors


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ACE Inhibitors

Angiotensin I (10mer)

Inactive

ACE

Angiotensin II (8mer)

ActivePrototypical examples- captopril, enalapril, ramiprilUnwanted effects- initial dose hypotension,

cough

Captopril- first designer drug(Renin antagonists-) designed based on protease

structureaspartic proteaseimportance to HIV research


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Angiotensin II (8mer)

Active

Angiotensin II Antagonist

Angiotensin II Antagonists

Prototypical examples- losartan, valsartan, candesartanSide effects- hypotension but not cough

Angiotensin II Receptor Type 1


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Angiotensin Receptors

G-protein coupled receptors

Multiple subtypes

Angiotensin II type 1 Receptor (AT1 Receptor)

Angiotensin II type 2 Receptor (AT2 Receptor)

AT1 vascular effects/aldosterone release

AT2 growth and development?


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Antihypertensive drugs:

Antagonists at adrenoceptors

Pharmacology of Adrenergic Receptors(Adrenoceptors)

Fi ht Fli ht R


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Sympathetic Nerves

Noradrenaline

Adrenal Medulla

Adrenaline

Eye

Salivary Glands

Blood vessels

GI Tract

Bladder

Genitalia

Sweat glands

Lungs

Heart

Fight or Flight Response

Adrenergic Receptors


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Adrenergic Receptors

1 2 1 2 3X

Function of Adrenergic Receptors


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G qPhospholipase C

AdenylylCyclase

G sAdenylylCyclase

G i

Vasoconstriction(increase BP)

Relax GI tract

Vasodilation(decrease BP)

Bronchodilation Heart Rate& Force

TransmitterRelease

InsulinRelease

Relax Visceral

Smooth Muscle Bladder Sphincter Uterus Iris Radial Muscle

seminal tract pilomotor muscles

Contract VisceralSmooth Muscle

AdenylylCyclase

G s

1 12 2

Muscle Tremor

Release ofRenin

(Lypolysis)

(Glycogenolysis)

Function of Adrenergic Receptors

Lypolysis

Glycogenolysis

A i t


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Dobutamine SalbutamolPhenylephrine

Oxymetazoline

Clonidine-methylnoradrenaline

Methoxamine Isoprenaline

Noradrenaline (Norepinephrine)

Adrenaline (Epinephrine)

1 2 1 2

Agonists

A t i t


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PrazosinDoxazosin Yohimbine

AtenololMetoprolol Butoxamine

Phentolamine (competitive)Chlorpromazine

Phenoxybenzamine(insurmountable/non-competitive)

Propranolol

Labetalol

1 2 1 2

Antagonists

Uses of -adrenoceptor antagonists


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Treatment of Phaeochromocytoma

CT scan showingphaeochromocytoma

Phaeochromocytoma Tumour of adrenal medulla

Secretes adrenaline erratically

Episodes of severe hypertension

Phentolamine- used as treatment

Phenoxybenzamine- used during surgery

Uses of adrenoceptor antagonists

d i


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Phentolamine-non-selective -adrenoceptor antagonist-unsuitable for the treatment of hypertension

-adrenoceptor antagonists asAntihypertensive Agents

Prazosin

-1-selective adrenoceptor antagonist-useful for the treatment of hypertension

Simultaneous blockade of and adrenoceptors


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1

2

Simultaneous blockade of 1- and 2- adrenoceptorsby phentolamine

Phentolamine1Block 1 AR-evoked

contraction

Vasodilation

NA

BP

NA

Phentolamine

Autoinhibition of noradrenalinerelease prevented

Unacceptablereflex tachycardia


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1

2

Prazosin1Block 1 AR-evokedcontraction

Vasodilation

NA

BP

Acceptablereflex tachycardia

NA

Selective blockade of 1- adrenoceptors by prazosinPrazosin

No effect


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Prazosin

Dilates arterioles and veins by blocking

1 -adrenoceptors.

Used where other therapy has proved ineffective orunacceptable.

Unwanted effects:

postural hypotension (fades).urinary incontinenceretrograde ejaculation

relaxation of bladder neck


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Propranolol Competitive antagonist Non-selective -adrenoceptor antagonist Relatively lipid soluble (good penetration of CNS)

Atenolol Competitive antagonist Relatively selective 1- adrenoceptor antagonist Relatively water soluble (poor penetration of CNS)

Antagonists at -adrenoceptors



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Anti-hypertensive drugs

?



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Sympatheticnerves

cardiac output

Renal sympatheticnerves

renin release sympathetic tone

11

Efferentarteriole

Glomerulus

Juxtaglomerularapparatus Vasomotor centre inmedulla oblongata

Anti-hypertensive drugs

-adrenoceptor Antagonists : Unwanted Effects


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Bronchoconstriction- bronchial asthma

- bronchitis- emphysema

Precipitation of cardiac failure/ heart block- patients with heart disease- carvedilol

Hypoglycaemia- patients with diabetes- mask of sympathetic sweating, tachycardia and tremor

Vivid dreams- propranolol (practolol)- not a problem with atenolol

- Raynauds phenomenon and claudication

Cold extremities

-adrenoceptor Antagonists : Unwanted Effects

Aged over 55 years


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Step 4

Summary ofantihypertensive

drug treatment

ged o e 55 yea sor black person ofAfrican or Caribbeanfamily origin of anyage

Aged under55 years

C2A

A + C2

A + C + D

Resistant hypertension

A + C + D + consider furtherdiuretic3, 4 or alpha- or

beta-blocker5

Step 1

Step 2

Step 3

Key

A ACE inhibitor or low-cost angiotensin IIreceptor blocker (ARB)1C Calcium-channelblocker (CCB)D Thiazide-like diuretic

See slide notes for details of

hypertension - causes and treatments

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