Presenter : Dr Isvaran Subramaniam

Moderator : Dr Nizar

CONTENTIntroduction

ManagementNon-pharmacologicPharmacologic

Conclusion

IntroductionDiagnosis of Hypertension

the average of two or more DBP measurements on at least two subsequent visits is 90 mm Hg or more

or when the average of multiple SBP readings on two or more subsequent visits is consistently greater than 140 mm Hg

Classification of blood pressure levels

Optimal           = <120/<80 Normal            = <130 /<85 High normal    = 130-139/85-89

labelled "pre-hypertension" in USA

Hypertension Mild Hypertension         (Grade 1) = 140-159/90-99 Moderate hypertension  (Grade 2) = 160-179/100-109 Severe hypertension       (Grade 3) = 180/ 110

Classified into

Primary or Essential HPT : 95%

Secondary HPT : <5% Renal – Renal artery stenosis, glomerulonepritis Endocrine – Cushing’s, phaeochromocytoma Drugs/Chemical – OCP, steroids Others – coarctation of aorta, pre-eclampsia

Regulation of Normal BP

magnitude of the arterial pressure depends on two fundamental hemodynamic variables:

cardiac outputtotal peripheral resistance

Uncontrolled BPIHDCVARenal impairmentHypertension RetinopathyHypertension Crisis

Management of Hypertension

The goal of antihypertensive therapy is to reduce overall cardiovascular risk and thus cardiovascular morbidity and mortality

This may be achieved by maintaining SBP < 140 mmHg and DBP < 90 mmHg

Management includesNon Pharmacologic Interventions

Lifestyle ModificationsPharmacologic Therapy

Lifestyle Modificationsreduced dietary sodium and

increased calcium and potassium from food sources

weight loss for overweight patients

regular physical activitymoderation of alcohol

consumption smoking cessation

ANTI HYPERTENSIVES 6 classes of drugs;

SympatholyticsVasodilatorsAngiotensin Converting Enzyme Inhibitors

Angiotensin-II Receptor BlockersCalcium Channel BlockerDiuretics

Sympatholytics

Sympatholytics

1. Adrenergic-receptor blockersAlpha – PrazosinBeta – Atenolol, Propanolol, EsmololAlpha-Beta – Labetalol

2.Central Alpha-2 agonistClonidine, Methldopa

3. Postganglionic BlockersReserpine, Guanethidine

Adrenergic-receptor blockers

ORGANORGAN ACTIONACTION RECEPTORRECEPTORHeartHeart

Heart rateHeart rate

AV nodal AV nodal conductionconduction

ContractilityContractility

Vascular Smooth Vascular Smooth MuscleMuscle

Skin; SplanchnicSkin; Splanchnic

Skeletal muscle Skeletal muscle

Skeletal muscleSkeletal muscle

Bronchial TreeBronchial Tree

Gastrointestinal Gastrointestinal tracttract

Smooth muscle, Smooth muscle, wallwall

Smooth mucle Smooth mucle

sphinctersphincter

Saliva secretionSaliva secretion

Gastric acid Gastric acid secretionsecretion

Pancreatic Pancreatic secretionsecretion

IncreaseIncrease

IncreaseIncrease

IncreaseIncrease

VasoconstrictionVasoconstriction

VasodilationVasodilation

VasoconstrictionVasoconstriction

BronchodilationBronchodilation

RelaxesRelaxes

ContractsContracts

IncreaseIncrease

11

11

11

1 1

2 2

1 1

22

1 1 22

11

11

What are alpha blockers? Alpha blockers work by dilating blood

vessels.Therefore reduces afterload.Alpha blockers include:

Doxazosin (brand name Cardura) Prazosin (Minipress) Terazosin (Hytrin)

What are beta blockers? Beta blockers lower high blood pressure by

slowing down the heart rate and decreasing the force of contraction of the heart.

Increase coronary blood flow due to increase diastolic filling time

Some common beta blockers include: Atenolol (Tenormin) Betaxolol (Kerlone) Metoprolol (Lopressor) Propranolol (Inderal) Timolol (Blocadren)

What are alpha-beta blockers? Alpha-beta blockers relax blood vessels and

slow down the heart.

Alpha-beta blockers include labetalol (brand name Normodyne)

Alpha Blockers

PRAZOSIN( Alpha 1 -blocker )

quinazoline derivative Highly selective alpha-1-blockerproduces peripheral vasodilation; vascular tone in

both resistance (arterioles) and capacitance (veins) vessels is reduced

resulting in decreased Vascular Resistance, CO and BP

not associated with reflex tachycardia

Pharmacokinetics Prazosin

administered orally 60% bioavailability protein binding 90%nearly completely metabolized by the liverEliminated in bile and faeceselimination half-time is about 3 hours

(prolonged by cardiac failure)

Side Effects Prazosin

‘first dose phenomenon’ ; dizziness, faintness, syncope soon after the administration of the first dose

vertigofluid retentionorthostatic hypotensiondryness of the mouth, nasal congestion,

nightmares, urinary frequency, lethargy, and sexual dysfunction

Phentolaminecompetitive antagonism3-5 times more active at alpha-1 compared to

alpha-2, with some Beta adrenergic agonist and anti-serotoninergic activity

Causes marked reduction in BP with reflex tachycardia

Positive inotropic action probably due to indirect action via noradrenaline release due to alpha-2-blockade

Side effects : palpitation, vomitting

PhenoxybenzamineIrreversible alpha-adrenergic blocker

Non-competitiveChemically related to nitrogen mustardsUsed mainly for control of Hypertension due

to phaeochromocytomaMore alpha-1 effect than alpha-2Onset : 1 hour, duration : several days

Side effects :

Postural hypotensionTacycardiaRetrograde ejaculationNasal congestionmiosis

Beta Blockers

• Some beta-blockers, when they bind to the beta-adrenoceptor, partially activate the receptor while preventing norepinephrine from binding to the receptor.

• These partial agonists therefore provide some "background" of sympathetic activity while preventing normal and enhanced sympathetic activity.

• These particular beta-blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA).

• Some beta-blockers also possess what is referred to as membrane stabilizing activity (MSA).  This effect is similar to the membrane stabilizing activity of sodium channel blockers that represent Class I antiarrhythmics. • Usually at high concentration• Reduce phase 0 and phase 4 slope

The first generation of beta-blockers were non-selective, meaning that they blocked both beta1 (b1) and beta2 (b2) adrenoceptors.

Second generation beta-blockers are more cardioselective in that they are relatively selective for b1 adrenoceptors.

Note that this relative selectivity can be lost at higher drug doses

CLASSIFICATION

Clinical Effectnegative inotropic and chronotropic effectsconduction speed (AVN) is sloweddecreased the rate of spontaneous phase 4

depolarization antidysrhythmic effect

Side Effects increased airway resistanceunmask the signs of hypoglycaemiaprecipitate cardiac failurePeripheral Vascular Disease and

Raynaud’s phenomenonhyperkalaemiamemory loss and mental depressionwithdrawal hypersensitivity

PROPANOLOLnon-selective blocker

equal antagonism at beta-1 and beta-2lacks of ISA; pure antagonist the first beta-antagonist introduced

Pharmacokinetics Propanololrapidly and almost completely GIT

absorptionextensive hepatic first-pass metabolism

(70%); poor bioavailabilityextensively bound to plasma proteins (90%

to 95%) clearance is by hepatic metabolism to

active metabolite, 4-hydroxypropranolol (equivalent in activity to propanolol)

Used in :

HypertensionPortal HypertensionAnginaMigraineArrhytmiasAnxietythyrotoxicosis

ESMOLOLselective beta-1 blocker; lacks of ISA

Pure antagonistrapid-onset and short-acting preventing or treating haemodynamic

instability intraoperatively in response to noxious stimulation, e.g. during intubation

Pharmacokinetics Esmolol

Intra-venousrapid metabolism in blood by hydrolysis of the

methyl ester in RBCinactive acid metaboliteselimination half-time 10 minutes in urinepoor lipid solubility; limits transfer into the

CNS or across the placenta

Alpha-Beta Blocker

LABETOLOLselective alpha-1 antagonist nonselective beta-1 and beta-2 antagonist Beta : Alpha

Oral = 3 : 1IV = 7 : 1

Some intrinsic sympatomimetic activityuseful in management of PIH

Pharmacokinetics Labetolol

extensive first pass metabolism30-40% bioavailabilitymetabolism is by conjugation to glucuronic

acid< than 5% excreted unchanged in the

urineelimination half-time is 5 to 8 hours

(prolonged in liver disease and unchanged in renal dysfunction)

Side Effects Labetolol

Orthostatic hypotension (most common) Beta-antagonists effects

BronchospasmCongestive heart failureHeart blockFatigueMental depression

Fluid retention

Central Alpha-2 agonist

CLONIDINE centrally acting alpha-2 agoniststimulates alpha-2 inhibitory neurons in

the medullary vasomotor centerresulting in reduction of SNS outflow from

the CNS to peripheral tissuesmanifested as decreases in BP, HR and COLicensed in the US as a extradural route

for pain therapyUsed as a migraine prophylaxis

Pharmacokinetics Clonidine well absorbed after oral administration60% of the drug excreted unchanged in

the urineduration of action; 8 hours

Side Effects Clonidine dry mouthsedationwithdrawal syndrome; hyperadrenergic

states resembling phaechromocytomaretention of Na+ and waterskin rashesconstipation

METHYLDOPA

inhibits SNS from the vasomotor center to the periphery

resulting in decrease SVR and BP

Pharmacokinetics Methyldopa

oralincomplete absorption (25-50%)low protein binding 15%maximal effect within 4 to 6 hours after an

oral dose and persists for as long as 24 hrs

Side Effects Methyldopa

Sedation / confusionHepatic dysfunction, necrosis; maybe fatal

Rebound hypertension Retention of Na + and water Sexual dysfunctionBradycardiaSLE like symptoms

Postganglionic Blockers

RESERPINEinterferes with the cathecholamines

uptake into the storage vesiclesdepletes stores of catecholamines which

causes decreased CO and bradycardia, leading to hypotension

Crosses the blood brain barrierDuration of action : 1-2 weeksRarely used now

Side Effects Reserpine

Orthostatic hypotension (prominent)

Sedation and drowsinessMental depression Signs of PNS predominance include:

Bradycardianasal stuffinessXerostomiaincreased gastric H+ secretionexaggerated gastrointestinal motility

(abdominal cramps and diarrhea)

2. Vasodilators

HydralazineNitroprusside

HYDRALAZINEdecreases BP by a direct relaxant effect on

vascular smooth muscle (on arterioles greater than veins)

pronounced on the coronary, cerebral, renal, and splanchnic circulations

interference with Ca2+ transport in vascular smooth muscle

Clinical Uses Hydralazine

treatment of a hypertensive crisis; 2.5 to 10 mg IV effect begins within 15 mins and lasts 3 to 4

hours

Pharmacokinetics Hydralazine

extensive hepatic first-pass metabolism metabolized partially by acetylation;

slow and rapid acetylatorselimination half-time; 3 hours< than 15% of the drug excreted

unchanged in the urine

Side Effects HydralazineNa + and water retention vertigo, diaphoresis, nausea, and

tachycardiamyocardial stimulation can evoke

angina pectorislupus erythematosus-like syndrome (10% to 20%)

drug fever, urticaria, polyneuritis, anemia, and pancytopenia, peripheral neuropathies

Nitroprussidecauses relaxation of arterial and venous

vascular smooth muscle onset is almost immediate, and its duration is

transient, continuous intravenous infusion to maintain a therapeutic effect

extreme potency; necessitates careful titration of dosage and frequent monitoring of blood pressure

Used in cardia failure, hypotensive anaesthesia

Unstable solutionProtect from lightUse within 24 hours

Mechanism of Actionproduce NO, after contact with thiol

groups in the vascular smooth results in increased concentration of cGMP

leading to vasodilatation in arteries and veins

may decrease Ca2+ entry into muscle cells

Reduce SVR while maintaining cardiac output and tissue perfussion

Metabolized in the liver and kidney, producing thiocyanate

thiocyanate is cleared slowly by the kidney, with an elimination half-time of 4 to 7 daysaccumulates with prolonged therapy or in renal

failureclinical toxicity is rare

100x less toxic than cyanideskeletal muscle weakness, nausea, and

mental confusion

Cyanide Toxicitydose-dependentshould be suspected

in any patient who is resistant to the hypotensive effects of the drug despite adequate infusion rates

in a previously responsive patient who becomes

unresponsive to the BP-lowering effects of the drug despite increasing doses (tachyphylaxis)

mixed venous PO2 is elevateddevelopment of metabolic acidosisdecreased cerebral oxygen useCNS dysfunction in awake patients

Treatment of Cyanide Toxicity immediate discontinuation 100% oxygenNaHCO3sodium thiosulfate, 150 mg/ kg IV over 15 minutes, is a

recommended therapy acts as a sulfur donor to convert cyanide to thiocyanate

severe case; slow administration of sodium nitrate, 5 mg/ kg IV convert Hb to metHb metHb acts as an antidote; converting cyanide to

cyanmethemoglobinhydroxycobalamin (vit B12)

reacts with cyanide to form cyanocobalamin

Glyceryl TrinitrateUsed for MI, cardiac failureAlso acts via NO ( mainly venous )Used also as a tocolytic drugS/E :

HeadacheFlushingTachycardiatachyphylaxis

3. Calcium Channel Blocker

Calcium channel blockers prevent calcium from flowing into heart muscle cells and muscle cells of the blood vessel walls, resulting in slowing of heart rate and relaxation of blood vessels.

Acts more at the L-type calcium channels

Common calcium channel blockers include: Amlodipine (brand name Norvasc) Diltiazem (Cardizem) Felodipine (Plendil) Nicardipine (Cardene) Nifedipine (Procardia) Verapamil (Calan, Covera-HS, Verelan)

CCBAPotent negative inotropic and chronotropic

effectsVerapamil

Acts mainly on the myocardium and conducting system

To treat supraventricular arrhytmias, angina and hypertension

Severe myocardial depression may occur, especially with combination with Beta blockers

CCBAPeripheral effect, with minimal direct

myocardial activityMay cause reflex tachycardiaNifedipine

Acts mainly on coronary and systemic vascular muscle, with little myocardial depression

Used in angina and hypertensionSystemic vasodilatation may cause flushing

and headache Nimodipine

Used to relieve cerebral vasospasm following subarachnoid haemorrhage

Angiotensin Converting Enzyme Inhibitors

ACE InhibitorsACE converts inactive AT I to active AT IIAT II then acts to raise BP through;

Its potent vasoconstrictor effectBy stimulating secretion of aldosterone by the

adrenal cortex; which acting through kidney, causes Na+ retention and expands IV volume

ACE is also responsible for the metabolism of bradykinin, which is a potent vasodilator

CAPTOPRILcompetitive inhibitor of ACE; therefore

prevents the generation of AT IIinhibits AT II mediated vasoconstriction

and aldosterone secretionalso inhibits breakdown of bradykinin;

further contribute to its hypotensive effect

Pharmacokinetics Captopril

well absorbed after oral administration (60-70%)

onset; 15 minuteshalf-life; 1.7 hrs plasma protein binding is low (20-30%) excreted both through metabolism and by

urinary excretion of unchanged drug

Side Effects Captoprilskin rash sometimes acc. by fever and joint

discomfort (10%) and pruritisloss of taste sensation (1% to 2%) proteinuria and elevations in [creatinine]neutropenia (0.3%)abrupt fall in BP after initial dose; especially in

patients who are volume depleted cough and exacerbation of dyspnea and

wheezing in COAD (kinin effects)increase serum K + levels, especially in

patients with impaired renal function

Angiotensin II Receptor Antagonists

LOSARTANAT II receptor blocker (type AT1); hence

blocks the vasoconstrictor and aldosterone-secretion effects of AT II

25-50 mg once dailyextensive 1st pass metabolismactive metabolites is 10-40x more potentcan cause fetal morbidity and mortality

Diuretics

Diuretics counteract high blood pressure by signaling the kidneys to filter excess salts and water from the blood in the form of urine.   

 Increased urination decreases the amount of

blood in circulation, which, in turn, lowers blood pressure.

The removal of excess salt helps to flush sodium from the walls of the blood vessels, allowing the blood vessels to dilate.

DIURETICS

Now less commonly used

Can be classified intoThiazidesLoop diuretics

FrusemidePotassium-sparing diuretics

Amiloride, SpironolactoneCarbonic Anhydrase Inhibitors

Loop diuretics

inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb.

This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct.

This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss).

Thiazide diuretics

the most commonly used diureticinhibit the sodium-chloride transporter in the

distal tubule. Because this transporter normally only

reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis.

Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this  increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine.

hydrogen ion loss can lead to metabolic alkalosis.

Potassium-sparing diuretics.

Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport.

Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) at the distal segment of the distal tubule.

This causes more sodium (and water) to pass into the collecting duct and be excreted in the urine.

They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics.

The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine.

Carbonic anhydrase inhibitors

inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine.

These are the weakest of the diuretics and seldom used in cardiovascular disease.

Their main use is in the treatment of glaucoma.

Conclusionvarious types of antihypertensive availableinitial choice of antihypertensive needs to

be individualized for each patientconvenience and cost involved will

determine patient’s compliance and thus its effectiveness in preventing CVS morbidity and mortality

CLASS OF CLASS OF DRUGDRUG

COMPELLING COMPELLING INDICATIONSINDICATIONS

POSSIBLE IxPOSSIBLE Ix COMPELLINCOMPELLING C/IxG C/Ix

POSSIBLE POSSIBLE C/IxC/Ix

DiureticsDiuretics Heart failureHeart failureElderly patientsElderly patientsSystolic HPTSystolic HPT

DiabetesDiabetes GoutGout DyslipidemiaDyslipidemiaSexually active menSexually active men

Beta Beta blockersblockers

AnginaAnginaAfter myocardial infarctionAfter myocardial infarctionTachyarrhythmiasTachyarrhythmias

Heart failureHeart failurePregnancyPregnancyDiabetesDiabetes

Asthma and COPDAsthma and COPDHeart block*Heart block*

DyslipidemiaDyslipidemiaAthletes and Athletes and physically active ptsphysically active pts

PVDPVD

ACE ACE inhibitorsinhibitors

Heart failureHeart failureLV dysfunctionLV dysfunctionAfter MIAfter MIDiabetic nephropathyDiabetic nephropathy

PregnancyPregnancyHyperkalemiaHyperkalemiaBilateral RA stenosisBilateral RA stenosis

Calcium Calcium antagonistantagonistss

AnginaAnginaElderly patientsElderly patientsSystolic HPTSystolic HPT

PVDPVD Heart blockHeart block CHFCHF

Alpha Alpha blockersblockers

Prostatic hypertrophyProstatic hypertrophy Glucose intoleranceGlucose intoleranceDyslipidemiaDyslipidemia

Orthostatic Orthostatic hypotensionhypotension

AngiotensiAngiotensin II n II antagonistantagonistss

ACE inhibitor coughACE inhibitor cough Heart failureHeart failure PregnancyPregnancyBilateral RA stenosis Bilateral RA stenosis HyperkalemiaHyperkalemia