anti hypertensive module

8/2/2019 Anti Hypertensive Module

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Antihypertensive Drugs

Dr/Azza Baraka

Prof of Clinical Pharmacology

Faculty of Medicine

Alexandria University


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Definition

Elevation of ABP > 140/90 mm Hg. Can be caused by:

primary or essential hypertension

The pathophysiology might be:

vascular resistance cardiac output

arterial compliance.Primary Hypertension cannot be cured, but it can be controlled

Secondary hypertension, e.g. pheochromocytoma,

cured by treating cause


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Classification of blood pressure levels

Category Systolic (mmHg) Diastolic (mmHg)

Normal 100

Isolated systolic hypertension appears to resultfrom an increased stroke volume and/oraortic stiffness( arterial compliance).


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Treatment Goals

Short-term goal of antihypertensive therapy:

Reduce blood pressure

Long-term goal of antihypertensive therapy:

Reduce mortality due to hypertension-induced

end organ damage:

Encephalopathy

LVH -Congestive heart failure

Nephropathy


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ABP=COPX PVR=SV X HR X PVR

Modulators of COP SV( blood volume, venous return, Contractility).

Heart Rate . Modulators of PVR

- Diameter of peripheral arterioles

To BP:

1. LV systolic performance:negative inotropes andchronotropes

2. blood volume3. venous tone and thus

venous return.4. PVR


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Blood pressure treatment goals

Systolic BP be reduced to less than 140 mmHgand diastolic BP to less than 90 mmHg in the

general population of patients.

Lower systolic BP goal (


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Management of hypertension

Non pharmacological therapy1. Sodium Restriction2. DASH high fruit , vegetable, whole grains &

low fat dairy foods

Pharmacological therapy

ABCDEs

ACE inhibitors and AT-II antagonists

-adrenoceptor blockers Ca2+ channelblockers

Diuretics Extras: Vasodilators, centrally acting symptholytics,..


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Considerations for choice of initial

antihypertensive monotherapy

Target end organ damage

Coexisting : cardiovascular disease,

renal disease or diabetes.

Renin status (Age & Race)

Presence or absence of side effects

to the selected drug.


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Ideal antihypertensive drug

(1) decrease BP

(2) couple the antihypertensive effectiveness withno harmful side effects

(3) provide greater protection against the organdamage associated with hypertension.

(4) provide inhibition of the counter-regulatorymechanisms (SNS & Na retention). i.e. doesnot cause reflex tachycardia nor fluid retention


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First line antihypertensive drugs (A B C D )

Hypertension (HTN) can be classified as:

High renin hypertension (younger55 or black)Therefore HTN treated initially with one of two

categories of AHDs:

1-those that inhibit RAS, namely ACE inhibitors(A) and beta-blockers (B)

2- those that do not, namely calcium channel

blockers (C) and diuretics (D)


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Diuretics

Indications

Drug of choice for uncomplicated mild-

moderate HTN in black & elderly patients(low renin)

Drug of choice for isolated systolichypertension

Synergistic with other AHDs in severeHTN


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AT start of their use, they lower BP bycausing diuresis leading to a fall in plasmavolume & COP .

After chronic use they cause a reduction in

BP by VD PVR, likely related to shift ofsodium from vascular smooth muscle wall toECF.

In low doses, their side effects seem to beminimized.

Low dose Thiazide diuretics


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Advantages

Well tolerated with few side effects.

Have synergistic effect when added toother AHDs .

Relatively inexpensive.

Disadvantages Metabolic adverse effects

(hypokalemia,hypercalcemia etc); are

dose- related.Lose their effectiveness in renal insufficiency.


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Loop diuretics

Loop diuretics are used for hypertension associated

with renal insufficiency.


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-Adrenoceptor blockers Drugs of 1st choice for uncomplicated HTN in high

renin patients (


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-Adrenoceptor blockers Mechanism of blood pressure reduction

Reduction of HR and myocardial contractility Inhibition of renin release

Inhibition of CNS sympathetic outflow


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Types of-blockers

Non cardioselective

Cardioselective

Beta blockers with vasodilatory properties(Labetalol & Carvedilol).

All -blockers are EQUALLY effective in

reducing blood pressure but differ in sideeffects.


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Diuretics & beta blockers are notpreferred to be used as AHDs in

hypertensive diabetic patients.


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Drugs Interacting With the RAS

ACE inhibitors

ATII antagonists


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Physiology of Renin-

Angiotensin System


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Physiological Effects of AII:

1.

VC of arteries & veins2. + aldosterone secretion

3. + renal sodium resorption & RBF, glomerular capillary pressure

4. + LVH

5. Facilitate adrenergic transmission


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Mechanism of action of ACEIs

Inhibition of ACE

Angiotensin II

BradykininVD

AngiotensinII

Angiotensin I

BradykininInactive

product

CE


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echanism ofBP by ACEIs1. aldosterone release salt & water

retention

2. VD of both arterioles & veins

3. Decrease adrenergic activity


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Therapeutic Uses in Hypertension

Drug of choice in high renin hypertension (whiteor


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Advantages of ACE inhibitors &

ARBs as AHDs1. A & V dilation with no reflex

tachycardia & no fluid retention

2. Most effective AHD in LVH(remodeling).

3. Intraglomerular pressure so effective in

diabetic nephropathy.


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Types of ACE Inhibitors

Active molecules: Captopril,Lisinopril, Enalaprilat

Prodrugs: The remainder of ACEinhibitors, e.g. enalapril, lisinopril,..

All metabolized by liver except lisinoprilby kidney.

Ad ff t f ACEI


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Adverse effects of ACEIs

1. Hypotension esp in volume depleted individuals

2. Cough : dt accumulation of BK in the lung

It is a dry cough. Occur in 30% of patients

3. Angioedema: dt BK

4. Teratogenicity

5. Hyperkalemia due to aldosterone


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Contra-indication for ACEIs1. Pregnancy2. Bilateral renal artery stenosis

3. Low blood pressure: SBP< 90mmHg

4. Hyperkalemia


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Angiotensin II R antagonists

Block angiotensin II receptors subtype 1

Differences vs ACEIs:

ARBs do not affect BK system: No cough and No

angioedema


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Ca2+ Channel Blockers

Indications in hypertension:

Drug of choice in isolated systolic hypertension in

elderly if diuretic is contraindicated . low renin hypertension when diuretics are

contraindicated.

Hypertension with diabetes in presence ofcontraindication to ACEIs & ARBs


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CCBs Mechanism of antihypertensive

actionBlock calcium channels in the arterial smooth

muscles VDPVR

Block calcium channels in the cardiacmusclesHR &force of contraction

Types;

Dihydropyridines, e.g. nifedipine, amlodipine

Non dihydropyridines, e.g. verapamil & diltiazem


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DihydropyridinesNifedipine

Non dihydropyridinesDiltiazem Verapamil

>> selective action on vascular CC >> selective action on cardiac CC

Arterial vasodilation++++

minimal net effect on cardiac contractility

Reflex tachycardia

Arterial vasodilation ++

-ve inotropic

Heart rate

Therefore VD with no reflex tachycardia

Uses :Essential hypertension

Angina pectoris

Uses :Essential hypertension

Angina pectoris

Supraventricular arrhythmia

Side effects:

1.Hypotension

2.Reflex tachycardia

3.Flushing

4.Ankle oedema

Side effects:

1.Hypotension

2.Bradycardia

Contra-indication: tachyarrhythmia

Can be safely combined with BB

Contra-indication: HF & heart block, severe

bradycardia

Combination with BB is not safe


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Vasodilators

1-Arteriolar: Hydralazine

Never used as first choice in HTN; Try in severe hypertension

as part of a multidrug regimen or in pregnancy.

Adverse effects:

1. Reflex tachycardia

2. Salt & water retention

Should be combined with diuretic & beta blocker


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2- Vasodilators to A&V: Sodium nitroprusside

Acts by releasing NO that increase cGMPthat dilate A & V.

Clinical use:

Emergency treatment of severe hypertension

Given by IV infusion( it has a very short t )

Adverse effects

Hypotension,Reflex tachycardia

Prolonged infusion ( more than 72 hrs)Cyanide & Thiocyanate accumulation


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Centrally acting AHDs

Alpha methyl dopa: Preferredantihypertensive drug for

hypertension in pregnancy


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Preferred antihypertensive drugs forhypertension in pregnancy

Agent Com

Methyldopa Preferred on the basis of long-term follow-up

studies supporting safety

labetalol Increasingly preferred to

methyldopa because ofreduced side effects

CCB(nifedipine ) intermediate-releasetablets and slow-release

tablets could be used


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AHDs that do not cause reflex tachycardia:1-Beta blockers2-CCB(Non dihydropyridines)3-ACE inhibitors & ARBs AHDs that do not cause fluid retention:1. Diuretics

2. CCB(Non dihydropyridines)3. ACE inhibitors & ARBs


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AHDs used or CI in certain disease: Diabetes Beta-blockers and diuretics are CI.

ACE inhibitors & ARBs are of choice.

IHD Beta-blockers are used & offer a mortalitybenefit

LVH: ACE inhibitors & ARBs are used. Beta-blockers are used if ACE inhibitors & ARBs are CI.

Bronchial Asthma Beta-blockers CI. Renal Artery Stenosis (bilateral vs. unilateral)

ACE inhibitor orARBs are contraindicated.

Pregnancy ACE inhibitors and ARBs arecontraindicated, use methyl dopa.


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Hypertensive emergency vs hypertensive urgencyEmergency Urgency

Severe elevation in blood pressure (>

180/120 mm Hg)

Severe elevation in blood

pressure (> 180/120 mm Hg)

End organ damage without end organ damage

Treatment:

Parenteral Drugs Patients should always be managed in

an ICU to allow continuous monitoringof BP

Reducing mean B P by 10% during 1sthr and 15% within next 2-3hrs

E.g. Sodium nitroprusside ( IV infusion),

Treatment:

Oral antihypertensive.

Drugs Can be given in aclosely monitored outpatient

setting.

BP should not be lowered

more than 25% within the 1st

24hrs

Sublingual captopril,


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What could happen to this patient if he does notreceive treatment?

Case Study

Multiple PossibilitiesHeart: hypertrophy; myocardial infarction; heart failure

Brain: strokeKidney: renal failure; chronic kidney diseaseVasculature: peripheral vascular disease

Eye: retinopathy


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What is the most appropriate treatment forthis patient?

Case Study

-Assess BP for a third time in one month

-If elevated, suggest lifestyle change (exercise,diet etc)

-If unsuccessful, use diuretics (cheap& effective)


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If the patient develops diabetes would

you continue with diuretics?

-Use ACE inhibitors which are

renoprotective

drugs for hypertension in


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drugs for hypertension inpregnancy

Agent Com

IV labetalol Best avoided in women with asthmaor heart failure. Neonatology

should be informed, as parenterallabetalol may cause neonatal

bradycardia

IV hydralazine May increase the risk of maternal

hypotension

Oral nifedipine intermediate-releasetablets could be used

Agents used for Severe Hypertension(BP of >160/110 mmHg g)


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Drugs that cause Vasodilation and decreaseheart rate:

1-Central alpha 2 agonists,e.g. clonidine

2-Calcium channel blockers(non-dihydropyridines)

3-Combined alpha and beta blockers, e.g.

labetalol, carvedilol. Drugs that cause Vasodilation and that do

not affect heart rate: ACE inhibitors & ARBs


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Particular classes of antihypertensivetherapy have beneficial actions beyond

blood pressure and studies haveevaluated differences in cardiovascularprotection among classes. The LIFEand HOPE studies showed between-

class differences that may be due toeffects other than blood pressure-lowering .


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Drug therapy causes peripheral edema by two opposingmechanisms. First, as with nonspecific vasodilators such ashydralazine and minoxidil, sodium retention can be of sufficientmagnitude to cause edema. The sodium retention caused by thesedrugs is highly dose-dependent and when present almost always

requires diuretic therapy because it seldom remits spontaneouslyunless the dose of the nonspecific vasodilator is reduced [.4] Otherantihypertensives such as blockers, central agonists, andperipheral blockers can also be associated with the development ofsome peripheral edema, particularly when given in high doses [.5]Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are rarely associated with peripheraledema. If peripheral edema develops from the use of a calciumchannel blocker (CCB), it is not on the basis of salt and waterretention because this drug class is intrinsically natriuretic [.6]


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Another strategy useful for the resolution ofCCB-related edema is providing a

venodilator drug as a means to reducing thevenous hypertension that characterizes thisphenomenon[.13,37-39]Several drug

classes have relevant venodilating potential

and, in addition, can further reduce bloodpressure. This includes ACE inhibitors, ARBs,

and nitrates[.40]


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Four generations of dihydropyridines are now available. The first-generation(nicardipine) agents have proven efficacy against hypertension. However,because of their short duration and rapid onset of vasodilator action, thesedrugs were more likely to be associated with adverse effects. Thepharmaceutical industry responded to this problem by designing slow-releasepreparations of the short-acting drugs. These new preparations (second

generation) allowed better control of the therapeutic effect and a reduction insome adverse effects. Pharmacodynamic innovation with regard to thedihydropyridines began with the third-generation agents (amlodipine,nitrendipine). These drugs exhibit more stable pharmacokinetics, are lesscardioselective and, consequently, well tolerated in patients with heart failure.Highly lipophilic dihydropyridines are now available (lercanidipine, lacidipine).These fourth-generation agents provide a real degree of therapeutic comfortin terms of stable activity, a reduction in adverse effects and a broad

therapeutic spectrum, especially in myocardial ischaemia and potentially incongestive heart failure.


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Why we treatarrhythmia????????

Arrhythmias may require treatment becauserhythms that are too rapid, too slow, or

asynchronous can reduce cardiac output. Some

arrhythmias can precipitate more serious or evenlethal rhythm disturbanceseg, early prematureventricular depolarizations can precipitate

ventricular fibrillation. In such patients,antiarrhythmic drugs may be lifesaving. On the

other hand, the hazards of antiarrhythmic drugsand in particular the fact that they can precipitatelethal arrhythmias in some patientshas led to a

reevaluation of their relative risks and benefits. Ingeneral, treatment of asymptomatic or minimally

symptomatic arrhythmias should be avoided for this


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the P wave is generated by atrial depolarization, theQRS by ventricular muscle depolarization, and the T

wave by ventricular repolarization. Thus, the PR

interval is a measure of conduction time fromatrium to ventricle, and the QRS duration indicatesthe time required for all of the ventricular cells to

be activated (ie, the intraventricular conductiontime). The QT interval reflects the duration of the

ventricular action potential.Arrhythmias consist of cardiac depolarizations that

that deviate from the above description in one ormore aspects ie, there is an abnormality in the siteof origin of the impulse, its rate or regularity, or its

conduction


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Reduce LV systolic performance : negative inotropesbetablocker and calcium channel blockers (verapamil,diltiazem)).

Reduce blood volume : diuretics Reduce venous tone and thus venous return: Central

sympatholytics such as clonidine act to reduce overallsympathetic tone.

Reduce arterial tone (i.e. resistance) : Effective arterialdilators include angiotensin converting enzyme inhibitors ,

angiotensin receptor blockers , calcium channel blockers(nifedipine, amlodipine), potassium channel openers(minoxidil), nitric oxide donors (nitroprusside), alpha1blockers (prazosin, terazosin, doxazosin), and mixed alphaand beta-blockers (labetalol)


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Hypertension damages blood vessel walls. The prolongedvasoconstriction and high pressure within the vessels causesarterial smooth muscle to thicken to withstand the stress.Eventually, the tunica intima and tunica media thicken and

narrow the lumen. At this point, the vessels are permanentlynarrowed.

After the vessels are injured, biochemical mediators(histamines, leukotrienes, and prostaglandins) are released toincrease the endothelium's permeability. As permeability

increases, sodium, calcium, water, plasma proteins enter thevessel, causing further thickening and increasing theresponsiveness to stimuli, which causes vasoconstriction.


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Effects of Different Classes of Antihypertensive Drugs on SNS(Centrally and Peripherally Mediated Effects


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This nitrovasodilator selectivity, however,probably reflects the need for most organicnitrovasodilator drugs, such as glyceryl trinitrateor the isosorbide nitrates, to undergo

metabolic conversion to provide the activeprinciple, nitric oxide, and veins seem betterendowed with this metabolic pathway thanarteries (while platelets seem to lack itentirely)' 61-these considerations do not apply

to molsidomine, SIN- 1, or sodium nitroprussidewhich are sources of nitric oxide thatdo not depend on this metabolic step.also veins produce little No

so respond more to exogenous NO produced by nitrites


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Adverse Effects

Bradycardia

Heart failure Bronchospasm

Coldness of extremities

Withdrawal effects

Glucose metabolism


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5.Adverse Effects (Cont)

CNS effects Pregnancy

Rise in plasma triglyceride concentration;

decrease in HDL cholesterol Drug interactions: NSAID'S - can blunt effect of-blockers

Epinephrine - causes severe hypertension inpresence of-blockade

Ca2+channel blockers Conduction effects onheart are additive with blockers.


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Adverse Effects Unique toMethyldopa:

Heart block (methyldopa)

Immunological changes: positive

Coombs test (20% after 1 year), lupuslike syndrome, leukopenia, red-cellaplasia

Altered liver function 5%Avoid in depression


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Centrally acting imidazoline I(1)-receptor agonists

Such as moxonidine and rilmenidine induce peripheral

sympathoinhibition via the stimulation of I(1)-receptors in the medulla. Because of a rather weakaffinity for alpha(2)-adrenoceptors, the use of theseagents is associated with a lower incidence of adversereactions.

Although available data indicate that I(1)-receptoragonists are effective in patients with hypertension,

comparative data versus agents such as beta-blockers,diuretics, calcium channel antagonists and ACEinhibitors are required to establish their position in thetreatment of hypertension.


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Early after-depolarizations involve the reactivation of L-type Ca2+channelsduring prolonged repolarization, whereas DADs appear when Ca2+is released

from the sarcoplasmic reticulum (SR) during diastole. Diastolic Ca2+risesactivate the Na+Ca2+exchanger (NCX), which carries three Na+ions into

the cell in exchange for each Ca2+transported out, causing net inwardmovement of one positively charged ion per cycle and depolarizing the cell.

Oscillations in membrane potential that surpass the threshold potential triggerectopic beats, and ectopic firing provides the critical premature activation thatinitiates re-entrant activity, in the form of either a single rotor or multiple

rotors or wavelets that sustain fibrillation. Alternatively, repeated rapid firingfrom a focal source can be conducted irregularly through the atrial substrate,

producing fibrillatory activity. The very rapid atrial rate resulting from re-entryor triggered activity in turn abbreviates the effective refractory period (ERP),

entrant activity and promotes AF-which perpetuates re.6Ischaemia,

inflammation, fibrosis, and atrial dilatation also contribute to the AF substrate,and spatial variability of refractoriness is another important determinant ofsustained episodes of AF.10,9


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Normal cell sodium and potassiumactivities are restored by the Na-K-

ATPase pump, which extrudes thesodium that entered duringdepolarization and pumps in thepotassium that was lost during

repolarization.


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Impulse propagation Once an action potential forms in apatch of membrane (the source), current flows from thispatch to neighboring patches (the sink). Gap junctions are thelow resistance structures that allow ions to flow from one cellto another and, if the current flow is sufficient, to cause

sequential depolarization from cell to cell. The gap junctionsare actually active, opening and closing in response tochanges in pH, calcium, and, at times, voltage. In addition toion flow and gap junction resistance, impulse propagation canalso be affected by the orientation of fibers and of thecollagen matrix in which the fibers reside.


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Fast" tissues may conduct very slowly -declining from meters/sec to millimeters/sec in a number of circumstances. These

include inactivation of sodium channelsinduced by hyperkalemia or ischemia-induced acidosis, direct damage to the cells,or the effect of drugs, particularly

antiarrhythmic drugs.


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Action potential in slow response tissues Thesinoatrial (SA) and atrioventricular (AV) nodesrepresent slow response tissues, which havedifferent properties from the fast response tissues

(show table 1 .)Phase 0 depolarization depends onan inward calcium (not sodium) current via L-typecalcium channels [7.] These channels are selectivefor calcium, have a slower conduction velocity thanthe sodium channels, and take longer to reactivate.

Like the sodium channels, the calcium channels canexist in a resting, open, or inactivated state.


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In some cases, as with tissue damage orchanges in the extracellular milieu, fastresponse tissues can be converted to slowresponse tissues. In this setting, sodiumchannels become inactivated anddepolarization is dependent upon the slow

calcium channels.


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During faster heart rates, less time exists for thedrug to dissociate from the receptor, resulting in anincreased number of blocked channels and

enhanced blockade. These pharmacologic effectsmay cause a progressive decrease in impulseconduction velocity and a widening of the QRScomplex. This property is known as "use-dependency" and is seen most frequently with the

class IC agents, less frequently with the class IAdrugs, and rarely with the class IB agents


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The Class IB drugs lidocaine ,mexiletine ,andtocainide have less prominent sodium channelblocking activity at rest, but effectively block the

sodium channel in depolarized tissues. They tend tobind in the inactivated state (which is induced bydepolarization) and dissociate from the sodiumchannel more rapidly than other Class I drugs. As aresult, they are more effective with tachycardias

than with slow arrhythmias.


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The Class IC drugs flecainideandpropafenone also preferentially bind to the inactivated sodiumchannel. They dissociate slowly from the channel,

resulting in increased effect at more rapid rate, aphenomenon called use-dependence. Thischaracteristic may contribute to the enhancedproarrhythmic effect of these drugs. The Class ICdrugs have little effect on the duration of the action

potential .Propafenonehas significant -blockingactivity.


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Certain arrhythmogenic matrices are common, suchas those induced by ischemia or infarction. In thissetting, a certain effect of a drug becomespredominant and predictable, as with Class Iactivity in ischemia, and a drug classificationappears accurate. However, the major drug effectmay be quite different if a different proarrhythmicmatrix exists. Consider, for example, the differences

indigitalisaction in hypokalemia and hyperkalemia.


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Note that during one cycle of depolarization and repolarization, the sodiumchannel exists in three different states:

Resting.

Active, as the channels open during phase 0 depolarization.

Inactive, which occurs at positive potentials (end of phase 0) and duringmarked depolarization (as during the phase 2 plateau). During recovery, thechannel returns to the resting state.

The resting and inactive states are different physiologically, even though thesodium channel is effectively closed in both settings. In the resting state, thechannel can be opened by the attainment of the threshold potential. In

comparison, the inactive channel cannot be activated until it cycles to theresting state. These different states are important clinically, since someantiarrhythmic drugs (such as the Class IB and IC antiarrhythmic drugs)preferentially bind to inactivated sodium channels (see below.)


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Potential mechanisms by which b-blockersmay lower systemic vascular resistance

Inhibition of b-1 mediated renin release

Inhibition of central autonomic nervoussystem

Resetting of the baroreflex

Effect on prejunctional b-receptors:reduction in noradrenaline release

Increase in vasodilator prostaglandins

anti hypertensive module

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