hypertension. management.pdf

A P R I L 2 0 0 7 VO L . 1 4 1 1 9HOS P I TA L PHARMAC I S T

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Hypertension is a risk factor formany coronary events. However,blood pressure can usually bereduced with appropriate treat-ment, reducing the risk of stroke, coronaryevents, heart failure and renal failure.

Many different factors are involved in thepathogenesis of hypertension.These includeincreased cardiac output, increased periph-eral resistance, vasoconstriction and reducedvasodilation.The kidneys also play a role inthe regulation of blood pressure by control-ling sodium and water excretion, and thesecretion of renin, which influences vascular tone and electrolyte imbalance.Neuronal mechanisms such as the sympa-thetic nervous system and endocrine systemsare also involved in blood pressure regula-tion.These systems are therefore targets fordrug therapy to reduce blood pressure.

Target blood pressures The optimal systolic blood pressure (SBP) is

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with thiazide diuretics may experienceimpotence, which is usually reversible onwithdrawal of treatment.

Beta-blockers Beta-blockers block beta-adrenoceptors inthe body.These receptors are subclassified asbeta-1 receptors or beta-2 receptors. Beta-1receptors are mainly located in the heart andbeta-2 receptors are mostly found in thelung, peripheral blood vessels, and skeletalmuscle. However, beta-2 receptors can befound in the heart and beta-1 receptors canalso be found in the kidney. Beta-receptorsare also found in the brain.

Stimulation of beta-receptors in the brainand periphery promotes the release of neu-rotransmitters which increase sympatheticnervous system activity. Stimulation of beta-1 receptors in the sino-atrial node and themyocardium increases heart rate and force ofcontraction.Stimulation of beta-receptors inthe kidney promotes renin release, increas-ing the activity of the renin-angiotensin-aldosterone system.The overalleffect of stimulation of these receptors isincreased cardiac output, increased periph-eral vascular resistance and an increase inaldosterone-mediated sodium and waterretention.

Treatment with beta-blockers antagonisesall of these effects resulting in a reduction inblood pressure, although the principal anti-

hypertensive mechanism of this group ofdrugs is unclear.

Selective beta-blockers (commonly calledcardioselective beta-blockers), for examplebisoprolol, primarily act on beta-1 recep-tors. However they are not specific forbeta-1 receptors so should be used with cau-tion in patients with a history of asthma andbronchospasm. Non-selective beta-blockers(eg, propranolol) block both beta-1 andbeta-2 receptors.

Beta-blockers with partial agonist activity(sometimes known as intrinsic sympath-omimetic activity), eg acebutolol, act as abeta-stimulant when adrenergic activity isminimal (eg, during sleep) but exert a beta-blocking effect when adrenergic activity isincreased (eg, during exercise).This has thebenefit of reducing bradycardia during theday. Some beta-blockers, such as labetololand carvedilol, also block the effects ofperipheral alpha-adrenoceptors. Others,such as celiprolol, exert beta-2 agonist orvasodilator activity.

Beta-blockers are excreted hepatically orrenally depending on the water or lipid solubility of each drug.Those eliminated bythe liver usually require multiple daily dos-ing while those excreted renally generallyhave longer half-lives and can be adminis-tered once daily. Beta-blockers should neverbe abruptly stopped but should be with-drawn gradually, especially in patients withangina, or rebound symptoms can occur.

Side effects Blockade of beta-2 receptorsin the bronchi can precipitate bron-chospasm, even when cardioselectivebeta-blockers are used. Other adverse effectsof beta-blockers include bradycardia,impairment of myocardial contractility, andcold extremities caused by vasoconstrictionfrom blockade of beta-2 receptors in thesmooth muscle of peripheral blood vessels.

Awareness of hypoglycaemia in somepatients with insulin-dependent diabetesmellitus can be reduced. This is becausebeta-blockers block sympathetic nervoussystem activity which is responsible for thewarning signs of hypoglycaemia. Reducedsympathetic outflow may also account forthe feelings of malaise experienced by somepatients taking beta-blockers.

Vivid dreams and nightmares can occa-sionally occur, especially with lipid solublebeta-blockers such as propranolol. Impo-tence can also occur. The non-selectivebeta-blockers can cause an increase in serumtriglyceride levels and a decrease in HDL.

ACE inhibitors Angiotensin-converting enzyme (ACE)inhibitors competitively inhibit the forma-tion of angiotensin II from its inactiveprecursor angiotensin I, which is found inthe blood,blood vessels,kidney,heart, adren-al gland and brain.

Angiotensin II is a potent vasoconstrictorwhich also promotes aldosterone release andcentral and peripheral sympathetic activity.Inhibiting its formation therefore reducesblood pressure. If the renin-angiotensin-aldosterone system is already activated (eg,due to sodium depletion, or diuretic thera-py), the antihypertensive effect of ACEinhibitors will be greater.

ACE is also responsible for the breakdownof kinins, including bradykinin, which havea vasodilatory effect. Inhibition of thisbreakdown effect results in a more pro-nounced antihypertensive effect.

There are significant pharmacokineticdifferences between the ACE inhibitors.Captopril is rapidly absorbed but has a shortduration of action, so is useful for initialassessment of how a patient will respond toACE inhibition. The first dose of an ACEinhibitor should be administered at nightbecause a profound drop in blood pressuremay occur; this effect is enhanced in patientswith low sodium levels.

Angiotensin II antagonists Angiotensin II receptors are found in bloodvessels and other targets.They are subclassifiedinto AT1 and AT2 receptors.The AT1 receptormediates the pharmacological responses ofangiotensin II, such as vasoconstriction andaldosterone release, and is therefore the targetfor drug treatment. The role of the AT2receptor is less well understood.

Panel 1:Target blood pressures for pharmacological treatment1

Initial blood pressure

Systolic 220mmHg ordiastolic 160mmHg

Systolic 180219mmHgor diastolic 110119mmHg





Action

Treat immediately

Confirm over one to two weeks and treatif these readings are sustained

Confirm over three to four weeks andtreat if these readings are sustained

Advise lifestyle changes, initially reassessweekly and treat if these readings are sus-tained on repeat measurements over fourto 12 weeks

Confirm within 12 weeks and treat ifthese readings are sustained

Advise lifestyle changes and reassessmonthly. Treat persistent mild hyperten-sion if the 10-year cardiovascular diseaserisk is 20 per cent

Complications*

No

No

Yes

No

Yes

No

* Cardiovascular complications, target organ damage or diabetes

Many tissues contain enzyme pathwayswhich are capable of converting angiotensinI into angiotensin II without using ACE.Therefore there may be advantages inblocking the renin-angiotensin system viathe AT1 receptor antagonist pathway withan angiotensin II receptor antagonist.

Angiotensin II receptor antagonists havemany properties similar to those of ACEinhibitors, although they do not inhibit thebreakdown of kinins. Because of the renaleffects, ACE inhibitors and angiotensin IIreceptor antagonists are contraindicated inbilateral renal artery stenosis and in severe

stenosis of the artery supplying a singlefunctioning kidney.

Side effects of ACE inhibitors andangiotensin-II receptor antagonistsBefore starting treatment with an ACEinhibitor or angiotensin II receptor antago-nist a patients renal function and electrolytelevels should be checked. This monitoringshould continue during treatment becauseboth classes of drug can occasionally impairrenal function.

Both ACE inhibitors and angiotensin IIreceptor antagonists cause hyperkalaemiadue to reduced aldosterone production, sopotassium supplements and potassium spar-ing diuretics should be avoided in thesepatients.

One difference between the two classes isthat a dry cough is a common side effect ofACE inhibitors, exhibited in up to 15 percent of patients. Angiotensin II receptorantagonists are not associated with thecough because they do not interfere withthe inhibition of bradykinin breakdown.

Calcium channel blockers Calcium channel blockers (less correctlycalled calcium channel antagonists) reducecalcium ion influx into myocardial cells, thecells within the specialised conducting

The most recent guidance from the National Institute for Health and Clinical Excellenceon the treatment of hypertension is as follows:

Step 1 In hypertensive patients aged 55 years or older or in black patients of any age, firstchoice therapy should be a calcium channel blocker or thiazide-type diuretic. In patientsunder 55 years, the first choice for initial therapy should be an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin II receptor antagonist if ACEinhibitors are not tolerated).

Step 2 If an additional drug is required, adding an ACE inhibitor to a calcium channelblocker or a diuretic (or vice versa) is recommended.

Step 3 If treatment with three drugs is required then the combination of an ACEinhibitor (or angiotensin II receptor antagonist), calcium channel blocker and thiazide-type diuretic should be used.

Step 4 If a fourth drug is required then a higher dose of thiazide diuretic should be considered, or an alternative diuretic, beta-blocker or alpha blocker.All drug doses should be up-titrated as per the British National Formulary.

Panel 2:New NICE guidelines2

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system of the heart, and the cells of vascularsmooth muscle. The effect of this is toreduce myocardial contractility, depress theformation and propagation of electricalimpulses within the heart and promotevasodilator activity, interfering with theconstriction of vascular smooth muscle.All of these are calcium ion-dependentprocesses.

There are three classes of calcium channelblockers: the dihydropyridines (eg, nifedip-ine and amlodipine); the phenylalkalamines(verapamil) and the benzothiazipines (dilti-azem). The dihydropyridines have distinctperipheral vasodilator properties so areeffective antihypertensives while verapamiland diltiazem have cardiac effects and areused to reduce heart rate and prevent angina.

All calcium channel blockers aremetabolised by the liver.

Side effects Facial flushing, headache andswelling of the ankles are often seen, due tothe vasodilatory effect of the dihydropyri-dine calcium channel blockers. Abdominalpain and nausea may also occur.

The gastrointestinal tract is also affectedby the influx of calcium ions so calciumchannel blockers often cause gastrointesti-nal disturbances, which may includeconstipation.

Alpha-blockers Alpha-blockers (alpha-1 adrenoceptorblocking agents) block peripheral alpha-1adrenoceptors, causing vasodilatory effectsdue to relaxation of vascular smooth muscle.They are indicated for resistant hyperten-sion.

Side effects Alpha-blockers can cause pos-tural hypotension, which is commonly seenafter administration of the first dose.Alpha-blockers may be beneficial in older menbecause they may improve symptoms ofprostate enlargement.

Other groupsVasodilator antihypertensive drugs (eg,hydralazine, minoxidil) lower blood pressureby relaxation of vascular smooth muscle.Centrally acting antihypertensives (eg,clonidine, methyldopa, moxonidine) act onalpha-2 adrenoceptors or related receptorsin the brainstem, reducing sympathetic out-flow to the heart, blood vessels and kidneys,leading to a reduction in blood pressure.

Side effects Vasodilator antihypertensivescan cause fluid retention.Liver function testsshould be monitored during treatment withhydralazine because it is hepatically cleared.

Hydralazine has also been associated with sys-temic lupus erythematosus. Minoxidil hasbeen associated with hypertrichosis (hirsutism)and so may be unsuitable for use in women.

Centrally acting agents are not specific orselective enough to avoid central nervoussystem side effects such as sedation, drymouth and drowsiness, which commonlyoccur. Methyldopa has a similar mechanismof action to clonidine but can causeimmunological side effects, including pyrex-ia, hepatitis and haemolytic anaemia.

Choice of therapy An update of the National Institute for Healthand Clinical Excellence guideline on hyper-tension was published last year (see Panel 2,p121),2 together with the British Hyperten-sion Society,as recently published clinical trialsprovided further evidence for the treatment ofhypertension .3

The main changes to the NICE guidelineare that beta-blockers are no longer the rec-ommended first line treatment for anypatient group. Beta-blockers were found tobe less effective at reducing major cardiovas-cular events, especially stroke, than othertypes of antihypertensives.4

Atenolol was the beta-blocker used inmost of the studies. When the trials whichused atenolol were excluded from the

Younger than55 years

55 years or olderor black patients of any

age

A C or D

A + C or A + D

A + C + D

AddFurther diuretic therapy

orAlpha-blocker

orBeta-blocker

Consider seeking specialist advice

Figure 1: Diagrammatic representation of the National Institute for Healthand Clinical Excellence guidelines for the treatment of hypertension(adapted from reference 2).

A = ACE inhibitor (consider angiotensin II receptor antagonist if ACE intolerant)

C = Calcium channel blockerD = thiazide-type diuretic

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review, the evidence base for the use of beta-blockers in the treatment of hypertensionwas much weaker than for the other drugclasses. It was concluded that, in the absenceof other compelling indications for a beta-blocker (eg, angina), they should not berecommended as an initial treatment forhypertension.

Beta-blockers were also found to be lesseffective than ACE inhibitors or dihydropy-ridine calcium channel blockers in reducingthe risk of diabetes, especially in patientsalready taking a thiazide diuretic. If a patienttaking beta-blockers requires a second drug,an ACE inhibitor or calcium channel block-er should be added, rather than a thiazide.

Special considerationsPregnancy Centrally acting agents have apoor CNS profile. However, methyldopa isused in pregnancy, due to its long-term safe-ty data and beta-blockers are used in thethird trimester. Intravenous labetolol isreserved for use in pregnancy in a hyperten-sive crisis. A controlled release formulationof nifedipine has also been used in pregnan-cy but is unlicensed.

Ethnic group Thiazide diuretics and thedihydropyridine calcium channel blockersare more effective than beta-blockers inAfro-Caribbean patients. ACE inhibitorsand angiotensin II antagonists have beenshown to increase the risk of stroke in thisgroup of patients and are therefore not rec-ommended as first line therapy.5,6

ElderlyThe new NICE guidance states thatthiazide diuretics or dihydropyridine calci-um channel blockers should be the first linetherapy in elderly people.2 However, atten-tion should be paid to renal function duringtreatment with a thiazide because the elderlyare more at risk of renal impairment.Patients over 80 years old should be offeredthe same treatment as patients aged over 55years.

Diabetes Patients with diabetes may requirea combination of antihypertensive drugs toachieve their optimal target blood pressure.ACE inhibitors are the initial treatment ofchoice because they can delay the progres-sion of microalbuminuria to nephropathy.Patients with diabetic nephropathy shouldbe treated with an ACE inhibitor or anangiotensin II receptor antagonist to min-imise the risk of further renal deterioration,even if their blood pressure is normal.

Renal disease ACE inhibitors can reduceor abolish glomerular filtration and cancause severe and progressive renal failure.They are therefore contraindicated inpatients with bilateral renal artery stenosis.However, ACE inhibitors are unlikely tohave an adverse effect on overall renal

function in patients with unilateral renalartery stenosis. A dihydropyridine calciumchannel blocker can be added if furtherblood pressure lowering is required, but thi-azide diuretics may be ineffective.

Systolic hypertension Isolated systolichypertension (ISH) is defined as an SBP ofgreater than 160mmHg with a DBP lessthan 90mmHg. Patients with ISH should beoffered the same treatment as patients withraised SBP and raised DBP,because ISH car-ries the same risk of complications.2

The dihydropyridine calcium channelblockers have been used in the treatment ofisolated systolic hypertension in the elderly,especially where a thiazide diuretic is con-traindicated.

Accelerated hypertension Accelerated orvery severe hypertension, defined as a DBPof greater than 140mmHg, requires urgentmedical attention. Beta-blockers such asatenolol or labetolol or the dihydropyridinecalcium channel blockers are indicated forthis condition. DBP should be reduced to100110mmHg during the first 24 hours.Blood pressure should be reduced furtherover the next two to three days using a com-bination of diuretics, vasodilators and ACEinhibitors, if required.

If intravenous treatment is required thensodium nitroprusside or glyceryl trinitrate isrecommended.

The cardiology pharmacistAs a member of the multidisciplinary team,the pharmacist has an important role to playin the treatment of hypertension.

To aid concordance or ensure compliancewith a medication regimen the pharmacistcan give information about the benefits andside effects of drugs so that patients canmake an informed decision about theirtreatment.This information should includewhy the medicine is needed and the risks ofnot taking it. Practical points, such as ensur-ing that the medicine is prescribed oncedaily if possible, may also improve adherence.

Other medicines that a patient is takingshould also be reviewed. Concurrent non-steroidal anti-inflammatory drugs, the oralcontraceptive pill, glucocorticoids, and sym-pathomimetics can all increase bloodpressure. These medicines, some of whichcan be bought over the counter, should beavoided in patients with high blood pressure.

It is important to remember that a patientmay have additional co-morbidities. Thepharmacist can advise and review co-existing disease states to ensure the mostappropriate therapy choice is made.

To help reduce costs, pharmacists can alsoensure that non-proprietary drugs are pre-scribed when appropriate.

References1. British National Formulary (52). London: British

Medical Association and Royal PharmaceuticalSociety of Great Britain;2006.

2. National Institute for Health and ClinicalExcellence. Hypertension. Management ofhypertension in adults in primary care.London:NICE;2006.

3. Dahlof B, Sever PS, Poulter N, Wedel H, BeeversDG, Caulfield M. Prevention of cardiovascularevents with an antihypertensive regimen ofamlodipine adding perindopril as required versusatenolol adding bendroflumethiazide as required,in the Anglo-Scandinavian Cardiac OutcomesTrial-Blood Pressure Lowering Arm (ASCOT-BPLA):a multicentre randomised controlled trial. Lancet2005;366:895906.

4. The National Collaborating Centre for ChronicConditions.Hypertension. Management ofhypertension in adults in primary care: partialupdate. London;Royal College of Physcians:2006.

5. Wright JT, Dunn JK, Cutler JA, Davis BR, CushmanWC, Ford CE. Outcomes in hypertensive black andnonblack patients treated with chlorthalidone,amlodipine and lisinopril. JAMA2005;293:15951608.

6. Dahlof B, Devereux RB, Kjeldsen SE, Julius S,Beevers G, Faire U et al. Cardiovascular morbidityand mortality in the Losartan Intervention ForEndpoint reduction in hypertension study (LIFE): arandomised controlled trial against atenolol.Lancet 2002;359:9951003.

Further readingi. Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi

H, Kanmatsuse K et al. Comparison of nifedipineretard with angiotensin converting enzymeinhibitors in Japanese hypertensive patients withcoronary artery disease: the Japan MulticenterInvestigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertension Research2004;27:44956.

ii. Julius S, Kjeldsen SE, Weber M, Brunner HR,Ekman S, Hansson L et al. Outcomes inhypertensive patients at high cardiovascular risktreated with regimens based on valsartan oramlodipine: the VALUE randomised trial. Lancet2004;363:202231.

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