Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 25A) pptx

• Hypertension and angina pectoris: how drugs act • Drugs used in both hypertension and angina Diuretics Vasodilators organic nitrates, calcium channel blockers.ACE inhibitors, angiotens

Arterial hypertension, angina

pectoris, myocardial infarction

SYNOPSIS

Hypertension and coronary heart disease

(CHD) are of great importance Hypertension

affects above 20% of the total population of the

USA with its major impact on those over age

50 CHD is the cause of death in 30% of males

and 22% of females in England and Wales.

Management requires attention to detail, both

clinical and pharmacological.

The way drugs act in these diseases is

outlined and the drugs are described according

to class.

• Hypertension and angina pectoris: how

drugs act

• Drugs used in both hypertension and angina

Diuretics

Vasodilators

organic nitrates, calcium channel

blockers.ACE inhibitors, angiotensin

II-receptor antagonists

Adrenoceptor blocking drugs, and (

Peripheral sympathetic nerve terminal

Autonomic ganglion-blocking drugs

Central nervous system

Treatment of angina pectoris

• Acute coronary syndromes and myocardial

infarction

• Arterial hypertension

• Sexual function and cardiovascular drugs

• Phaeochromocytoma

Hypertension: how drugs act

Consider the following relationship:

Blood pressure =

cardiac output x peripheral resistance Therefore drugs can lower blood pressure by:

• Dilatation of arteriolar resistance vessels.

Dilatation can be achieved through direct relaxation of vascular smooth muscle cells, by stimulation of nitric oxide (NO) production, or

by blocking (suppressing) endogenous vasconstrictors, noradrenaline (norepinephrine) and angiotensin

• Dilatation of venous capacitance vessels; reduced

venous return to the heart (preload) leads to reduced cardiac output, especially in the upright position

• Reduction of cardiac contractility and heart rate.

• Depletion of body sodium This reduces plasma

volume (transiently), and reduces arteriolar response to noradrenaline (norepinephrine) Modern antihypertensive drugs lower blood pressure with minimal interference with homeo-static control, i.e change in posture, exercise

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23 A R T E R I A L H Y P E R T E N S I O N , A N G I N A P E C T O R I S, Ml

Angina pectoris: how

drugs act

Angina can be viewed as a problem of supply and

demand Drugs used in angina pectoris are those

that either increase supply of oxygen and nutrients,

or reduce the demand for these — or both

Supply can be increased by: cardiac work and

myocardial oxygen need by:

• dilating coronary arteries

• slowing the heart (coronary flow, uniquely,

occurs in diastole, which lengthens as heart rate

falls)

Demand can be reduced by:

• reducing afterload, (i.e peripheral resistance), so

reducing the work of the heart in perfusing the

tissues

• reducing preload, (i.e venous filling pressure);

according to Starling's Law of the heart,

workload and therefore oxygen demand varies

with stretch of cardiac muscle fibres

• slowing the heart

Drugs used in

hypertension and angina

Two groups of drugs, p-adrenergic blockers and

calcium channel blockers, are used in both

hyper-tension and angina Several drugs for hyperhyper-tension

are used also in the treatment of heart failure

DiuretiCS (see also Ch 26)

Diuretics, particularly the thiazides, are useful

anti-hypertensives They cause an initial loss of sodium

with a parallel contraction of the blood and

extra-cellular fluid volume The effect may reach 10% of

total body sodium but it is not maintained After

several months of treatment, the main blood

press-ure lowering effect appears to reflect a reduced

responsiveness of resistance vessels to endogenous

vasoconstrictors, principally noradrenaline While this hyposensitivity may be a consequence of the sodium depletion, thiazides are generally more effec-tive antihypertensive agents than loop diuretics, despite causing less salt loss, and evidence suggests

an independent action of thiazides on an unidentified ion-channel on vascular smooth muscle cell mem-branes Maximum effect on blood pressure is delayed for several weeks and other drugs are best added after this time Adverse metabolic effects of thiazides

on serum potassium, blood lipids, glucose tolerance, and uric acid metabolism led to suggestions that they should be replaced by newer agents not having these effects It is, however, now recognised that unnecessarily high doses of thiazides have been used

in the past and that with low doses, e.g bendro-fluazide (bendroflumethiazide) 1.25-2.5 mg/d or less (or hydrochlorothiazide 12.5-25 mg), thiazides are both effective and well-tolerated Moreover, they are not only by far the cheapest antihypertensive agents available worldwide but have proved to be the most effective in several outcome trials in preventing the major complications of hypertension, myocardial infarction and stroke The characteristic reduction in renal calcium excretion induced by thiazides may, in long-term therapy, also reduce the occurrence of hip fractures in older patients and benefit women with postmenopausal osteoporosis

Vasodilators ORGANIC NITRATES

Organic nitrates (and nitrite) were introduced into medicine in the 19th century.1 Denitration in the smooth muscle cell releases nitric oxide (NO), which

is the main physiological vasodilator, normally

pro-duced by endothelial cells Nitrodilators (a generic

term for drugs that release or mimic the action of NO) activate the soluble guanylate cyclase in vascular smooth muscle cells and cause an increase in intra-cellular cyclic GMP (guanosine monophosphate)

con-1 Murrell, W 1879 Nitroglycerin as a remedy for angina pectoris Lancet 1: 80-81 Nitroglycerin was actually first synthesised by Sobrero in 1847 who noted when he applied it

to his tongue it caused a severe headache.

centrations This is the second messenger that alters

calcium fluxes in the cell, decreases stored calcium,

and induces relaxation The result is a generalised

dilatation of venules (capacitance vessels) and to a

lesser extent of arterioles (resistance vessels), causing

a fall of blood pressure that is postural at first; the

larger coronary arteries especially dilate Whereas

some vasodilators can 'steal' blood away from

atheromatous arteries, with their fixed stenoses, to

other, healthier arteries, nitrates probably have the

reverse effect as a result of their supplementing

the endogenous NO Atheroma is associated with

impaired endothelial function, resulting in reduced

release of NO and, possibly, its accelerated

destruction by the oxidised LDL in atheroma (see

Ch 25)

The venous dilatation causes a reduction in

venous return, a fall in left ventricular filling pressure

with reduced stroke volume, but cardiac output

(per min) is sustained by the reflex tachycardia

induced by the fall in blood pressure

Pharmacokinetics The nitrates are generally well

absorbed across skin, and the mucosal surface of

the mouth or gut wall Nitrates absorbed from the

gut, however, are subject to extensive first-pass

metabolism in the liver, as is shown by the

sub-stantially larger doses required by that route over

sublingual application (this also explains why

swallowing a sublingual tablet of glyceryl trinitrate

terminates its effect) They are first denitrated and

then conjugated with glucuronic acid The t1/2

periods vary (see below) but for glyceryl trinitrate

(GTN) it is 1-4: minutes.

Tolerance to the characteristic vasodilator headache

comes and goes quickly (hours).2 Ensuring that a

continuous steady-state plasma concentration is

avoided prevents tolerance This is easy with

occasional use of glyceryl trinitrate, but with nitrates

having longer t1/2 (see below) and sustained release

formulations it is necessary to plan the dosing to

allow low plasma concentration for 4-8 h, e.g

over-2 Explosives factory workers exposed to a

nitrate-contaminated environment lost it over a weekend and some

chose to maintain their intake by using nitrate impregnated

headbands (transdermal absorption) rather than have to

accept the headaches and reacquire tolerance so frequently.

night; alternatively transdermal patches may be removed for a few hours if tolerance is suspected

Uses Nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure An excessive fall in blood pressure will reduce coronary flow as well as cause fainting due to reduced cerebral blood flow, and so it is important to avoid accidental overdosing Patients with angina should be instructed

on the signs of overdose — palpitations, dizziness, blurred vision, headache and flushing following by pallor — and what to do about it (below)

The discovery that coronary artery occlusion by thrombosis is itself 'stuttering' — developing gradually over hours — and associated with vaso-spasm in other parts of the coronary tree has made the use of isosorbide dinitrate (Isoket) by continuous i.v infusion adjusted to the degree of pain, a logical, and effective, form of analgesia for unstable angina Transient relief of pain due to spasm of other smooth muscle (colic), can sometimes be obtained,

so that relief of chest pain by nitrates does not prove the diagnosis of angina pectoris

Nitrates are contraindicated in angina due to anaemia

Adverse effects Collapse due to fall in blood pressure resulting from overdose is the commonest side effect The patient should remain supine, and the legs should be raised above the head to restore venous return to the heart

Nitrate headache, which may be severe, is prob-ably due to the stretching of pain-sensitive tissues around the meningeal arteries resulting from the increased pulsation that accompanies the local vasodilatation If headache is severe the dose should

be halved Methaemoglobinaemia occurs with heavy dosage

Interactions An important footnote to the use of nitrates (and NO-dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra) This agent targets

an isoform of PDE (PDE-5) expressed in the blood vessel wall Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors

of PDE-5, even at the doses effective in asthma A

23 A R T E R I A L H Y P E R T E N S I O N , A N G I N A P E C T O R I S , Ml

number of pericoital deaths reported in patients

taking sildenafil have been attributed to the

substantial fall in blood pressure that occurs when

used with a nitrate This is an ironic twist for an

agent in first-line use in erectile dysfunction that

was originally developed as a drug to treat angina.3

GLYCERYLTRINITRATE (see also above)

Glyceryl trinitrate (1879) (trinitrin, nitroglycerin,

GTN) (t1/2 3 min) is an oily, nonflammable liquid

that explodes on concussion with a force greater

than that of gunpowder Physicians meet it mixed

with inert substances and made into a tablet, in

which form it is both innocuous and fairly stable

But tablets more than 8 weeks old or exposed to

heat or air will have lost potency by evaporation

and should be discarded Patients should also be

warned to expect the tablet to cause a burning

sensation under the tongue if it is still contains

active GTN An alternative is to use a nitroglycerin

spray (see below); formulated as a pressurised

liquid GTN has a shelf life of at least 3 years

GTN is the drug of choice in the treatment of an

attack of angina pectoris The tablets should be

chewed and dissolved under the tongue, or placed

in the buccal sulcus, where absorption is rapid and

reliable Time spent ensuring that patients

under-stand the way to take the tablets and that the feeling

of fullness in the head is harmless, is time well

spent The action begins in 2 min and lasts up to 30

min The dose in the standard tablet is 300

micro-grams, and 500 or 600 microgram strengths are also

available; patients may use up to 6 mg daily in total

but those who require more than 2-3 tablets per

week should take a long-acting nitrate preparation

GTN is taken at the onset of pain and as a

pro-phylactic immediately before any exertion likely

to precipitate the pain Sustained-release buccal

tablets are available (Suscard), 1-5 mg Absorption

from the gastrointestinal tract is good, but there is

such extensive hepatic first-pass metabolism that

3 It has been argued that deaths on sildenafil largely reflect

the fact that it is used by patients at high cardiovascular risk.

But recent postmarketing data shows that death is 50 times

more likely after sildenafil taken for erectile failure than

alprostadil, the previous first-line agent Mitka M 2000

Journal of the American Medical Association 283: 590.

the sublingual or buccal route is preferred; an oral metered aerosol that is sprayed under the tongue (nitrolingual spray) is an alternative

For prophylaxis, GTN can be given as an oral (buccal, or to swallow, Sustac) sustained-release formulation or via the skin as a patch (or ointment); these formulations can be useful for victims of nocturnal angina.4

Venepuncture: the ointment can assist difficult venepuncture and a transdermal patch adjacent to

an i.v infusion site can prevent extravasation and phlebitis and prolong infusion survival

Isosorbide dinitrate (Cedocard) (t1/2 20 min) is used for prophylaxis of angina pectoris and for congestive heart failure (tabs sublingual, and to swallow) An i.v formulation 500 micrograms/ml

(Isoket) is available for use in left ventricular failure and unstable angina.

Isosorbide mononitrate (Elantan) (t1/2 4 h) is used for prophylaxis of angina (tabs to swallow) Hepatic first-pass metabolism is much less than for the dinitrate so that systemic bioavailability is more reliable

Pentaerythritol tetranitrate (Peritrate) (t1/2 8h) is less efficacious than its metabolite pentaerythritol trinitrate (t1/211 h)

CALCIUM CHANNEL BLOCKERS

Calcium is involved in the initiation of smooth muscle and cardiac cell contraction and in the pro-pagation of the cardiac impulse Actions on cardiac pacemaker cells and conducting tissue are described

in Chapter 24

Vascular smooth muscle cells Contraction of these cells requires an influx of calcium across the cell membrane This occurs through ion channels

4 Useful, but not always safe Defibrillator paddles and nitrate patches make an explosive combination, and it is not always in the patient's interest to have the patch as unobtrusive as possible (Canadian Medical Association Journal 1993 148: 790).

that are largely specific for calcium and are called

'slow calcium channels' to distinguish them from

'fast' channels that allow the rapid influx and efflux

of sodium

Activation of calcium channels by an action

po-tential allows calcium to enter the cells There follows

a sequence of events which results in activation of

the contractile proteins, myosin and actin, with

shortening of the myofibril and contraction of

smooth muscle During relaxation calcium is released

from the myofibril and, as it cannot be stored in the

cell, it passes out again through the channel Calcium

channel (also called calcium entry) blockers inhibit

the passage of calcium through the

voltage-dependent L- (for 'long-opening') class membrane

channels in cardiac muscle and conducting tissue,

and vascular smooth muscle, reduce available

intra-cellular calcium and cause the muscle to relax.5

There are three structurally distinct classes of

calcium channel blocker:

• Dihydropyridines (the most numerous)

• Phenylalkylamines (principally verapamil)

• Benzothiazepine (diltiazem)

The differences between their clinical effects can

be explained in part by their binding to different

parts of the L-type calcium channel All members of

the group are vasodilators, and some have negative

cardiac inotropic action and negative chronotropic

effect via pacemaker cells and depress conducting

tissue The attributes of individual drugs are

de-scribed below

The therapeutic benefit of the calcium blockers

in hypertension and angina is due mainly to their

action as vasodilators Their action on the heart

gives non-dihydropyridines an additional role as

Class 4 antiarrhythmics

Pharmacokinetics Calcium channel blockers in

general are well absorbed from the gastrointestinal

tract and their systemic bioavailability depends on

the extent of first-pass metabolism in the gut wall

and liver, which varies between the drugs All

5 Several calcium-selective channels have been described in

different tisues, e.g the N (present in neuronal tissue) and T

(transient, found in brain, neuronal and cardiovascular

tissue); the drugs discussed here selectively target the L

channel for its cardiovascular importance.

undergo metabolism to less active products, pre-dominantly by cytochrome P-450 CYP3A, which is the source of interactions with other drugs by enzyme induction and inhibition As their action is ter-minated by metabolism, dose adjustments for patients with impaired renal function are therefore either minor or unnecessary

Indications for use

• Hypertension: amlodipine, isradipine,

nicardipine, nifedipine, verapamil

• Angina: amlodipine, diltiazem, nicardipine,

nifedipine, verapamil

• Cardiac arrhythmia: verapamil

• Raynaud's disease: nifedipine

• Prevention of ischaemic neurological damage

following subarachnoid haemorrhage:

nimodipine

Adverse effects Headache, flushing, dizziness, palpitations and hypotension may occur during the first few hours after dosing, as the plasma concen-tration is increasing, particularly if the initial dose is too high or increased too rapidly Ankle oedema may also develop This is probably due to a rise in intracapillary pressure as a result of the selective dilatation by calcium blockers of the precapillary arterioles Thus the oedema is not a sign of sodium retention It is not relieved by a diuretic but dis-appears after lying flat, e.g overnight In theory the oedema should also be attenuated by combining the calcium blocker with another vasodilator which

is more effective (than calcium blockers) at relaxing the postcapillary venules, e.g a nitrate or an ACE inhibitor Bradycardia and arrhythmia may occur Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may

be felt

There has been some concern that the shorter-acting calcium channel blockers may adversely affect the risk of myocardial infarction and cardiac death The evidence is based on case-control studies which cannot escape the possibility that sicker patients, i.e with worse hypertension or angina, received calcium channel blockade The safety and efficacy of the class has been strengthened by the recent findings of two prospective comparisons with other antihypertensives.6

23A R T E R I A L H Y P E R T E N S I O N , A N G I N A P E C T O R I S, M

Interactions are quite numerous The drugs in this

group in general are extensively metabolised, and

there is risk of decreased effect with enzyme inducers,

e.g rifampicin, and increased effect with enzyme

inhibitors, e.g cimetidine Conversely, calcium

channel blockers decrease the plasma clearance of

several other drugs by mechanisms that include

delaying their metabolic breakdown The

conse-quence, for example, is that diltiazem and verapamil

cause increased exposure to carbamazepine, quinidine,

statins, ciclosporin, metoprolol, theophylline and

(HIV) protease inhibitors Verapamil increases

plasma concentration of digoxin, possibly by

interfering with its biliary excretion

Beta-adreno-ceptor blockers may exacerbate atrioventricular

block and cardiac failure Grapefruit juice raises the

plasma concentration of dihydropyridines (except

amlodipine) and verapamil

Individual calcium blockers

Nifedipine (t l / 2 2h) is the prototype

dihydro-pyridine It selectively dilates arteries with little

effect on veins; its negative myocardial inotropic

and chronotropic effects are much less than those of

verapamil There are sustained-release formulations

of nifedipine that permit once daily dosing with

minimal peaks and troughs in plasma concentration

so that adverse effects due to rapid fluctuation of

concentrations are also lessened Various methods

have been used to prolong, and smooth, drug

delivery, and bioequivalence between these

formu-lations cannot be assumed; prescribers should

specify the brand to be dispensed The adverse

effects of calcium blockers with a short duration of

action may include the hazards of activating the

sympathetic system each time a dose is taken The

dose range for nifedipine is 30-90 mg daily In

addition to the adverse effects listed above, gum

hypertrophy may occur Nifedipine can be taken

'sublingually', by biting a capsule and squeezing

the contents under the tongue In point of fact,

absorption is still largely from the stomach after this

6 Both the NORDIL and INSIGHT trials (Lancet 2000 356:

359-365, 366-372) confirmed that a calcium channel blocker

(diltiazem and nifedipine respectively) had the same efficacy

as older therapies (diuretics and/or -blockers) in

hypertension with no evidence of increased sudden death.

manoeuvre; it should not be used in a hypertensive emergency because the blood pressure reduction is unpredictable and sometimes large enough to cause cerebral ischaemia (see p 492)

Amlodipine has a t1/2 (40 h) sufficient to permit the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation Its slow association with L-channels and long duration of action render it unsuitable for emergency reduction of blood pressure where frequent dose adjustment is needed On the other hand an occasional missed dose is of little consequence Amlodipine differs from all other dihydropyridines listed in this chapter in being safe to use in patients with cardiac failure (the PRAISE7 Study)

Verapamil (t l / 2 4 h) is an arterial vasodilator with some venodilator effect; it also has marked negative myocardial inotropic and chronotropic actions It is given thrice daily as a conventional tablet or daily

as a sustained-release formulation Because of its negative effects on myocardial conducting and contracting cells it should not be given to patients with bradycardia, second or third degree heart block, or patients with Wolff-Parkinson-White syndrome to relieve atrial flutter or fibrillation Amiodarone and digoxin increase the AV block Verapamil increases plasma quinidine concen-tration and this interaction may cause dangerous hypotension

Diltiazem (t l / 2 5 h) is given thrice daily, or once or twice daily if a slow-release formulation is pre-scribed It causes less myocardial depression and prolongation of AV conduction than does verapamil but should not be used where there is bradycardia, second or third degree heart block or sick sinus syndrome

Isradipine (t1/2 8 h) is given once or twice daily (it is similar to nifedipine)

Nicardipine (t1/2 4 h) is given x 3/d

7 PRAISE = Prospective Randomised Amlodipine Survival Evaluation (see Packer M et al 1996 The effect of amlodipine

on morbidity and mortality in severe chronic heart failure New England Journal of Medicine 335: 1107-1114).

Nimodipine has a moderate cerebral vasodilating

action Cerebral ischaemia after subarachnoid

haemorrhage may be partly due to vasospasm;

clinical trial evidence indicates that nimodipine

given after subarachnoid haemorrhage reduces

cerebral infarction (incidence and extent).8 Although

the benefit is small, the absence of any more

effec-tive alternaeffec-tives has led to the routine administration

of nimodipine (60 mg every 4 hours) to all patients

for the first few days following subarachnoid

haemorrhage No benefit has been found in similar

trials following other forms of stroke

Other members include felodipine, isradipine,

laci-dipine, lercanilaci-dipine, nisoldipine.

ANGIOTENSIN CONVERTING

ENZYME (ACE) INHIBITORS AND

ANGIOTENSIN (AT) II RECEPTOR

ANTAGONISTS

Renin is an enzyme produced by the kidney in

response to a number of factors including adrenergic

activity ( 1-receptor) and sodium depletion Renin

converts a circulating glycoprotein (angiotensinogen)

into the biologically inert angiotensin I, which is

then changed by angiotensin converting enzyme

(ACE or kininase II) into the highly potent

vaso-constrictor angiotensin II ACE is located on the

luminal surface of capillary endothelial cells,

parti-cularly in the lungs; and there are also

renin-angiotensin systems in many organs, e.g brain,

heart, the relevance of which is uncertain

Angiotensin II acts on two G-protein coupled

receptors, of which the angiotensin 'AT1 subtype

accounts for all the classic actions of angiotensin As

well as vasoconstriction these include stimulation

of aldosterone (the sodium-retaining hormone)

production by the adrenal cortex It is evident that

angiotensin II can have an important effect on

blood pressure In addition, it stimulates cardiac

and vascular smooth muscle cell growth, contributing

probably to the progressive amplification in

hyper-tension once the process is initiated The AT2

receptor subtype is coupled to inhibition of muscle

growth or proliferation, but appears of minor

importance in the adult cardiovascular system The

8 Packard J D et al 1989 British Medical Journal 289: 636.

recognition that the AT1-receptor subtype is the important target for drugs antagonising angiotensin

II has led, a little confusingly, to two alternative nomenclatures for these drugs: either AT1-receptor blockers, or angiotensin II receptor antagonists (AURA)

Bradykinin (an endogenous vasodilator occurring

in blood vessel walls) is also a substrate for ACE Potentiation of bradykinin contributes to the blood pressure lowering action of ACE inhibitors in patients with low-renin causes of hypertension Either bradykinin or one of the neurokinin substrates

of ACE (such as substance P) may stimulate cough (below) The AT1 blockers differ from the ACE inhibitors in having no effect on bradykinin and do not cause cough Those that achieve complete blockade of the receptor are slightly more effective than ACE inhibitors at preventing angiotensin II vasoconstriction ACE inhibitors are more effective

at suppressing aldosterone production in patients with normal or low plasma renin

Uses

Hypertension The antihypertensive effect of ACE

inhibitors and AT1 receptor blockers results primarily from vasodilatation (reduction of peripheral resist-ance) with little change in cardiac output or rate; renal blood flow may increase (desirable) A fall in aldosterone production may also contribute to the blood pressure lowering action of ACE inhibitors Both classes slow progression of glomerulopathy Whether the long-term benefit of these drugs in hypertension exceeds that to be expected from blood pressure reduction alone remains controversial ACE inhibitors and AT1-receptor blockers are most useful in hypertension when the raised blood pressure results from excess renin production (e.g renovascular hypertension), or where concurrent use of another drug (diuretic or calcium blocker) renders the blood pressure renin-dependent The fall in blood pressure can be rapid, especially with short-acting ACE inhibitors, and low initial doses of these should be used in patients at risk: those with impaired renal function, or suspected cerebrovascular disease These patients may be advised to omit any concurrent diuretic treatment for a few days before the first dose The antihypertensive effect increases progressively over weeks with continued

adminis-23 A R T E R I A L H Y P E RT E N S I O N , A N G I N A P E C T O R I S , Ml

tration (as with other antihypertensives) and the

dose may be increased at intervals of 2 weeks

Cardiac failure (see p 517) ACE inhibitors have a

useful vasodilator and diuretic-sparing (but not

diuretic-substitute) action in all grades of heart

failure Their reduction of mortality in this condition,

due possibly to their being the only vasodilator

which does not reflexly activate the sympathetic

system, has made the ACE inhibitors more critical

to the treatment of heart failure than of

hyper-tension, where they are not usually an essential part

of management The AT1 blockers have not yet been

introduced for the treatment of cardiac failure This

may only be a matter of time, but the establishment

of new drugs for cardiac failure encounters the

problem of demonstrating efficacy against a

back-ground of existing ACE inhibitor therapy, where a

placebo control is no longer ethically acceptable

Diabetic nephropathy In patients with type I

(insulin dependent) diabetes, hypertension often

accompanies the diagnosis of frank nephropathy

and aggressive blood pressure control is essential to

slow the otherwise inexorable decline in renal

func-tion that follows ACE inhibitors appear to have a

specific renoprotective effect, possibly because of

the role of angiotensin II in driving the underlying

glomerular hyperfiltration in these patients.9 These

drugs are now considered first-line treatment for

hypertensive type I diabetics, although most patients

will need a second or third agent to reach the new

BP targets for these patients (see below) There is

also evidence that ACE inhibitors have a

proteinuria-sparing effect in type I diabetics with 'normal' BP,

but here it is less clear whether this effect extends

beyond just a BP-lowering effect.10 For hypertensive

type 2 diabetics with nephropathy, there are better

data to support use of AT1-receptor blockers than

ACE inhibitors for a renoprotective effect

indepen-dent of the blood pressure lowering effect

9 For a review, see: Cooper M E 1998 Pathogenesis,

prevention and treatment of diabetic nephropathy Lancet

352:213-219.

10 The EUCLID study group 1997 The EUCLID study.

Randomised, placebo-controlled trial of lisinopril in

normotensive patients with insulin-dependent diabetes and

normoalbuminuria or microalbiminuria Lancet 349:

1787-1792.

Myocardial infarction (MI) Following a myocardial infarction, the left ventricle may fail acutely from the loss of functional tissue or in the long-term from

a process of 'remodelling' due to thinning and enlargement of the scarred ventricular wall Angio-tensin II plays a key role in both of these processes and an ACE inhibitor given after an MI markedly reduces the incidence of heart failure The effect is seen even in patients without overt signs of failure, but who have low left ventricular ejection fractions during the convalescent phase (3-10 days) follow-ing their MI Patients such as this receivfollow-ing captopril in the SAVE trial,11 had a 37% reduction in progressive heart failure over the 60-month

follow-up period compared to placebo The benefits of ACE inhibition after MI are additional to those conferred by thrombolysis, aspirin and -blockers

Cautions Certain constraints apply to the use of ACE

• Heart failure: severe hypotension may result in

patients taking diuretics, or who are hypovolaemic, hyponatraemic, elderly, have renal impairment or with systolic blood pressure < 100 mmHg A test dose of captopril 6.25 mg by mouth may be given because its effect lasts only 4-6 h If tolerated, the preferred long-acting ACE inhibitor may then be initiated

in low dose

• Renal artery stenosis (whether unilateral, bilateral

renal or suspected from the presence of generalised atherosclerosis): an ACE inhibitor

may cause renal failure and is contraindicated.

• Aortic stenosis/left ventricular outflow tract

obstruction: an ACE inhibitor may cause severe,

sudden hypotension and, depending on severity,

is relatively or absolutely contraindicated.

• Pregnancy represents a contraindication (see

below)

• Angioedema may result (see below).

Adverse effects

ACE inhibitors cause persistent dry cough in 10-15% of patients Urticaria and angioedema (< 1

11 Swedberg K P et al 1992 New England Journal of Medicine 327: 669-677.

in 100 patients) are much rarer, occurring usually in

the first weeks of treatment The angioedema varies

from mild swelling of the tongue to life-threatening

tracheal obstruction, when s.c adrenaline

(epine-phrine) should be given The basis of the reaction is

probably pharmacological rather than allergic, due

to reduced breakdown of bradykinin

Impaired renal function may result from reduced

glomerular filling pressure, systemic hypotension

or glomerulonephritis, and plasma crearinine should

be checked before and during treatment

Hypo-natraemia may develop, especially where a diuretic

is also given; clinically significant hyperkalaemia

(see effect on aldosterone above) is confined to

patients with impaired renal function ACE

inhi-bitors are fetotoxic in the second trimester, causing

reduced renal perfusion, hypotension,

oligohy-dramnios and fetal death Neutropenia and other

blood dyscrasias occur Other reported reactions

include rashes, taste disturbance (dysguesia),

musculoskeletal pain, proteinuria, liver injury and

pancreatitis

AT1 receptor blockers are contraindicated in

pregnancy, but avoid most other complications —

particularly the cough and angioedema They are

the only antihypertensive drugs for which there is

no 'typical' side effect

Interactions Hyperkalaemia can result from use

with potassium-sparing diuretics Renal clearance

of lithium is reduced and toxic concentrations of

plasma lithium may follow Severe hypotension can

occur with diuretics (above), and with

chlorpro-mazine, and possibly other phenothiazines

Individual drugs

Captopril (Capoten) has a t l / 2 of 2 h and is partly

metabolised and partly excreted unchanged; adverse

effects are more common if renal function is

impaired; it is given twice or thrice daily Captopril

is the shortest-acting of the ACE inhibitors, one of

the few where the oral drug is itself active, not

requiring de-esterification after absorption

Enalapril (Innovace) is a prodrug (t l / 2 35 h) that is

converted to the active enalaprilat (t l / 2 10 h)

Effec-tive 24-h control of blood pressure may require

twice daily administration

Other members include cilazapril, fosinopril, imidapril,

lisinopril, moexipril, perindopril, quinapril, mmipril,

and trandolapril Of these, lisinopril has a marginally

longer t1/2 than enalapril, probably justifying its popularity as a once-daily ACE inhibitor Some of the others are longer-acting, with quinapril and ramipril having also a higher degree of binding to ACE in vascular tissue The clinical significance of these differences is disputed In the Heart Out-comes Prevention Evaluation (HOPE) Study of 9297 patients, ramipril reduced, by 20-30%, the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who were not known to have a low ejection fraction or heart failure.12 The authors considered that the results could not be explained entirely by blood pressure reduction

Losartan was the first AT1 receptor antagonist licensed in the UK It is a competitive blocker with a noncompetitive active metabolite The drug has a short t// (2 h) but the metabolite is much longer lived (t1/2 10 h) permitting once daily dosing Other

AT1 receptor antagonists in clinical use include

candesartan, eprosartan, irbesartan, telmisartan and valsartan Some of these appear more effective than

losartan, which is generally used in combination with hydrochlorothiazide In a landmark study this combination was 25% more effective than atenolol plus hydrochlorothiazide in preventing stroke.13 This class of drug is very well tolerated; in clinical trials their side effect profiles are indistinguishable or even better than placebo Unlike the ACE inhibitors they do not produce cough, and are a valuable alternative for the 10-15% of patients who dis-continue their ACE inhibitor for this reason AT1 receptor antagonists are used to treat hypertension but any role in cardiac failure or after myocardial infarction (as have ACE inhibitors) remains to be established

The cautions listed for the use of ACE inhibitors (above) apply also to AT1 receptor blockers

12 Yusuf S, Sleight P, Pogue J et al 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients The Heart Outcomes Prevention Evaluation Study Investigators New England Journal of Medicine 342:145-53.

13 Dahlof B et al 2002 Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Lancet 359: 995-1010.

23A R T E R I A L H Y P E R T E N S I O N , A N G I N A P E C T O R I S, Ml

Other vasodilators

Several older drugs are powerfully vasodilating,

but precluded from routine use in hypertension by

their adverse effects Minoxidil and nitroprusside

still have special indications

Minoxidil is a vasodilator selective for arterioles

rather than for veins, similar to diazoxide and

hydralazine Like the former, it acts through its

sulphate metabolite as an ATP-dependent potassium

channel opener It is highly effective in severe

hypertension, but causes increased cardiac output,

tachycardia, fluid retention and hypertrichosis The

hair growth is generalised and although a cosmetic

problem in women, it has been exploited as a

topical solution for the treatment of baldness in

men

Sodium nitroprusside is a highly effective

anti-hypertensive agent when given i.v Its effect is

almost immediate and lasts for 1-5 min Therefore it

must be given by a precisely controllable infusion

It dilates both arterioles and veins, which would

cause collapse if the patient stands up, e.g for toilet

purposes There is a compensatory sympathetic

discharge with tachycardia and tachyphylaxis to

the drug The action of nitroprusside is terminated

by metabolism within erythrocytes Specifically,

electron transfer from haemoglobin iron to

nitro-prusside yields methaemoglobin and an unstable

nitroprusside radical This breaks down, liberating

cyanide radicals capable of inhibiting cytochrome

oxidase (and thus cellular respiration) Fortunately

most of the cyanide remains bound within

erythro-cytes but a small fraction does diffuse out into the

plasma and is converted to thiocyanate Hence,

monitoring plasma thiocyanate concentrations during

prolonged (days) nitroprusside infusion is a useful

marker of impending systemic cyanide toxicity

Poisoning may be obvious as a progressive metabolic

acidosis or manifest as delirium or psychotic

symp-toms Toxic subjects are also reputed to emit the

characteristic bitter almond smell of hydrogen

cyanide Clearly nitroprusside infusion should not

be undertaken without meticulous regard for the

manufacturer's recommendations and precautions;

outside specialist units it may be safer overall to

choose another more familiar drug

Sodium nitroprusside is used in hypertensive emergencies, refractory heart failure and for con-trolled hypotension in surgery An infusion14 may begin at 0.3-1.0 micrograms/kg/min and control of blood pressure is likely to be established at 0.5-6.0 micrograms/kg/min; close monitoring of blood pressure is mandatory usually with direct arterial monitoring of blood pressure; rate changes of infu-sion may be made every 5-10 min

Diazoxide is chemically a thiazide but has no appreciable diuretic effect; indeed, like other potent arterial vasodilators it causes salt and water retention

It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f nicorandil and minoxidil), with little effect on veins The t1/2 is 36 h

The principal use of diazoxide has been in the emergency treatment of severe hypertension The maximum effect after an i.v bolus occurs within

5 min and lasts for at least 4 h The dangers from excessive hypotension are now recognised to out-weigh the benefit, and emergency use of diazoxide

is almost obsolete

Because it stimulates the same potassium channel in the pancreatic islet cells as is blocked by sulphonylureas, diazoxide causes hyperglycaemia This effect renders diazoxide unsuitable for chronic use in hypertension, but a useful drug to treat insulinoma Long-term oral administration causes the same problem of hair growth seen with minoxidil (see below and 'alopecia')

Hydralazine now has little use long-term for hyper-tension, but it may have a role as a vasodilator (plus nitrates) in heart failure It reduces peripheral

resistance by directly relaxing arterioles, with

negli-gible effect on veins In common with all potent arterial vasodilators, its hypotensive action is accompanied by a compensatory baroreceptor-mediated sympathetic discharge, causing tachycardia and increased cardiac output There is also renin release with secondary salt and water retention,

14 Light causes sodium nitroprusside in solution to decompose; hence solutions should be made fresh and immediately protected by an opaque cover, e.g metal foil The fresh solution has a faint brown colour; if the colour is strong it should be discarded.