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1 See Table 22.1, page 449 regarding use of the term cardioselective. Note: hybrid agents having [5-receptor block plus vasodilatation unrelated to adrenoceptor have been developed, e.g. nebivolol releases nitric oxide.

2 ^-selective drugs are considered to be up to 300 times (nebivolol) as effective against ^-receptors than P2-receptors.What selectivity really means, however, is that 300 times more of the blocker is required to achieve the same blockade of the [^-receptor as of the f^-receptor. Therefore, as the dose (concentration at receptors) rises the benefit of selectivity is gradually lost.

3 Celiprolol and labetalol both have partial P2-selective agonist activity.

1 See Table 22.1, page 449 regarding use of the term cardioselective. Note: hybrid agents having [5-receptor block plus vasodilatation unrelated to adrenoceptor have been developed, e.g. nebivolol releases nitric oxide.

2 ^-selective drugs are considered to be up to 300 times (nebivolol) as effective against ^-receptors than P2-receptors.What selectivity really means, however, is that 300 times more of the blocker is required to achieve the same blockade of the [^-receptor as of the f^-receptor. Therefore, as the dose (concentration at receptors) rises the benefit of selectivity is gradually lost.

3 Celiprolol and labetalol both have partial P2-selective agonist activity.

effect. Both classes of drug can precipitate heart failure and indeed no important difference is to be expected since patients with heart failure already have high sympathetic drive (but note that P-blockade can be used to treat cardiac failure, p. 477, 517).

Abrupt withdrawal may be less likely to lead to a rebound effect if there is some partial agonist action, since there may be less up-regulation of receptors, such as occurs with prolonged receptor block.

Some p-blockers have membrane stabilising (quinidine-like or local anaesthetic) effect. This property is clinically insignificant except that agents having this effect will anaesthetise the eye (undesirable) if applied topically for glaucoma (timolol is used in the eye and does not have this action), and in overdose.

The ankle jerk relaxation time is prolonged by P2-adrenoceptor block, which may be misleading if the reflex is being relied on in diagnosis and management of hypothyroidism.

Pharmacokinetics

The plasma concentration of a P-adrenoceptor blocker may have a complex relationship with its effect, for several reasons. First-order kinetics usually apply to elimination of drug from plasma, but the decline in receptor block is zero-order. The practical application is important: within 4 h of giving propranolol 20 mg i.v. the plasma concentration falls by 50%, but the receptor block (as measured by exercise-induced tachycardia) falls by only 35%. The relationship between the concentration of the parent drug in plasma and its effect is further obscured if pharmacologically active metabolites are also present. Additionally, for some of the lipid-soluble p-blockers, especially timolol, plasma t% may not reflect the duration of P-blockade since the drug remains bound to the tissues near the receptor when the plasma concentration is negligible.

Most p-adrenoceptor blockers can be given orally once daily in either ordinary or sustained-release formulations because the t'/2 of pharmacodynamic effect exceeds the elimination t/2 of the parent substance in the blood.

Lipid-soluble agents are extensively metabolised (hydroxylated, conjugated) to water-soluble substances that can be eliminated by the kidney. Plasma concentrations of drugs subject to extensive hepatic first-pass metabolism vary greatly between subjects (up to 20-fold) because the process itself is dependent on two highly variable factors: speed of absorption and hepatic blood flow, with latter being the rate-limiting factor.

Lipid-soluble agents readily cross cell membranes and so have a high apparent volume of distribution. They also readily enter the central nervous system, e.g. propranolol reaches concentrations in the brain 20 times those of the water-soluble atenolol.

Water-soluble agents show more predictable plasma concentrations because they are less subject to liver metabolism, being excreted unchanged by the kidney; thus their half-lives are greatly prolonged in renal failure, e.g. atenolol is increased from 7 to 24 h. Patients with renal disease are best not given drugs (of any kind) having a long t'/2 and an action terminated by renal elimination. Water-soluble agents are less widely distributed and may have a lower incidence of effects attributed to penetration of the central nervous system, e.g. nightmares.

• The most lipid-soluble agents are propranolol, metoprolol, oxprenolol, labetalol

• The least lipid-soluble (water-soluble) agents are atenolol, sotalol, nadolol

• Others are intermediate.

Classification of (3-adrenoceptor blocking drugs

• Pharmacokinetic: lipid-soluble, water-soluble, see above.

• Pharmacodynamic (Table 23.1). The associated properties (partial agonist action and membrane stabilising action) have only minor clinical importance with current drugs at doses ordinarily used and may be insignificant in most cases. But it is desirable that they be known, for they can sometimes matter and they may foreshadow future developments.

P-adrenoceptor blockers18 not listed in Table 23.1 include:

18 More than 40 are available worldwide.

• nonselective carteolol, bufuralol

• (¡¡-receptor selective: betaxolol, esmolol (ultrashort acting: minutes)

Uses of ^-adrenoceptor blocking drugs

Cardiovascular uses Angina pectoris (P-blockade reduces cardiac work and oxygen consumption).

Hypertension (p-blockade reduces renin secretion and cardiac output): there is little interference with homeostatic reflexes.

Cardiac tachyarrhythmias: p-blockade reduces drive to cardiac pacemakers: subsidiary properties (see Table 24.1) may also be relevant.

Myocardial infarction and f¡-adrenoceptor blockers. There are two modes of use that reduce acute mortality and prevent recurrence: the so-called 'cardioprotective' effect.

• Early use within 6 hours (or at most 12 h) of onset (i.v. for 24 h then oral for 3-4 weeks). Benefit has been demonstrated only for atenolol. Cardiac work is reduced, resulting in a reduction in infarct size by up to 25% and protection against cardiac rupture. Surprisingly, tachyarrhythmias are not less frequent — perhaps because the cardiac P2-receptor is not blocked by atenolol. Maximum benefit is in the first 24-36 h but mortality remains lower for up to one year. Contraindications to early use include bradycardia (< 55/min), hypotension (systolic < 90 mmHg) and left ventricular failure. A patient already taking a p-blocker may be given additional doses.

• Late use for secondary prevention of another myocardial infarction. The drug is started between 4 days and 4 weeks after the onset of the infarct and is continued for at least 2 years.

• Choice of drug. The agent should be a pure antagonist, i.e. without ISA.

Aortic dissection and after subarachnoid haemorrhage: by reducing force and speed of systolic ejection (contractility) and blood pressure.

Obstruction of ventricular outflow where sympathetic activity occurs in the presence of anatomical abnormalities, e.g. Fallot's tetralogy (cyanotic attacks):

hypertrophic subaortic stenosis (angina); some cases of mitral valve disease.

Hepatic portal hypertension and oesophageal var-iceal bleeding: reduction of portal pressure (see p. 656).

Cardiac failure (See also chapter 25). There is now clear evidence from prospective trials that P-blockade is beneficial in terms of mortality for patients with all grades of moderate heart failure. Data support the use of both nonselective (carvedilol, a-blocker as well) and Pj-selective (metoprolol and bisoprolol) agents. The survival benefit exceeds that provided by ACE inhibitors over placebo. The negative inotropic effects can still be significant, so the starting dose is low (e.g. bisoprolol 1.25 mg p.o. or carvedilol 3.625 mg b.d.) and may be tolerated only with additional anti-failure therapy e.g. diuretic.

Endocrine uses Hyperthyroidism: P-blockade reduces unpleasant symptoms of sympathetic overactivity; there may also be an effect on metabolism of thyroxine (peripheral deiodination from T4 to T3. A nonselective agent (propranolol) is preferred to counteract both the cardiac (p: and P2) effects, and tremor (p2).

Phaeochromocytoma: blockade of P-agonist effects of circulating catecholamines always in combination with adequate a-adrenoceptor block. Only small doses of a P-blocker are required. Other uses

• Central nervous system

Anxiety with somatic symptoms (nonselective p-blockade may be more effective than fSj-selective).

Migraine prophylaxis.

Essential tremor, some cases.

Alcohol and opioid acute withdrawal symptoms.

Glaucoma: (carteolol, betaxolol, levobunolol and timolol eye drops) act by altering production and outflow of aqueous humour.

Adverse reactions due to ^-adrenoceptor blockade

Bronchoconstriction (P2-receptor) occurs as expected, especially in patients with asthma (in whom even eye drops can be fatal).19 In elderly chronic bronchitics there may be gradually increasing broncho-constriction over weeks (even with eye drops). Plainly risk is greater with nonselective agents, but p.-receptor selective members are not [3,-selective and may precipitate asthma.

Cardiac failure may arise if cardiac output is dependent on high sympathetic drive (but (3-blockade can be introduced at very low dose to treat cardiac failure (above). The degree of heart block may be made dangerously worse.

Incapacity for vigorous exercise due to failure of the cardiovascular system to respond to sympathetic drive.

Hypotension when the drug is given after myocardial infarction.

Hypertension may occur whenever blockade of P-receptors allows pre-existing a-effects to be unopposed, e.g. phaeochromocytoma.

Reduced peripheral blood flow, especially with nonselective members, leading to cold extremities which, rarely, can be severe enough to cause necrosis; intermittent claudication may be worsened.

Reduced blood flow to liver and kidneys, reducing metabolism and biliary elimination of drugs, is liable to be important if there is hepatic or renal disease.

Hypoglycaemia, especially with nonselective members, which block P2-receptors, and especially in diabetes and after substantial exercise, due to impairment of the normal sympathetic-mediated homeo-static mechanism for maintaining the blood glucose, i.e. recovery from iatrogenic hypoglycaemia is

19 A 36-year-old patient with asthma collected from a pharmacy, chlorphenamine for herself and oxprenolol for a friend. She took a tablet of oxprenolol by mistake. Wheezing began in one hour and worsened rapidly; she experienced a convulsion, respiratory arrest and ventricular fibrillation. She was treated with positive-pressure ventilation (for 11 h) and i.v. salbutamol, aminophylline and hydrocortisone. She survived (Williams I P et al 1980 Thorax 35:160). There is a logical — or rather pharmacological — link between the use of timolol as eye drops and the risk of asthma. For local administration, a drug needs high potency, meaning that half the maximal response is achieved with a physically small

(and therefore locally administrable) amount of drug. The principal determinant of potency of a receptor antagonist is its affinity for the receptor, which in turn reflects how long each molecule remains bound to the receptor — technically, the dissociation rate constant. This is why one drop of timolol down the lacrimal duct (of the wrong patient) can kill!

delayed. But since oc-adrenoceptors are not blocked, hypertension (which may be severe) can occur as the sympathetic system discharges in an 'attempt' to reverse the hypoglycaemia. In addition, the symptoms of hypoglycaemia, in so far as they are mediated by the sympathetic (anxiety, palpitations), will not occur (though cholinergic sweating will) and the patient may miss the warning symptoms of hypoglycaemia and slip into coma. Pj-selective drugs are preferred in diabetes.

Plasma lipoproteins: HDL-cholesterol falls and triglycerides rise during chronic P-blockade with nonselective agents, pj-selective agents have much less impact overall. Patients with hyperlipidaemia needing a P-blocker should generally receive a Pj-selective one.

Sexual function: interference is unusual and generally not supported in placebo-controlled trials.

Abrupt withdrawal of therapy can be dangerous in angina pectoris and after myocardial infarction and withdrawal should be gradual, e.g. reduce to a low dose and continue this for a few days. The existence and cause of a P-blocker withdrawal phenomenon is debated, but probably occurs due to up-regulation of P2-receptors. It is particularly inadvisable to initiate an a-blocker at the same time as withdrawing a p-blocker in patients with ischaemic heart disease, since the p-blocker causes reflex activation of the sympathetic system. The P-blocker withdrawal phenomenon appears to be least common with partial agonists and most common with Pj-selective antagonists. Rebound hypertension is insignificant.

Adverse reactions not certainly due to ^-adrenoceptor blockade

These include loss of general wellbeing, tired legs, fatigue, depression, sleep disturbances including insomnia, dreaming, feelings of weakness, gut upsets, rashes.

Oculomucocutaneous syndrome occurred with chronic use of practolol (now obsolete) and even occasionally after cessation of use.20 Other members either do not cause it, or so rarely do so that they are under suspicion only and, properly prescribed, the benefits of their use far outweigh such a very low risk. The mechanism of the syndrome is uncertain.

Overdose

Overdose, including self-poisoning, causes bradycardia, heart block, hypotension and low output cardiac failure that can proceed to cardiogenic shock; death is more likely with agents having membrane stabilising action (see Table 23.1). Bronchoconstriction can be severe, even fatal, in patients subject to any bronchospastic disease; loss of consciousness may occur with lipid-soluble agents that penetrate the central nervous system. Receptor blockade will outlast the persistence of the drug in the plasma. Rational treatment includes:

• Atropine (1-2 mg i.v. as 1 or 2 bolus doses) to eliminate the unopposed vagal activity that contributes to bradycardia. Most patients will also require direct cardiac pacing.

20 Practolol was developed to the highest current scientific standards; it was marketed (1970) as the first cardioselective p-blocker and only after independent review by the UK drug regulatory body. All seemed to go well for about 4 years (though skin rashes were observed) by which time there had accumulated about 200 000 patient years of experience with the drug, and then, wrote the then Research Director of the industrial developer, 'came a bolt from the blue and we learnt that it could produce in a small proportion of patients a most bizarre syndrome, which could embrace the skin, eyes, inner ear, and the peritoneal cavity' and also the lung (oculomucocutaneous syndrome). The cause is likely to be an immunological process to which a small minority of patients are prone, 'with present knowledge we cannot say it will not happen again with another drug'. That the drug caused this peculiar syndrome was recognised by an alert opthalmologist who ran a special clinic for external eye diseases. In 1974 he suddenly became aware that he was seeing patients complaining of dry eyes but with unusual features. Instead of the damage (blood vessel changes with metaplasia and keratinisation of the conjunctive) being on the front of the eye exposed by the open lids, it was initially in the areas behind and protected by the lids. He noted that these patients were all taking practolol. Quite soon the whole syndrome was defined, as above. Some patients became blind and some required surgery for the peritoneal disorder and a few died as a consequence.

The drug was first restricted to brief use by injection in emergency control of disorders of heart rhythm, but is now obsolete even for that.

The developers acknowledged moral (though not legal) liability for the harm done and paid compensation to affected patients. They were not negligent because current science did not provide a possibility of predicting the effect, i.e. 'state of the art defence' applied. The law did not provide for strict liability or no-fault compensation (see p. 10).

• Glucagon, which has cardiac inotropic and chronotropic actions independent of the P-adrenoceptor (dose 50-150 micrograms/kg in glucose 5% i.v., repeated if necessary) to be used at the outset in severe cases (an unlicenced indication).

• If there is no response, i.v. injection or infusion of a P-adrenoceptor agonist is used, e.g. isoprenaline (4 micrograms/min, increasing at 1-3-min intervals until the heart rate is

50-70 beats/min).

• In severe poisoning the dose may need to be high and prolonged to surmount the competitive block.21

• Other sympathomimetics may be used as judgement counsels, according to the desired receptor agonist actions (Pr P2, a) required by the clinical condition, e.g. dobutamine, dopamine, dopexamine, noradrenaline, adrenaline.

• For bronchoconstriction, salbutamol may be used; aminophylline has nonadrenergic cardiac inotropic and bronchodilator actions and should be given i.v. very slowly to avoid precipitating hypotension.

Treatment may be needed for days. With prompt treatment death is unusual.

Interactions

Pharmacokinetic. Agents metabolised in the liver provide higher plasma concentrations when another drug that inhibits hepatic metabolism, e.g. cimetidine, is added. Enzyme inducers enhance the metabolism of this class of p-blockers. P-adrenoceptor blockers themselves reduce hepatic blood flow (fall in cardiac output) and reduce the metabolism of blockers and other drugs whose metabolic elimination is dependent on the rate of delivery to the liver, e.g. lignocaine (lidocaine), chlorpromazine.

Pharmacodynamic. The effect on the blood pressure of sympathomimetics having both a- and p~ receptor agonist actions is increased by block of p

21 For example, 115 mg of isoprenaline i.v. were infused over 65 h to treat one case. Lagerfelt J et al 1976 Acta Medica Scandinavica 199: 517.

receptors leaving the a-receptor vasoconstriction unopposed (adrenaline added to local anaesthetics may cause hypertension); the pressor effect of abrupt clonidine withdrawal is enhanced, probably by this action. Other cardiac antiarrhythmic drugs are potentiated, e.g. hypotension, bradycardia, heart block. Combination with verapamil (i.v.) is hazardous in the presence of atrioventricular nodal or left ventricular dysfunction because the latter has stronger negative inotropic and chronotropic effects than do other calcium channel blockers.

Most NSAIDs attenuate the antihypertensive effect of p-b lockers (but not perhaps of atenolol), presumably due to inhibition of formation of renal vasodilator prostaglandins, leading to sodium retention.

P-adrenoceptor blockers potentiate the effect of other antihypertensive particularly when an increase in heart rate is part of the homeostatic response (Ca-chartnel blockers and a-adrenoceptor blockers).

Non-selective p-receptor blockers potentiate hypoglycemia of insulin and sulphonylureas.

Pregnancy

P-adrenoceptor blocking agents are used in hypertension of pregnancy, including pre-eclampsia. Both lipid- and water-soluble members enter the fetus and may cause neonatal bradycardia and hypo-glycaemia. They are not teratogenic in pregnancy.

Notes on some individual ^-adrenoceptor blockers

(For general pharmacokinetics, see p. 476)

Propranolol is available in standard (b.d. or t.i.d.) and sustained-release (once daily) formulations. When given i.v. (1 mg/min over 1 min, repeated every 2 min up to 10 mg) for cardiac arrhythmia or thyrotoxicosis it should be preceded by atropine (1-2 mg i.v.) to prevent excessive bradycardia; hypotension may occur.

Atenolol has a prp2 selectivity of 1:15. It is widely used for angina pectoris and hypertension, in a dose of 25-100 mg orally once a day. The tendency in the past has been to use higher than necessary doses. When introduced, atenolol was considered not to need dose-ranging, unlike propranolol, but this was in part because the initial dose was already at the top of the dose-response curve. Some 90% of absorbed drug is excreted by the kidney and the dose should be reduced when renal function is impaired, e.g. to 50 mg/day when the glomerular filtration rate is 15-35 ml/min. The X.% is 7 h.

Bisoprolol is more pt-selective than atenolol (ratio 1:50). Although a relatively lipid-soluble agent, its tl/2 is one of the longest (11 h), and there is not the wide range of dose-requirement seen with propranolol. As with atenolol, it is worth starting at a low dose (5 mg), to avoid causing unnecessary tiredness, and especially when trying to obtain the maximum benefit of its selectivity. There is no need to alter doses when renal or hepatic function is reduced.

Nebivolol resembles bisoprolol in terms of lipo-philicity and t/ (10 h) but is more fl -selective (ratio 1:300). Its unique feature is a direct vasodilator action (due to the d-isomer of the racemate, the 1-isomer being the p}-antagonist). The mechanism appears to be through direct activation of nitric oxide production by vascular endothelium.

Combined (3,- and a-adrenoceptor blocking drug

Labetalol is a racemic mixture, one isomer is a P-adrenoceptor blocker (nonselective), another blocks a-adrenoceptors; its dual effect on blood vessels minimises the vasoconstriction characteristic of nonselective P-blockade so that for practical purposes the outcome is similar to using a p,-selective P-blocker (see Table 23.1). It is less effective than drugs like atenolol or bisoprolol for the routine treatment of hypertension, but is useful for some specific indications.

The P-blockade is 4-10 times greater than the ablockade, varying with dose and route of administration. Labetalol is useful as a parenterally administered drug in the emergency reduction of blood pressure. Ordinary p-blockers may lower blood pressure too slowly, in part because reflex stimulation of unblocked a-receptors opposes the fall in blood pressure. In most patients, even those with severe hypertension, a gradual reduction in blood pressure is desirable to avoid the risk of cerebral or renal hypoperfusion, but in the presence of a great vessel dissection or of fits a more rapid effect is required (below).

Postural hypotension (characteristic of cx-receptor blockade) is liable to occur at the outset of therapy and if the dose is increased too rapidly. But with chronic therapy when the (J-receptor component is largely responsible for the antihypertensive effect, it is not a problem.

Labetalol reduces the hypertensive response to orgasm in women.

The il/2 is 4 h; it is extensively metabolised in the hepatic first-pass. The drug needs to be taken thrice daily in a dose of 100-400 mg t.d.s.

For emergency control of severe hypertension the most convenient regime is to initiate infusion at 1 mg/min, and titrate upwards at half-hourly intervals as required. The infusion is stopped as blood pressure control is achieved, and re-initiated as frequently as required until regular oral therapy has been successfully introduced.

Serotonin (5-HT) receptor + a-adrenoceptor blocking drugs

Ketanserin appears to act principally to block serotonin vasoconstrictor (subtype 5-HT2) receptors but also has significant a-adrenoceptor blocking activity (its affinity ratio for the two receptors is 1:5). The latter explains its hypotensive action and use in Raynaud's disease. It is not available in many countries and offers no advantages over pure a-blockers such as doxazosin.

Serotonin (5-hydroxytryptamine, 5-HT) is syn-thesised in enterochromaffin cells, largely in the gut, and also extensively taken up into blood platelets from which it is released to have vascular effects. It has complex effects on the cardiovascular system, varying with the vascular bed and its physiological state; it generally constricts arterioles and veins and induces blood platelet aggregation; it stimulates intestinal and bronchial smooth muscle. Carcinoid tumours secrete serotonin and symptoms may be benefited by serotonin antagonists, e.g. cyproheptadine, methysergide and sometimes by octreotide (see Index). It is a neurotransmitter in the brain.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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