Category:Betablockers

From Ganfyd

Introduction

Beta adrenergic receptor antagonists (beta-blockers) are an extremely useful class of drugs, widely used to treat hypertension, ischaemic heart disease and heart failure.

History

Propranolol, the first clinical beta blocker was discovered and characterised by Sir James Black^[1] and marketed by ICI (Imperial Chemical Industries) whose descendant drug marketing arm merged to become one of the components of Astra-Zeneca. Sir James Black received the Nobel Prize in Physiology or Medicine for this work in 1988. This is not surprising, considering that until propranolol the only treatment for angina was nitrates. GTN is still used today and it is an interesting historical footnote that the fortune built up from making GTN a safe explosive helped reward a successor inventor whose compound actually improves mortality rather than just morbidity.

Raymond Ahquist first had the idea of separate alpha and beta adrenergic receptors in 1948, but he had considerable trouble getting this theory accepted initially. His concept finally hit the world in 1954 when he was able to expound it in a chapter of Drill's Pharmacology in Medicine textbook.

James Black, at that time a Clinical Pharmacologist read this while preparing a medical student lecture and instead of just accepting the observation made the step to realising its pharmacological potential. In 1958, he approached ICI with his ideas into investigations into ways of reducing myocardial oxygen demand and was offered a job. His ideas were contrary to the prevailing thought of the time which held that nitrates seemed to work by vasodilation which increased oxygen supply to the heart. Indeed this thought had led to the development of dipyridamole which is actually used now in chemical cardiac stress studies !

Sir James' approach was based on myocardial oxygen consumption being a function of pulse rate and blood pressure, with the goal of lowering pulse rate without lowering blood pressure and so worsening myocardial ischaemia. In collaboration with John Stephenson, a medical chemist also at ICI, he started synthesising and testing compounds. This was considerably helped by reports of the properties of dichloroisoprenaline by two Eli Lilly scientists in 1958. The compound ICI 38,174 (pronethalol, nethialide) was synthesised and proved to be much more specific than the partial agonist properties of dichloroisoprenaline. However ICI 38,174 induced tumours in mice and an analogue, ICI 45,520, soon replaced it and was in due course launched to the world in 1964 as Inderal.

Propranolol was subsequently shown to reduce, over 3 years, the mortality from myocardial infarction by a factor of 4. However, it should not be assumed that all betablockers have this effect or even that the evidence base for benefit as as good as for say many ACE inhibitors. Interestingly non-smokers may benefit more from beta-blockers than smokers.

Perhaps the most interesting historical footnotes are that the FDA did not approve propranolol until 1973, so creating an immense natural experiment and that propranolol and its methodology of discovery and exploitation was to be the model for pharmaceutical industry drug development for the next 40 years. Sir James Black used similar methodology with his later discovery of cimetidine the first clinical H2-receptor antagonist.

Clinical Use

Indications

• Angina (most)shown to be likely to be beneficial
• Secondary prevention of ischaemic cardiac events shown to be beneficial
• Hypertension (most) shown to be likely to be beneficial There is level 1a evidence that they are second line in context of a relatively weak effect in reducing stroke and the absence of an effect on coronary heart disease where 75% of randomised controlled trial evidence base is with atenolol ^[2].
• Myocardial infarction (most, but particularly atenolol and metoprolol for early mortality and acebutolol, metoprolol - particularly as sustained released), propranolol and timolol. Use bisoprolol and carvedilol where there is heart failure ! ) as shown to be beneficial
• Heart failure (some - bisoprolol and carvedilol) shown to be beneficial
• Glaucoma -(Timolol, betahexolol,carteolol,levobunolol,metipranolol has unknown effectiveness
• Thyrotoxicosis - use propranolol
• Migraine(some - lipid soluble such as propranolol) has unknown effectiveness
• Essential Tremor(some - lipid soluble such as propranolol)shown to be likely to be beneficial
• Anti-arrhythmics
  • Atrial fibrillation - many would consider now as first choice for rate control rather than digoxin, amiodarone or verapamil which are often selected before for non-evidence based reasons
    • Acute AF - Timolol shown to be likely to be beneficial
  • supra-ventricular arrythmias
    • Esmolol iv
    • Sotalol oral (Also in ventricular tachycardia) but note potential for mortality increase in context ischaemic heart disease)
• Perioperative for cardioprotection is of unknown effectiveness. While there is weak evidence for bisoprolol started at least a week before surgery (some of this work may result from scientific misconduct), modified release metoprolol is likely to be ineffective or harmful when given to non-cardiac surgical patients as it decreased myocardial infarction while increasing mortality (from infections), strokes, hypotension and significant bradycardia. ^[3]

Clinical Differences

There are extremely important clinical differences between the beta blockers which led to delay in recognising their potential in treating heart failure for over 30 years and leads to much relatively ineffective and illogical prescribing of say water soluble Atenolol to treat essential tremor, use of short acting drugs when long acting drugs are safer in established therapy (eg in peri-operative situations). These differences will continue to be controversial, but clinicians will often find colleagues using a popular drug such as Atenolol to treat vaso-vagal syncope when it has been proved not to work. A drug with marked intrinisic sympathomimetic activity (ISA) such as pindolol may be more logical in baroreceptor syncope (it does seem to work, but with no clinical trial evidence). Cardioselective beta blockers such as atenolol, bisoprolol, metoprolol, nebivolol have been claimed to be less likely to induce bronchospasm but in real life this is only likely to be relevance in treating patients with COPD, not asthma. Indeed ocular beta-blockers such as timolol are often a cause of respiratory symptoms in the elderly.

Clinical Issues

Other drugs may achieve some of their benefit by their beta blocker properties. An example is amiodarone. Unopposed beta blockers should not be used when phaeochromocytoma is suspected although the combined alpha and beta blocker, labetalol has been shown to be safe in this situation.

Toxicity

The most important toxicity issues relate to blockage of beta receptors in the lungs and induction of symptomatic bradycardias

Group Contra-indications

• Asthma
  • However there is active research studying the issue of whether chronic administration of certain betablockers might not decrease airways hyperreactivity and inflammation^[5]. Nadolol may be safe in mild asthma^[6].
• Second or third degree heart block
• Unstable heart failure

Group Cautions and Interactions

• Verapamil combination is particularly negatively inotropic
• Care in heart failure. Select a proven drug and titrate up slowly to the effective proven dose.
• COPD but the drugs may be tolerated with prolongation of life !
• Smoking tends in those on non-selective β1 blockers to cause hypertension through increases in adrenaline secretion. Drugs such as bisoprolol might be better choices in smokers.

Group Side effects

• Bronchospasm
• Bradycardias including induction of complete heart block
• Hypotension
• Blunting insulin responsiveness
• Aggravation of psoriasis

Any doctor who uses only one betablocker is failing to apply evidence based medicine to their patients.

Pharmacology

References