The History and Developmental Advances of Beta Blockers - Essay Example

The history and developmental advances of beta blockers The animal and human bodies are governed by actions some of which are in the conscious control, known as voluntary actions, and some, which are not in conscious control and are influenced by endogenous biochemical and electric activities, known as the involuntary actions. The latter is a mystery which has been unraveled up to some extent and the research till date has suggested that the involuntary actions are under autonomic nervous control which has been broadly classified into the Sympathetic and the Parasympathetic nervous systems. The main neurotransmitter of the Sympathetic autonomic nervous system is Noradrenalin and drugs exerting Noradrenalin like actions are called sympathomimetic drugs. Drugs exerting antagonistic effects at sympathetic nerve endings are called sympatholytics. Similarly the neurotransmitter of the Parasympathetic system is Acetyl choline. Drugs accordingly are called parasympathomimetics/lytics. Both these neurotransmitters exert their specific action by interacting with target cells on specialized cellular sites called receptors. The original concept of receptor sites was introduced independently by Ehrlich and Langley as early as the late nineteenth century. It is now well established that receptors are part of macromolecular complexes on effector cells with which drug molecules interact to produce effects. Isolation and characterization of receptors has been done by radioligand binding studies. The receptors of the sympathetic system have been broadly classified into α and β receptors with further sub classifications. Similarly the receptors of the parasympathetic system have been broadly classified as muscarinic and nicotinic receptors. Medical interventions have been designed during the course of research in therapy whereby either mimicking or antagonizing the role of these neurotransmitters has been exploited for beneficial effects. β blockers are the drugs or molecules which block the action of Noradrenalin on the β receptors which has a very specific role to play in maintaining physiological equilibrium in the body. β receptors are present throughout specialized cells in the body and play important roles in physiological function. They are predominant in cardiac cells, small coronary vessels, smooth muscles like trachea, bronchi, blood vessels, intestines, vas deferens, liver, diaphragmatic striated muscles, uterus and non innervated tissues like erythrocytes, lymphocytes, mast cells and polymorphonuclear leucocytes. The type of β receptors in different organs are further subdivided into β1, β2 and β3 sub types. The therapeutic interventions are accordingly different in these subtypes of β receptors. Various drugs based on their property to alter activity of the neurotransmitter at β adrenergic receptors have been developed for a wide variety of conditions in cardiovascular, respiratory, ocular as well as other miscellaneous conditions. The first drug which had proven selective blockade of β adrenergic receptors was Dichloroisoproterenol (DCI). However it was not used for therapy in humans because it also had a prominent β receptor stimulant action i.e. it was a partial agonist. Propranolol was the first beta blocker to be used successfully in cardiovascular disease therapy as it had no intrinsic sympathomimmetic activity. Discovered by Sir James W. Black in the late 1950s it revolutionized therapy for angina and hypertension. It was however, a non selective beta blocker i.e. it blocked both β1 and β2 receptors. It lead to the development of more beta blockers which were selective and specific in action. A number of beta blockers were developed and newer agents are still coming up with advances in research. Classification of β blockers: Propranolol is a competitive β-adrenergic antagonist that is devoid of agonist activity, and it remains the prototype with which other β blockers are compared. However it exerts equal antagonistic activity on both β1 and β2 receptors. Hence it is non selective. Hence receptor selectivity is the criterion on the basis of which the β blockers are classified. 1. Non Selective β blockers: Propranolol, Nadolol, Timolol, Pindolol and Labetolol 2. β1 Selective blockers: Metoprolol, Atenolol, Esmolol and Acebutolol The therapeutic actions of beta blockers are used in a wide variety of situations. By blocking the action of the involuntary nervous system on the heart, beta blockers relieve stress on the heart. They slow the heart beat (negative chronotrophic effect), lessen the force (negative inotrophic effect) with which the heart muscle contracts and reduce blood vessel contraction in the heart, brain, and throughout the body. Beta blockers are used to treat abnormal heart rhythms (cardiac arrhythmias). They are used specifically to prevent abnormally fast heart rates (tachycardia) or irregular heart rhythms such as premature ventricular beats. Since beta blockers reduce the demand of the heart muscle for oxygen and the chest pain of angina pectoris occurs when the oxygen demand of the heart exceeds the supply, beta blockers can be useful in treating angina. They have also become an important drug in improving survival after a person has had a heart attack. Due to their effect on blood vessels, beta blockers can lower the blood pressure and be of value in the treatment of hypertension. Beta blockers reduce the pressure within the eye (the intraocular pressure), probably by reducing the production of the liquid (aqueous humor) within the eye, and so are used to lessen the risk of damage to the optic nerve and loss of vision in glaucoma. Other uses for beta blockers include the prevention of migraine headaches and stage fright (social phobia), and the treatment of certain types of tremors (familial or hereditary essential tremors). Pharmacological properties of β blockers β receptor blockade has little effect on the normal heart of an individual at rest but exerts a profound effect in an individual during exercise or stress when the autonomic sympathetic activity in the heart is at its peak level. The effects of beta blockers in different body systems are discussed below: 1. Cardiovascular System: Beta blockers slow the heart rate and decrease myocardial contractility. They attenuate the expected increase in heart rate during exercise and stress when the heart is under stimulation by sympathetic activity. Cardio selective beta blockers preferentially inhibit β1 receptors that are principally found in the myocardium. Non cardio selective beta blockers also inhibit β2 receptor sites, which are found in smooth muscle in the lungs, blood vessels, and other organs. Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting cardiac muscles. The heart has both b1 and b2 adrenoceptors, although the predominant receptor type in number and function is b1. Beta-blockers prevent norepinephrine or epinephrine from binding to the beta-adrenoceptor by competing for the binding site. Because there is generally some level of sympathetic tone on the heart, beta-blockers are able to reduce sympathetic influences that normally stimulate chronotropy (heart rate), inotropy (contractility), dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers cause decreases in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater effect when there is elevated sympathetic activity. Vascular smooth muscle has β2 adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors promote relaxation of the vascular smooth muscle which does not occur when beta blockers are administered. Compared to their effects in the heart, beta-blockers have relatively little vascular effect because β2 adrenoceptors have only a small modulator role on basal vascular tone. Nevertheless, blockade of β2 adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This occurs because beta-blockers remove a small β2 adrenoceptor vasodilator influence that is normally opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence. 2. Pulmonary System: Non selective β blockers like Propranolol block the β2 adrenergic receptors in bronchial smooth muscle. This has only a minor effect in the pulmonary function of a normal individual but in asthmatics and those suffering from chronic pulmonary obstructive disease this can lead to life threatening bronchoconstriction. Hence they are contraindicated for treatment of cardiovascular diseases in people having respiratory disorders. 3. Metabolic Effects: β adrenergic antagonists play a role in the modification of carbohydrate and lipid metabolism. Non selective β blockers may adversely affect recovery from hypoglycaemia in insulin dependent diabetics as the normal physiological role of Noradrenalin is to promote glycogenolysis and mobilization of glucose reserves in response to hypoglycaemia. However β blockade impairs insulin release very rarely and selective β1 blockers are preferred in diabetics for cardiovascular disorders. β adrenergic receptors activate hormone sensitive lipase in fat cells, leading to the release of free fatty acids into the circulation. This is an important energy source of the muscles when subjected to exercise. Blockade of these receptors with non selective beta blockers can attenuate the release of free fatty acids from the adipose tissue. Therapeutic use of Beta blockers: 1. Hypertension: β blockers are used in conjunction with other antihypertensive medications as a combination therapy. In general, beta blockers are not considered first-line therapy for high blood pressure, but may be added to an antihypertensive regimen, either as a stand-alone drug or in combination with other blood pressure lowering drugs. 2. Angina: Beta blockers are considered a first-line treatment for chronic stable angina, especially if the angina is induced by exercise. They reduce the heart’s demand for oxygen by negative chronotropic and inotropic effects. Beta blocker use can decrease the risk of repeat heart attacks and death, improve exercise tolerance in patients of angina and decrease the frequency of angina episodes. Among heart attack patients, beta blockers have been shown to decrease the oxygen demands of the heart muscle, decrease the risk of dangerous heart rhythms and improve the heart function. 3. Heart failure: Beta blockers are an effective treatment for heart failure and may significantly improve the survival rates. Better prognosis results in heart failure patients that are treated with beta blockers before, during and after hospitalization. 4. Arrhythmias & Palpitations: Beta blockers have been successfully used to prevent postoperative atrial fibrillation. 5. Pre medication: β blockers are used as premedication before coronary artery bypass surgery and other non-cardiac surgeries, particularly those involving a vascular procedure. Beta blockers, when used before and continued for at least one month after surgery, help prevent a heart attack following the operation. Beta blocker use before and after surgery has proved beneficial to those with known coronary artery disease. 6. Hypertrophic cardiomyopathy: A condition characterized by an abnormal growth of muscle fibers on the heart muscle. 7. Hyperthyroidism: Beta blockers have been found to relieve some symptoms associated with this condition. 8. Migraine: Beta blockers have been successfully used to prevent migraines. 9. Anxiety or tremors: They are sometimes beneficial in treating panic attacks during stage performance by musicians and orators. 10. Glaucoma: Local and systemic use of beta blockers for treating Glaucoma is beneficial. Potential side effects with β blockers: Allergic reaction Bradycardia (slowing of heart rate) Worsening of heart failure Drowsiness, weakness or fatigue Cold hands and feet, or an increased general sensitivity to cold Dizziness or lightheadedness, especially after getting up from a standing or lying position Headache or ringing in ears (tinnitus) Shortness of breath (dyspnoea) or wheezing Fainting (syncope) Vivid dreams, nightmares, depression, memory loss and (rarely) hallucinations Increase in cholesterol levels Increased insulin resistance Erectile dysfunction (impotence) Reduced sex drive in both men and women Abdominal cramps or (rarely) diarrhea, constipation and/or nausea Latest generation of beta-blockers The Propranolol molecule has been modified during the course of medical research to yield more cardio selective beta blockers with minimal side effects. Sustained release preparations have been made in order to reduce dose frequency. Some of the newer agents are mentioned below: Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Labetalol, Metoprolol tartrate, Metoprolol succinate(extended release), Nadolol, Penbutolol, Pindolol ,Nebivolol, Propranolol long-acting and Timolol By the time beta blockers became available, diuretics had already been shown to prevent cardiovascular events, primarily strokes. It was considered unethical to compare a beta blocker to placebo in patients who were likely to benefit from a diuretic. For this reason, most large, long-term trials of beta blocker therapy for hypertension use a comparison group taking a diuretic rather than a placebo. Unlike diuretics, then, beta blockers have not been clearly demonstrated to be more effective than placebo in reducing cardiovascular events when used as initial therapy in the general population of patients with hypertension. Beta blockers are equally efficacious in controlling blood pressure in patients with hypertension. No beta blocker has been demonstrated to be more efficacious or to result in better quality of life than other beta blockers, either as initial therapy or when added to a diuretic or ACE inhibitor. Evidence from long-term trials is mixed; overall, beta blockers are generally less effective than diuretics, and usually no better than placebo, in reducing cardiovascular events. β Blockers have generally demonstrated smaller cardiovascular effects, compared with other antihypertensive classes, despite similar reductions in blood pressure. This may be due to the ineffectiveness of traditional β-blockers in reducing central aortic pressure which is a strong, independent predictor of cardiovascular outcome. However some of the newer β-blockers, which have been developed so as to exert vasodilatation which is independent of β-blockade, provide beneficial effects in cases of arterial stiffness and endothelial dysfunction. This leads to reductions in central aortic pressure and improvements in prognosis. For example, the vasodilating β-blocker nebivolol was shown to improve forearm blood flow and arterial stiffness and, in a large clinical study, to significantly reduce morbidity and mortality among patients with chronic heart failure. Recommendations/Indications Table for β blocker usage Drug Hypertension Chronic Stable Angina Atrial Arrhythmias Migraine Heart failure Post Myocardial Infarction Acebutolol YES YES Atenolol YES YES YES Betaxolol YES Bisoprolol YES Carteolol YES Carvedilol YES YES Labetalol YES Metoprolol tartarate YES YES YES Metoprolol succinate (extended release) YES YES YES Nadolol YES YES Penbutolol YES Pindolol YES Propranolol YES YES YES YES Propranolol Long Acting YES YES YES YES Timolol YES YES YES Contraindications for Beta Blocker use: β blockers should be used with caution in the following conditions: Bradycardia: Beta blockers can further reduce the heart rates of these patients to dangerously low levels, increasing the risk of heart failure, angina and loss of consciousness. Heart block (partial or complete loss of electrical communication between the chambers of the heart). Asthma, emphysema or bronchitis. Beta blockers can cause constriction of bronchioles, possibly worsening these lung diseases. Chronic obstructive pulmonary disease: Beta blockers may aggravate this condition and should be avoided in patients with severe COPD. Among patients with mild to moderate disease, they should be used at low doses or possibly in combination with another medication. Peripheral vascular disease. Beta blockers may cause worsening of symptoms among patients with vascular disease, including cold extremities and, in some cases, tissue death and gangrene. Kidney or liver disease. These conditions may cause beta blockers to be removed from the body at a slower rate, increasing the risk of overdose and/or side effects. Diabetes. Beta blockers may mask the symptoms of hypoglycaemia and slow or impair the body’s recovery from an episode of insulin-induced hypoglycemia. Insulin resistance and metabolic syndrome, two known risk factors for heart attack. Beta blockers may increase blood glucose levels. In addition, beta blockers may make the following disorders worse: Raynaud syndrome: A painful condition caused by the temporary constriction of the small arteries in the hands and feet. Psoriasis: A chronic skin condition characterized by red patches with white scales. Clinical depression or a history of this condition. Myasthenia gravis: A progressive weakness of voluntary muscles Toxicity with β Blockers Therapeutic use of β blockers slows the heart rate and reduces myocardial contractility (negative inotropic action) leading to hypotension. Activation of presynaptic β2 adrenergic receptors increases Noradrenalin release in sympathetic nerve endings. Blockade of these receptors leads to reduced neurotransmitter release which causes more hypotension. β2 receptor blockade inhibits relaxation of smooth muscle in blood vessels, bronchi, the gastrointestinal system, and the genitourinary tract. In addition, beta-adrenergic receptor antagonism inhibits both glycogenolysis and gluconeogenesis, which may result in hypoglycaemia. The membrane stabilizing activity of some β-blockers may be important in overdose as they produce a quinidine-like effect on the action potential as a result of sodium channel blockade. This predisposes the patient to further ventricular arrhythmias. Coma and seizures may occur as a result of cellular hypoxia from poor cardiac output, a direct central nervous system effect caused by sodium channel blocking, or hypoglycaemia. Patients with underlying cardiovascular diseases and undergoing multi drug therapy are more vulnerable to β-blocker toxicity. REFERENCES: 1. Brodde Otto-Erich, β-1 and β-2 adrenoceptor polymorphisms: Functional importance, impact on cardiovascular diseases and drug responses1, Pharmacology & Therapeutics 117 (2008) 1–29 2. Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, Eighth Edition, Pergamon Press 3. http://www.webmd.com/heart-disease/default.htm 4. Jorde Ulrich P. et al, Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: Time to pace?, European Journal of Heart Failure 10 (2008) 96–101 5. Meharg Stephen S. , Help for the Anxious Performer Music Educators Journal, Vol. 75, No. 2. (Oct., 1988), pp. 34-37. 6. Pedersen Michala E. and Cockroft John R., The latest generation of beta-blockers: New pharmacologic properties, Journal Current Hypertension Reports, Publisher Current Medicine Group LLC Issue Volume 8, Number 4 / July, 2006 7. Slomka Jacquelyn, Playing with Propranolol The Hastings Center Report, Vol. 22, No. 4. (Jul. - Aug., 1992), pp. 13-17. 8. Toda Noboru, Vasodilating β-adrenoceptor blockers as cardiovascular therapeutics, Pharmacology & Therapeutics 100 (2003) 215– 234 9. ValeAllister, Director of the National Poisons Information Service, (Birmingham Unit) and the West Midlands: BETA BLOCKERS, MEDICINE 35:11 2007 Published by Elsevier Ltd. Read More