1. Almost 60 years ago, the compound dichloroisoproterenol hydrochloride was found to inhibit the activities of epinephrine and is considered as the first [beta]-blocker ([beta]-adrenergic-blocking agent). However, the availability of intravenous and oral formulations with proven efficacy in cardiovascular disease would not be realized for several more years.1[beta]-Blockers are now one of the most prescribed classes of drugs worldwide.
2. Old news is good news. The ability to modulate excessive catecholamine activity reaffirms the belief of the "ancients" who thought that the imbalance of body humors could cause disease whereas the correction of a humoral balance would restore health.
3. [beta]-Blockers are award-winning drugs. The 1998 Nobel Prize in medicine was awarded to Dr James W. Black, who is credited with the development of the prototype commercial [beta]-blocker, propranolol hydrochloride, in 1964.2 Propranolol hydrochloride was the first major pharmacological innovation in the treatment of angina since nitroglycerin 100 years earlier.
4. [beta]-Blockers now have applications that extend beyond cardiovascular uses, including reducing intraocular pressure in patients with open-angle glaucoma. When used for ophthalmic indications, [beta]-blocker solutions are some of the few topical ocular preparations that are frequently associated with systemic complications such as bradycardia. This happens when the drug is absorbed into the systemic circulation after channeling through the nasolacrimal duct into the nasal mucosa.
5. Take your pick. [beta]-Blockers have heterogeneous pharmacological effects. Some [beta]-blockers exhibit [beta]1 receptor selectivity and act predominately on the myocardium (metoprolol, atenolol). Others are nonselective and block both the [beta]1 receptors in the heart and [beta]2 receptors that are concentrated in the lungs (propranolol, nadolol). Still others block both [beta] and [alpha] receptors (carvedilol, labetalol). [alpha] Receptors are located in smooth muscle of the peripheral vasculature and bladder neck, among other places.
6. Any association with patients reporting feeling "spacey" on [beta]-blockers? Many landmark clinical trials of [beta]-blockers have acronyms that give reference to the cosmos. The GEMINI* trial compared outcomes for metoprolol tartrate and carvedilol in patients with diabetes, whereas COPERNICUS** and COMET*** evaluated the effects of [beta]-blockers in patients with heart failure.3-5
7. Some [beta]-blockers have intrinsic sympathomimetic activity, meaning these drugs may partially stimulate adrenergic receptors. Examples include pindolol and carteolol. Historically, these [beta]-blockers have been preferred in patients with asthma because they are considered less likely to provoke bronchospastic activity. The advent of [beta]1 selective or cardioselective [beta]-blockers, such as atenolol and metoprolol, has reduced this niche role for [beta]-blockers with intrinsic sympathomimetic activity.
8. Anxious before a presentation? You are not alone. Americans rank public speaking among their top fears. Propranolol and related compounds have been used to treat performance anxiety since the 1970s. In a double-blind crossover trial, James et al6 examined the effect of oxprenolol on stage fright in student string musicians; their musical performance, adjudicated by professional musicians, improved.
9. Lipophilic [beta]-blockers such propranolol and pindolol cross the blood-brain barrier and may be more likely to cause adverse effects associated with central nervous system adrenergic blockade, such as depression and sexual dysfunction.
10. Although there are few serious pharmacokinetic drug interactions with commonly used [beta]-blocking drugs, many drugs have pharmacodynamic interactions with [beta]-blockers, often resulting in bradycardia. Examples include other drugs with pharmacology that modulates the sympathetic nervous system (clonidine, methyldopa) and drugs associated with bradycardia via parasympathetic nervous system modulation (donepezil, methacholine) or other mechanisms (calcium channel blockers).
11. Although the pharmacodynamic interactions described earlier can create medication management challenges, [beta]-blockers can complement selected vasodilator therapies by blunting their associated reflex tachycardia baroreceptor response.
12. Although [beta]-blockers are no longer the drug of choice to treat hypertension, they are used to reduce portal hypertension in patients with liver cirrhosis and to aid in the management of delirium tremens.
13. Propranolol is the [beta]-blocker of choice to treat symptoms of hyperthyroidism. In addition to directly blocking the adrenergic stimulation associated with hyperthyroidism, propranolol prevents the conversion of T4 to T3 via inhibition of 5'-monodeiodinase.
14. Therapy for [beta]-blocker overdose includes not only obvious choices, such as atropine and epinephrine, but also disparate therapies ranging from glucagon to calcium to insulin.
15. The conventional wisdom on [beta]-blocker use in heart failure patients has evolved over the years. Until the early 1990s, [beta]-blockers were thought to be detrimental to patients with heart failure. As evidence accumulated, it became clear that the opposite was true, and today, [beta]-blockers are considered life-saving cornerstones of heart failure therapy for patients with a reduced ejection fraction.
16. Bet on it. The trifecta of adrenergic antagonism, the blockade of [beta]1, [beta]2, and [alpha]1 receptors, is the unique pharmacokinetic profile of carvedilol and labetalol. You can bet that these drugs cause vasodilation, but carvedilol also has antioxidant properties and promotes [beta]-arrestin activity. Recent evidence indicates that the [beta]-arrestin activation may be cardioprotective, based on its ability to mediate antiapoptotic signaling.7
17. One of the newest kids on the "block," nebivolol, adds a novel vasodilatory action on arteries and veins via potentiation of the nitric oxide pathway. The drug also has significant antioxidant effects.
18. The World Anti-Doping Agency publishes the list of prohibited substances in competitive sports. World Anti-Doping Agency has banned the use of [beta]-blockers in archery, automobile racing, billiards, darts, golf, ski jumping, and underwater sports.8
19. Effective enough to be banned in competition, [beta]-blockers remain as first-line treatment for essential tremors despite our poor understanding of the pathophysiological mechanism of tremor.
20. Optimizing [beta]-blocker therapy is complicated! Responses to these drugs are dose-related and may be influenced by genetic variation, drug metabolism, and the patient's underlying rhythm.
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