A history of glaucoma pharmacology.

The history of glaucoma pharmacology begins in 1862 with the isolation of physostigmine from the calabar bean. The discovery of epinephrine's intraocular pressure lowering capacity came along some 40 years later. During the 20th century, drug discovery and development accelerated, with the introduction of carbonic anhydrase inhibitors, beta blockers, and prostaglandin analogs. This survey of the history of glaucoma medications reviews some of the pivotal stories behind the development of the drugs that we use daily to manage our patients with glaucoma. In addition, some unmet needs that persist in glaucoma pharmacology are discussed.

Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

The low-affinity site of the beta1-adrenoceptor and its relevance to cardiovascular pharmacology.

beta-Adrenoceptor blocking agents (beta-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant beta-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (beta(1H)AR), but cause cardiostimulation mainly through a low-affinity site (beta(1L)AR) of the myocardial beta(1)-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca(2+) current density and Ca(2+) transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca(2+) transients and arrhythmic cardiocyte contractions. Other beta-blockers, which do not cause cardiostimulation, consistently have lower affinity for beta(1L)AR than beta(1H)AR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant beta(1)-adrenoceptors and on beta(1)-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of beta(1H)AR but left intact the pharmacology of beta(1L)AR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

beta-Adrenergic blockers: a 50-year historical perspective.

The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs over the past 50 years represent one of the major advances in human pharmacotherapy. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment of so many cardiovascular and noncardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of disease, and on the molecular level, both the structure and the function of the 7 transmembrane G protein receptors, which mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1-selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. Indeed, the beta-adrenergic blockers have provided us with a great clinical legacy for now and in years to come.

Beta-adrenergic blocking agents: past, present, and future perspectives.

The 'proof of concept' of beta-blockade for heart failure (i.e. that the pharmacologic actions of beta-blockers are beneficial) is now firmly established, as the treatment of heart failure has progressed from using positive inotropic stimulation, via drugs with no direct effect on cardiac function, to beta-blockers with negative intropic effects. This review addresses some remaining issues regarding beta-blockade in heart failure. The mechanism of action of beta-blockers in heart failure is more likely to be improved intrinsic cardiac myocyte function and prevention or reversal of remodeling, than restoration of beta-adrenergic signal transduction. The role of the differentiating characteristics of beta-blockers is not clear at this time, and there is no compelling evidence to select one agent over another on the basis of individual drug properties. Recent reports suggest that beta-blockers reduce the combined risk of all-cause mortality and hospitalizations by about 30-35%. These results are heavily influenced by experience with carvedilol, but other agents tested include metoprolol, bucindolol, bisoprolol, and nebivolol. Responsiveness to beta-blockers is not related to patients' age, sex, or race, or to the etiology or severity of heart failure. Beta-blockers are currently recommended as adjunctive treatment in patients who remain mildly to moderately symptomatic while receiving added digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Existing gaps in our knowledge must be filled in order to achieve optimal clinical application of beta-blockers. Ongoing studies will provide much of the information required. The role of beta-blockers will probably expand as we improve our understanding of the pathophysiology of heart failure, and especially of the remodeling process.

Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology.

The history of cardiology encompasses some of the most revered names in medical history, many belonging to physicians who have advanced knowledge beyond their time. However, there have been countless others whose work in the basic sciences has paid large dividends to clinical cardiology. The original example of such an individual is William Harvey, whose reasoned experimentation led to the understanding of the circulation of blood. Another such man, Sir James Black, has contributed to basic scientific and clinical knowledge in cardiology, both as a physician and as a basic scientist. His invention of propranolol, the beta adrenergic receptor antagonist that revolutionized the medical management of angina pectoris, is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century. His method of research, his discoveries about adrenergic pharmacology, and his clarification of the mechanisms of cardiac action are all strengths of his work. In 1988, he was awarded the Nobel Prize in Medicine. Sir James's conclusions and method of research have continued to influence work in clinical pharmacology and cardiovascular medicine. Thus, the development of propranolol runs parallel to most other great achievements in medicine: the genius of a few builds on the accomplishments of many, and the discovery influences thinking long after the breakthrough has occurred.

Beta-blockage therapy and cardiovascular disease. Past, present, and future.

The concept of two patterns of catecholamine activity was first described at the turn of the century by Langely and Dale. In the late 1940s, Ahlquist conceptualized the alpha- and beta-blocking actions of catecholamines. Sir James Black's research in the 1950s led to the introduction of pronethalol and then of propranolol into the therapeutics of angina and arrhythmias. Early beta-receptor blocking compounds were noted not only to be competitive inhibitors of the beta receptor but to have a direct depressant, membrane-stabilizing action. Later compounds, such as pindolol, were noted to have partial agonist activity. Practolol, metoprolol, atenolol, and similar "cardioselective", or beta-selective, drugs were subsequently described. Agents that combine beta blockade with alpha blockade or vasodilator action have been developed recently. There are various therapeutically advantageous pharmacodynamic differences among the beta-blocking drugs, such as less effect of beta 1-selective drugs on bronchial smooth muscle. Lipid solubility, systemic bioavailability, first-pass liver metabolism, renal excretion, and brain penetration are pharmacokinetic properties that further distinguish one agent from another. After the initial predicted therapeutic uses, beta-blocking drugs were used in hypertension and subsequently have been applied in a wide range of cardiovascular conditions. Recent work clearly demonstrating a cardioprotective effect in the post-myocardial infarction period is a major reason that use of the agents is likely to remain high.

The Long Way to a Successful Medical Therapy of Heart Failure with Beta-blockers in Children with Heart Disease.

Heart failure remains the main cause of death in children with heart disease. In USA and Europe hospital mortality of children with heart failure is about 7% of children, nearly twice as high as in adults. In this review a group of authors report about their experience with beta-blockers in childhood heart failure. Most of them start to treat children with severe heart failure at a time - 20 years ago - when beta blockers seem to be contraindicated in this situation. The physicians and their patients and/or parents all are aware of the risk of this decision. However, unproven medical therapies for heart failure are the most important therapeutical dilemma in pediatric cardiology. The authors carefully observed a highly selected group of patients with the highest risk to die and had the patience to wait for the longtime follow up. Today - based upon this experience -we know that beta blockers are safe and may save the lives of many children with heart disease all over the world. Together with young colleagues who enthusiastically support this idea the authors now intend to break down the "wall of ignorance" for this promising therapy in pediatric cardiology.

The major impacts of James Black's drug discoveries on medicine and pharmacology.

James Black has many claims to pharmacological fame as the creator of two new classes of drugs (beta-blockers and H2 antihistamines) and as a tireless innovator in drug discovery strategies and analytical procedures. The latter attributes in particular assisted Black in the invention of the prototypes for the two major classes of drugs for which he is best known, propranolol and cimetidine. The clinical impact of these drugs on both morbidity and mortality has been profound. In addition, the application of his analytical approach to drug discovery and pharmacology led others in the field to create many other new classes of drugs. Shortly before he died in 2010, Black wrote a retrospective review of his research career that provides insight into his innovative thinking and career success. This overview affords readers a very personal picture of the man, his ideas and his contributions.