Assessment of systemic effects of different ophthalmic beta-blockers in healthy volunteers.

Systemic beta-blockade after single doses of ophthalmic beta-blockers (one drop in each eye) was investigated in healthy volunteers in two randomized, double-blind, crossover, placebo-controlled studies. beta-Blockade was evaluated by displacement of the bronchodilator (specific airway conductance), positive chronotropic (heart rate), and tremorogenic (finger tremor amplitude) dose-response curve for inhaled isoproterenol. In study 1, 0.5% betaxolol, 0.6% metipranolol, and 0.5% timolol were tested in 16 subjects. Compared with placebo, all beta-blockers resulted in a significant systemic beta-blockade (p greater than 0.05); the increasing order of potency was betaxolol, metipranolol, and timolol. In study 2, 2% butylamino-phenoxy-propanol-acetate (BPPA; a noncardioselective but topically oculoselective drug) and 1% timolol were investigated in 12 subjects. Placebo and BPPA showed no differences (p greater than 0.05), whereas timolol resulted in a significant beta-blockade (p less than 0.05). Topical oculoselectivity is an important aspect of drug safety of beta-blocking eyedrops. Measure of tremor is appropriate to evaluate beta 2-blockade.     

Systemic effects of topical ophthalmic medications

Ophthalmic drugs topically applied have significant systemic absorption, which may result in widespread adverse side effects. All physicians involved in the care of patients receiving these drugs should be cognizant of such actions, interactions, and toxic effects. They should also be familiar with the prevention, diagnosis, and treatment of these effects, as well as the mechanisms of systemic drug absorption.     

The use of beta-blockers to decrease adverse perioperative cardiac events.

As the population ages, more surgeries are performed on patients with increased risk factors. Many of these surgeries will result in complications and mortality. Myocardial ischemia is often associated with cardiac complications in the perioperative patient. Unfortunately, an episode of myocardial ischemia will result in a 70% mortality rate. Perioperative patients are complex because of their atypical presentation, incisional pain, and the effects of analgesia. The critical care nurse must be able to determine a patient's risk factors and surgical risks and then take measures to ensure that the patient receives adequate treatment both before and after surgery. beta-Blockers may decrease a patient's risk of developing myocardial ischemia, yet they are often underused. A multidisciplinary approach is needed to ensure the proper use of beta-blockers in an effort to reduce cardiac complications in the perioperative elderly patient.     

Titration of beta-blockers in heart failure. How to maximize benefit while minimizing adverse events

Data from large clinical trials indicate that beta-blocker therapy can be successfully initiated and adjusted upward in most patients with stable chronic heart failure who already take standard heart failure therapy. Such therapy typically includes ACE inhibitors, diuretics, and digoxin. With optimal titration and maintenance strategies, beta-blockers are effective and well tolerated in these patients. It is recommened that all patients with clinically stable mild to moderate chronic heart failure (NYHA class II or III), no contraindications to beta-blocker use, and an LVEF less than 40% should be treated with beta-blockers. Based on the results of recent clinical trials on heart failure, beta-blocker therapy should be initiated at a low dose and slowly tirtrated upward as tolerated. A patient's heart failure should be stable for at least 2 weeks before the dose is adjusted upward. Slow titration facilitates maximal tolerability. In primary care practice, physicians should apply titration strategies and target dosed that have been demonstrated to reduce morbidity and mortality in clinical trials. Although worsening heart failure or other adverse events occur in a minority of patients who take beta-blockers, these effects can be managed by adjusting the dose of ACE inhibitor or diuretic, or both, or by temporarily withholding the beta-clocker. Currently, professional treatment guidelines recommend beta-blocker therapy in combination with ACE inhibitors an diuretics as the standard of care in the treatment of heart failure.     

Diazepam prevents some adverse effects of succinylcholine.

Neuromuscular, circulatory, and adverse effects of intravenous succinylcholine (SCh), mg/kg, were compared in 3 groups of 40 patients each. Group I served as control; group II received diazepam, 0.05 mg/kg, 5 min before SCh; and group III was given d-tubocurarine (d-Tc), 0.05 mg/kg, for pretreatment. Diazepam pretreatment prevented muscle fasciculations, increases in serum potassium (K+) and creatinine phosphokinase (CPK) levels, increased heart rate and arterial pressure, and postoperative myalgia associated with SCh administration. The neuromuscular blocking action of SCh was not affected. Pretreatment with d-Tc did not abolish increases in serum K+ and CPK levels, was associated with a higher incidence of postoperative myalgia, and decreased the onset and magnitude of SCh-induced muscle paralysis. Our data demonstrate that diazepam, a predominant centrally acting muscle relaxant, is more effective than d-Tc in preventing the adverse effects of SCh, a peripherally acting muscle relaxant.     

A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.     

Cardiac effects of beta-adrenergic receptor antagonists: beta-moderators versus beta-blockers

Two adrenergic receptor antagonists, acebutolol and propranolol, were observed to depress rabbit heart contractile force and adrenaline-stimulated adenylate cyclase activity at 1 X 10-(5) to 1 X 10-(3) M and 1 X 10-(6) to 1 X 10-(3) M concentrations, respectively. Acebutolol depressed sarcoplasmic reticular and mitochondrial calcium uptake at 5 X 10-(3) to 10-(2) M concentrations. On the other hand, propranolol was found to decrease calcium uptake activities of sarcoplasmic reticular and mitochondrial fractions at 1 X 10-(4) to 1 X 10-(2) M and 1 X 10-(3) to 1 X 10-(2) M concentrations, respectively. On the basis of these results with calcium transport systems, it is proposed that beta-antagonists with a mild depressant effect, such as acebutolol, may be called beta-moderators, whereas those with a strong effect, such as propranolol, may be called beta-blockers.     

New anticonvulsants--new adverse effects

Ongoing refinements in pharmacology continue to provide new medications for the treatment of seizure disorders and other neurologic conditions. The authors present the cases of two children who developed relatively uncommon adverse effects to new anticonvulsant medications, including metabolic acidosis with topiramate and hyponatremia with oxcarbazepine. In one of our two patients, intraoperative acidosis related to topiramate was noted. Appropriate investigation with documentation of normal serum lactate resulted in the exclusion of other potentially serious causes of acidosis and in the identification of topiramate as the causative agent. In our second patient, hyponatremia and status epilepticus resulted from therapy with oxcarbazepine. Prompt recognition of hyponatremia, fluid restriction, and cessation of oxcarbazepine therapy resulted in prompt correction of the hyponatremia. We review previous reports of these adverse effects with topiramate and oxcarbazepine, describe the pathophysiology of these metabolic alterations, provide treatment strategies, and make suggestions for monitoring patients during therapy with these anticonvulsant medications.     

Psychiatric adverse effects of corticosteroids

Psychiatric adverse effects during systemic corticosteroid therapy are common. Two large meta-analyses found that severe reactions occurred in nearly 6% of patients, and mild to moderate reactions occurred in about 28%. Although disturbances of mood, cognition, sleep, and behavior as well as frank delirium or even psychosis are possible, the most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Conversely, long-term therapy tends to induce depressive symptoms. Dosage is directly related to the incidence of adverse effects but is not related to the timing, severity, or duration of these effects. Neither the presence nor the absence of previous reactions predicts adverse responses to subsequent courses of corticosteroids. Corticosteroid-induced symptoms frequently present early in a treatment cycle and typically resolve with dosage reduction or discontinuation of corticosterolds. In severe cases or situations in which the dose cannot be reduced, antipsychotics or mood stabilizers may be required. This review offers an approach to identifying and managing corticosteroid-induced psychiatric syndromes based on the type of symptoms and anticipated duration of corticosteroid treatment.     

Hematologic adverse effects of clopidogrel

Clopidogrel is used as a frontline antiplatelet agent in patients with coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Hematologic complications and bleeding have been the most feared outcome of antithrombotic and antiplatelet agents. Among the thienopyridines, clopidogrel is considered to be a safer alternative to ticlopidine due to its decreased incidence of hematologic adverse effects. Although thrombotic thrombocytopenia purpura is the most reported hematologic adverse effect of clopidogrel; neutropenia, acquired hemophilia, isolated thrombocytopenia or idiopathic immune thrombocytopenia, and thrombotic thrombocytopenia purpura with hemolytic uremic syndrome are other rare yet recognized hematologic adverse effects of clopidogrel. Patients treated with clopidogrel should be carefully monitored for hematologic adverse effects especially in the first 2 to 3 months after initiation of therapy. Early recognition and prompt initiation of treatment can be life saving in patients who have hematologic adverse effects to clopidogrel. We have drafted this review by performing literature search using Medline, Pubmed, and EMBASE search engine with relevant search words for all reported hematologic adverse effects and manifestations of clopidogrel and their management.     

Management of adverse drug effects

Adverse drug reactions (ADRs) are still considered one of the main problems of drug therapy. ADRs are associated with considerable morbidity, mortality, decreased compliance and therapeutic success as well as high direct and indirect medical costs. Several considerations have to come into play when managing a potential ADR. It is critical to establish an accurate clinical diagnosis of the adverse event. Combining information about drug exposure together with considering other possible causes of the reaction is crucial to establish a causal relationship between the reaction and the suspected drug. Identification of the underlying pathogenesis of an ADR together with the severity of the reaction will have profound implications on continuation of drug therapy after an ADR. Since spontaneous reports about ADRs are a key stone of a functioning post-marketing surveillance system and therefore play a key role in improving drug safety, health care professionals are highly encouraged to report ADRs to a local or national organization. However, because the majority of ADRs is dose-dependent and therefore preventable, individualization of pharmacotherapy may have a major impact on reducing such events.     

The adverse health effects of tobacco and tobacco-related products.

Tobacco use continues to occur in epidemic proportions and with it, significant morbidity and mortality. One third of smokers will die prematurely of a smoking-related disease. This article reviews the adverse health effects of tobacco use so that clinicians can be aware of the benefits patients will reap when they stop using this lethal substance.