Beta blockers are generally well tolerated and most adverse effects are mild and transient. Reactions may be more severe after intravenous than oral doses; ocular use has also been associated with systemic adverse effects. The most frequent and serious adverse effects are related to their beta-adrenergic blocking activity. Among the most serious adverse effects are heart failure, heart block, and bronchospasm. Troublesome subjected effects include fatigue and coldness of the extremities; when beta-blockers are used for long-term treatment of asymptomatic diseases such as hypertension, such effects may be an important determinant of patient compliance. Cardiovascular effects include bradycardia and hypotension; heart failure or heart block may be precipitated or worsened in patients with underlying cardiac disorders. Abrupt withdrawal of beta blockers may exacerbate angina and may lead to sudden death.