CARVEDILOL

Carvedilol is a nonselective beta blocker/alpha-1 blocker indicated in the treatment of mild to severe congestive heart failure (CHF). It is marketed under various trade names including Carvil (Zydus Cadila), Coreg (GSK), Dilatrend (Roche), Eucardic (Roche), and Carloc (Cipla) as a generic drug (as of September 5, 2007 in the U.S.), and as a controlled-release formulation, marketed in the US as Coreg CR (GSK). Carvedilol was discovered by Robert R. Ruffolo, Jr. It has had a significant role in the treatment of congestive heart failure.

(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine


USE AND DOSE

Carvedilol is indicated in the management of congestive heart failure (CHF), as an adjunct to conventional treatments (ACE inhibitors and diuretics). The use of carvedilol has been shown to provide additional morbidity and mortality benefits in severe CHF. Carvedilol (Carvil) is available at the following doses 3.125 mg (smallest), followed by 6.25 mg,12.5 mg, and 25 mg white tablets.

Hypertension  -  Oral
Adult: Initially, 12.5 mg once daily increased to 25 mg once daily after 2 days. Alternatively, initial dose of 6.25 mg bid increased to 12.5 mg bid after 1-2 wk, increased further if necessary to 50 mg once daily or in divided doses.
Elderly: 12.5 mg once daily.

Angina pectoris  -  Oral
Adult: Initially, 12.5 mg bid increased to 25 mg bid after 2 days.

Heart failure  -  Oral
Adult: Initially, 3.125 mg bid, doubled to 6.25 mg bid after 2 wk if tolerated, then gradually increased to the max dose the patient can tolerate at intervals of not <2 dose:="" max="" wk.="">85 kg: 50 mg bid; <85 25="" bid.="" kg:="" mg="" p="">
Left ventricular dysfunction post myocardial infarction  - Oral
Adult: Initially: 6.25 mg bid, if tolerated, after 3-10 days, increase to 12.5 mg bid and then to a target dose of 25 mg bid.


PHARMACOLOGY

Carvedilol is both a beta blocker (β1, β2) and alpha blocker (α1):
Norepinephrine stimulates the nerves that control the muscles of the heart by binding to the β1- and β2-adrenergic receptors. Carvedilol blocks the binding to those receptors, which both slows the heart rhythm and reduces the force of the heart's pumping. This lowers blood pressure thus reducing the workload of the heart, which is particularly beneficial in heart failure patients.
Norepinephrine also binds to the α1-adrenergic receptors on blood vessels, causing them to constrict and raise blood pressure. Carvedilol blocks this binding to the α1-adrenergic receptors too, which also lowers blood pressure.
Relative to other beta blockers, carvedilol has minimal inverse agonist activity. This suggests that carvedilol has a reduced negative chronotropic and inotropic effect compared to other beta blockers, which may decrease its potential to worsen symptoms of heart failure. However, to date this theoretical benefit has not been established in clinical trials, and the current version of the ACC/AHA guidelines on congestive heart failure management does not give preference to carvedilol over other beta-blockers.
Carvedilol does also act as FIASMA (functional inhibitor of acid sphingomyelinase).

SIDE EFFECTS - The most common side effects include dizziness, fatigue, hypotension, diarrhea, asthenia, bradycardia, and weight gain

DRUG INTERACTIONS

Epinephrine WITH  carvedilol
Beta-blockers like carvedilol may reduce the effects of epinephrine. If you have been using carvedilol, you may not respond as well to epinephrine when it is given to treat an emergency such as shock or a severe allergic reaction. In addition, the combination may cause severe high blood pressure and reduced heart rate. Your healthcare provider should always be told if you are receiving, or have recently received, beta-blocker therapy. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Albuterol WITH carvedilol
Talk to your doctor before using carvedilol if you are also receiving treatment with albuterol. Carvedilol can sometimes cause severe narrowing of the airways and worsen your breathing problems. Carvedilol is normally not recommended if you have asthma, a history of asthma, or severe chronic obstructive pulmonary disease (COPD). Let your doctor know if you experience wheezing, shortness of breath, chest tightness, or other breathing difficulties if you do use these medications together. Your doctor or pharmacist may be able to suggest alternatives that do not interact. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Methyldopa WITH carvedilol
Ask your doctor before using carvedilol together with methyldopa. This can cause lead to a serious increase in your blood pressure. Call your doctor if you experience nausea, vomiting, sweating, flushing, stiff neck, headache, or heart palpitations. If you take both medications together, tell your doctor if you have any of these symptoms. You may need a dose adjustment or need your blood pressure checked more often if you take both medications. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Aminophylline WITH carvedilol
Ask your doctor before using carvedilol together with aminophylline. Using these medications together can make carvedilol less effective and increase the effects of aminophylline. Contact your doctor if you experience nausea, vomiting, insomnia, tremors, restlessness, uneven heartbeats, or difficulty breathing. If your doctor does prescribe these medications together, you may need a dose adjustment or special test to safely use both medications. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

GENERALLY AVOID: The pharmacologic effects of theophyllines and beta-blockers are opposite. Nonselective and high doses of cardioselective beta-blockers may cause severe or fatal bronchospasm by opposing theophylline-induced bronchodilation. Ophthalmic beta-blockers undergo significant systemic absorption and may also interact. In addition, propranolol and other beta-blockers may reduce the CYP450 hepatic metabolism of theophylline, and serum theophylline levels may be increased.
MANAGEMENT: Oral and ophthalmic nonselective beta-blockers (e.g., carteolol, carvedilol, levobunolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol) are considered contraindicated in patients with bronchospastic diseases. Cardioselective beta-blockers should generally be avoided, or used with extreme caution if no other alternatives are available and the benefits outweigh the risks of potentially severe bronchospasm. If patients do receive this combination, they should be closely monitored for increased serum theophylline levels but decreased bronchodilatory effectiveness.


Terbutaline WITH carvedilol
Talk to your doctor before using carvedilol if you are also receiving treatment with terbutaline. Carvedilol can sometimes cause severe narrowing of the airways and worsen your breathing problems. Carvedilol is normally not recommended if you have asthma, a history of asthma, or severe chronic obstructive pulmonary disease (COPD). Let your doctor know if you experience wheezing, shortness of breath, chest tightness, or other breathing difficulties if you do use these medications together. Your doctor or pharmacist may be able to suggest alternatives that do not interact. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

GENERALLY AVOID: Beta-blockers may antagonize the effects of beta-2 adrenergic bronchodilators and precipitate acute, life-threatening bronchospasm in patients asthma or other obstructive airway diseases. The mechanism involves increased airway resistance and reduced bronchodilation due to blockade of beta-2 adrenergic receptors. The interaction may also occur with ophthalmically applied beta-blockers, which are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Due to opposing effects on beta-2 adrenergic receptors, propranolol has been used in the treatment of salbutamol overdose.

MANAGEMENT: The use of beta-2 adrenergic bronchodilators in combination with beta-blockers, including ophthalmic formulations, should generally be avoided. If concomitant use is required, a cardioselective beta-blocker (e.g., acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nebivolol) is usually preferred. Nevertheless, caution is advised and respiratory status should be closely monitored, as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. In general, nonselective beta-blockers are considered contraindicated in patients with obstructive airways disease.