Adrenergic beta-antagonist

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Beta-blockers timeline.

Adrenergic beta-receptor blockaders (beta-blockers) are "drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety".[1]

Beta-blockers vary within the class regarding their properties. Beta-blockers that have low intrinsic sympathomimetic activity (ISA), low membrane stabilizing activity, high beta 1-selectivity, and high lipophilicity may be more effective.[2]

Classification

Generically available beta-blockers, which subclassify based on selective aspects of their action, include: include:[3][4][5]

They further divide by frequency of dosing, cost, and other factors.

Selectivity Agents Applications
Nonselective propranolol, timolol, nadolol, pindolol, penbutolol, carteolol migraine (propranolol)
Cardioselective/beta 1-selectivity Atenolol, Metoprolol, Bisoprolol, Metoprolol, Acebutolol, Betaxolol myocardial infarction (metoprolol), heart failure (Carvedilol)
Intrinsic sympathomimetic activity Acebutolol, Pindolol, Penbutolol row 2, cell 3
Beta-blockers with alpha blocking activity Carvedilol, Labetalol Heart failure (Carvedilol)


Cardioselective/beta 1-selectivity

Even among drugs selective for the beta-1 adrenergic receptor, drugs vary in their selectivity.[6] Adrenergic beta-antagonists that are selective for the beta-1 adrenergic receptor may be better for patients at risk of stroke.[7]

Generic beta-blockers with selectivity for the beta-1 adrenergic receptor:[4][8]

Non-generic:

  • Betaxolol

Non-selective

Non-selective drugs include propranolol, timolol, nadolol, pindolol, penbutolol, and carteolol.

Intrinsic sympathomimetic activity

Generic beta-blockers with intrinsic sympathomimetic activity (less resting bradycardia and lipid changes):[4]

  • Acebutolol
  • Pindolol

Non-generic:

  • Penbutolol

Beta-blockers with alpha blocking activity

Generic beta-blockers with alpha blocking activity (more orthostatic hypotension):[4]

History

Propranolol was developed by James Black who later received the Nobel Prize for this and other work.[11]

Mechanism of action

Beta-blockers may have reduced effect due to inability to lower central blood pressure as well as other antihypertensives.[12]

Pharmacogenetics

The pharmacogenetics of beta-blockers have been reviewed.[13]

G-protein-coupled receptor kinase

Regarding the treatment of heart failure, there is conflicting evidence whether beta-blockers are as effective in African-American patients as in Anglo patients.[14] This may be due to a polymorphism in African-American patients of the G-protein-coupled receptor kinase (GRK5) that confers a natural "genetic beta-blockade".[15][16]

G protein–coupled cell surface receptor kinase 2 (GRK2) genetic polymorphisms may also affect the response to adrenergic beta-antagonists.[17]

Adrenergic receptor

Genetic polymorphisms of beta-1 (ADRB1) may affect the response to adrenergic beta-antagonist treatment of heart failure.[18]

Single-nucleotide polymorphism of the beta-1 (ADRB1) adrenergic receptor, specifically c.389A>G, may increase cardiac ischemia and SNP of the beta-2 (ADRB2) adrenergic receptor, specifically, c.16G>A SNP of the 4 SNPs studied, may increase hypotension in perioperative care.[19]

Single-nucleotide polymorphism of the beta-2 (ADRB2) adrenergic receptor, specifically c.46G>A and c.79C>G of the four SNPs studied, may affect the response to adrenergic beta-antagonist treatment of acute coronary syndrome.[20]

Genetic polymorphisms of alpha-2C (ADRA2C) may affect the response to adrenergic beta-antagonist treatment of heart failure.[21]

Cytochrome P-450

Beta-blockers such as metoprolol that are metabolized by cytochrome P-450 CYP2D6 allele and may have more drug interactions[22] and inherited variations in metabolism.[23]

Although poor metabolism due to CYP2D6 polymorphisms may be present in patients with drug toxicity due to metoprolol[24], small studies suggest that careful, slow titration [25][26] and avoidance of other drugs metabolized by CYP2D6[27] may avoid drug toxicity from polymorphisms of cytochrome P-450.

Dosage

In the 1980s, beta-blockers were thought to be effective if given once daily.[28][29][30] However, in the 1990s[31] and even the 1980s[32] recognition occurred that beta-blockers varied on their duration of action.

Costs of selected beta-blockers from DrugStore.com
  Cost
Atenolol 100 mg - 90 tablets $34.97
Bisoprolol 10 mg - 90 tablets $94.05
Metoprolol succinate 200 mg - 90 tablets $204.58
Metoprolol tartrate 100 mg - 180 tablets $25.97

Clinical uses

The effect of adrenergic beta-antagonists on heart rate may be more predictive than the amount of drug in predicting the drug's benefit[33] or harm[34]. This may be due to invidual molecular variations in adrenergic receptors, G-protein-coupled receptor kinases, and metabolism by cytochrome P-450.

The individual beta-blockers have been compared in the treatment of various diseases.[35]

Coronary heart disease

Selected studies of early adrenergic beta-antagonists for reducing hospital mortality after acute myocardial infarction.[36][37][38][39]
Study Patients Intervention Authors' conclusions Notes
Brandler[36]
Meta-analysis of randomized controlled trials
2010
72,249 patients in 18 trials
(Includes 45,852 patients from the COMMIT trial[37])
Various "This systematic review failed to demonstrate a convincing in-hospital mortality benefit for using beta-blockers early in the course of patients with an acute or suspected MI."
COMMIT (Chen)[37]
Randomized controlled trial
2000
45,852 patients Metoprolol 5-15 mg IV immediately then 50 mg orally every 6 hr for 2 days, then 200 mg controlled release orally once a day for 28 days "The use of early beta-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission." Cardiogenic shock increased 3.9% to 5%.
Stroke increased from 1% to 1.1% (no statistical significance)
Freemantle[38]
Meta-analysis of randomized controlled trials
2000
29,260 patients in 51 trials
(Does not include the COMMIT trial)
Various "...4% reduction in the odds of death in short term trials (-8% to 15%)."
ISIS-1[39]
Randomized controlled trial
2000
45,852 patients Atenolol 5-10 mg IV immediately, followed by 100 mg/day (either 50 mg twice a day or 100 mg once a day) orally for 7 days "...highly significant (2p less than 0.0002) evidence of an effect on the combined end-point of death, arrest, or reinfarction, suggesting that treatment of about 200 patients would lead to the avoidance of 1 reinfarction, 1 arrest, and 1 death during days 0-7." Use of inotropes increased from 3.3% to 5%
Strokes not recorded.
For more information, see: Coronary heart disease.


Adrenergic beta-antagonists were first shown to be effective in 1981.[40]

Adrenergic beta-antagonists do not definitely reduce short term mortality while in the hospital (see evidence table), but may improve long germ mortality.[36][38]. Metoprolol may[2] or may not[38] be the best beta-blocker for secondary prevention of myocardial infarctions according to meta-analyses of randomized controlled trials.

Cohort studies suggest that atenolol may[41] or may not[42] be better than other adrenergic beta-antagonists.

Heart failure

For more information, see: Heart failure.


Beta-blockers were originally thought to be contraindicated in patients with heart failure. However, trials eventually showed benefit of the drugs.Metoprolol can benefit patients with heart failure.[43][44]

Two cohort studies suggest that atenolol and carvedilol may be more effect than metoprolol for the treatment of heart failure.[45][46]

Drugs with intrinsic sympathomimetic activity may have less benefit[38] A systematic review of randomized controlled trials concluded "metoprolol, carvedilol, and bisoprolol all exhibited statistically significant mortality rate reductions compared with placebo, the data were inconclusive for nebivolol or atenolol" and "for every heart rate reduction of 5 beats/min with β-blocker treatment, a commensurate 18% reduction in the risk for death occurred."[33]

Hypertension

For more information, see: Hypertension.

Beta-blockers may[47] or may not[48] be a good first choice medication in treating hypertension - at least for patients without coronary heart disease. A meta-analysis[34] and accompanying editorial[49] have concluded that the more the drug lowers the heart rate, the lower the benefit of the drug. The harm may be confined to elderly patients.[50] Alternatively, or in addition:

  • beta-blockers may not lower the central aortic pressure as much other anti-hypertensive agents despite similar effects on the brachial systolic pressure.[51]
  • beta-blocker trials suffer from not doing beta-blockers often enough. Most trials in the meta-analysis used atenolol once per day. Only in the INVEST trial, atenolol was dosed twice a day if needed and in this trial atenolol was as effective as a calcium channel blocker.[52]

Additional physiologic problems with beta-blockers are:[53]

  • decrease heart rate which increases stroke volume and increases pulse pressure
  • decrease heart rate allow for more prolonged diastolic perfusion of the coronary arteries

Beta-blockers may be less effective than diuretics in the treatment of elderly patients with hypertension due to reduced ability to prevent coronary heart disease.[54]

Contraindications

Cocaine abuse is thought to be a contraindication, but the association between beta-blockers and adverse events among cocaine users is not certain.[55]

References

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