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BE BETA A BL BLOCKE CKERS
- Antagonize beta-1 receptors on the heart
- Affects HR, BP, LVEF
- Clinical response: cardioprotection from MI, death, or heart failure
- Pharmacogenetic Implications
- CYP2D6 (PK)
- ADRB1, ADRB2, and GRK5 (PD)
- Metoprolol and CYP2D6
- Most common variant *4 results in absence of activity
- *4 carriers have higher exposure to metoprolol → beta blockade
- Bisoprolol, Atenolol and carvedilol do not require CYP2D6 for
metabolism
Voora D, Ginsburg G. Clinical Application of Cardiovascular Pharmacogenetics. Am Coll Cardiol. 2012;60(1):9-20. doi:10.1016/j.jacc.2012.01.067
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DPWG GUIDELINES FOR METOPROLOL AND CYP2D6
Phenotype (Genotype) Therapeutic Dose Recommendation Clinical Relevance PM (2 inactive alleles) Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 75%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol). Long-standing discomfort (48-168 hr)F. ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness) IM (2 decreased activity alleles, or 1 active and 1 inactive allele, or 1 decreased activity and 1 inactive allele) Heart failure: select alternative drug (e.g., bisoprolol, carvedilol) or reduce dose by 50%. Other indications: be alert to ADEs (e.g., bradycardia, cold extremities) or select alternative drug (e.g., atenolol, bisoprolol). Short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia UM (gene duplication in absence of inactive
alleles) Heart failure or other indications: select alternative drug (e.g., bisoprolol, carvedilol) or titrate dose to a maximum of 250% of the normal dose. Long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism
Adapted from Table: DPWG Guideline for Metoprolol and CYP2D6. [Internet]. Accessed on 6/15/2016. Available at https://www.pharmgkb.org/chemical/PA450480#tabview=tab0&subtab=31
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