ATENOLOL

• Action to be taken:No action needed
• Rationale: Tenormin undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Therefore its not anticipated that Atenolol will interact with cannabis.

CARVEDILOL

• Cytochrome P450 enzyme substrate: CYP2D6, CYP1A2, CYP2C9, CYP3A4, CYP2E1, CYP2C19
• Action to be taken: Caution and close monitoring for cardiac effects (blood pressure and heart rate)
• Rationale: The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolized by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolised by CYP2C9 and to a lesser extend by CYP2D6. Other CYP450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. In vitro studies show that cannabis is also metabolized by CYP450 enzymes. The major pathway of metabolism is governed by CYP3A4, CYP219 and CYP29. Furthermore, cannabis has also shown to be a weak inhibitor of CYP 450 enzymes. Therefore based on available data cannabis and carvedilol may compete for CYP450 enzymes, thus impact each others metabolism.
  

METOPROLOL

• Cytochrome P450 enzyme substrate: CYP2D6
• Action to be taken: Caution and close monitoring for cardiac effects (blood pressure and heart rate)
• Rationale: Co-administration of metoprolol, a primary substrate of CYP2D6, and SSRIs that are CYP2D6 may result in significantly increased metoprolol serum concentrations.19,84 An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. Fluvoxamine also increased the clinical effects (e.g. , orthostatic hypotension) of metoprolol due to inhibition of metoprolol metabolism. Paroxetine (CYP2D6 inhibitor) increased metoprolol peak plasma concentrations and half-life by about 2-fold; this interaction was associated with prolonged beta-blockade. Both citalopram and escitalopram mildly inhibit the hepatic CYP2D6 isoenzyme. This can result in increased concentrations of drugs metabolized via the same pathway, including propranolol. While data are unavailable for escitalopram, concomitant administration of citalopram and metoprolol resulted in a two-fold increase in the plasma concentrations of metoprolol. The co-administration of metoprolol and citalopram did not produce any clinically significant effects on blood pressure or heart rate. Increased serum levels of the beta-blockers could result in alterations in cardioselectivity or other clinical effects.

NADOLOL

• Action to be taken: No action needed
• Rationale: Nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys. Therefore its not anticipated that Nadolol will interact with cannabis.

PROPRANOLOL

• Cytochrome P450 enzyme substrate: CYP2D6, CYP1A2, and CYP2C19
• Action to be taken: Caution and monitor
• Rationale: Reduced clearance and increased serum concentrations of propranolol have been reported during concurrent use of cimetidine. Cimetidine is a CYP2D6 inhibitor while propranolol is a CYP2D6 substrate.Fluvoxamine can also inhibit cytochrome P450 isoenzymes and has been shown to interfere with propranolol clearance. However clinical symptoms of excessive beta-blocker effects were not seen.

 TIMOLOL 

• Cytochrome P450 enzyme substrate: CYP2D6
• Action to be taken: Caution and monitor for side effects
• Rationale: Timolol is a substrate of CYP2D6. Theoretically the metabolism of timolol may be affected by drugs that are inhibitors of CYP2D6. Co-administration should be done cautiously; patients should be monitored for adverse effects associated with timolol.

 

References

1. Tenormin(atenolol) package insert. AstraZeneca Pharmaceuticals LP Wilmington, DE 2011
   
2. Coreg (carvedilol) package insert.  GlaxoSmithKline Research Triangle Park, NC 2011
   
3. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
   
4. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
5. Cimetidine tablets package insert. Sellersville, PA:Teva Pharmaceuticals USA Inc.;2010 Oct.
   
6. Inderal LA (propranol sustained-release) capsules. Philadelphia, PA: Akrimax Pharmaceuticals. 2012 Jun.
   
7. Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P4501A2. Clin Pharmacokinet1995;29: Suppl 1:20—5.
8. Blocadren® (timolol maleate) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2002 Mar.
9. Toprol-XL (metoprolol succinate) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2007 Jul.
10. Luvox (fluvoxamine) package insert. Baudette, MN: ANI Pharmaceuticals, Inc.; 2014 Jul.
11. Hemeryck A, Lefebvre RA, De Vriendt C, et al. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther. 2000;67:283—91.
12. Celexa® (citalopram) package insert. St. Louis, MO; Forest Pharmaceuticals, Inc.; 2004 Jan.
13. Corgard(nadolol) package insert. King Pharmaceuticals, Inc., Bristol, TN 2007
14. Zisaki A, Miskovic L, Hatzimanikatis V. Antihypertensive Drugs Metabolism: An Update to Pharmacokinetic Profiles and Computational Approaches. Current Pharmaceutical Design. 2015;21(6):806-822. doi:10.2174/1381612820666141024151119.