Cardiovascular Drug-Drug Interactions

Anderson, Joe R.; Nawarskas, James J.

doi:10.1016/s0733-8651(05)70209-5

Cited by 31 publications

(9 citation statements)

References 157 publications

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“…Both ␣ 2A AR and ␤ 1 AR are abundantly expressed in the brain, and heterodimerization of these two receptors might therefore underlie previously reported functional cross-talk between endogenous ␣ 2 -and ␤-adrenergic receptors in brain tissue (2)(3)(4)(5)(6)(7)(8). Therapeutic drugs acting on ␣ 2 ARs (such as clonidine) and ␤-adrenergic receptors (such as propranolol and metoprolol) are commonly utilized in the treatment of hypertension and are known to exhibit significant clinical interactions (48,49). The heterodimerization of ␣ 2A AR and ␤ 1 AR described here may help to provide new insights into both physiological cross-talk between ␣ 2 -and ␤-adrenergic receptors and clinical interactions between therapeutic drugs acting on these receptor subtypes.…”

Section: Discussionmentioning

confidence: 99%

Heterodimerization of α2A- and β1-Adrenergic Receptors

Castleberry

et al. 2003

Journal of Biological Chemistry

113

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The physiological actions of epinephrine and norepinephrine are mediated via the activation of the following three distinct classes of G protein-coupled receptors (GPCR) 1 : ␣ 1 -, ␣ 2 -, and ␤-adrenergic receptors. Each class of adrenergic receptor (AR) is comprised of three closely related subtypes as follows: ␣ 1A -, ␣ 1B -, and ␣ 1D AR, which couple primarily to G q to stimulate phospholipase activity; ␣ 2A -, ␣ 2B -, and ␣ 2C AR, which couple primarily to G i to inhibit adenylyl cyclase activity; and ␤ 1 -, ␤ 2 -, and ␤ 3 AR, which couple primarily to G s to stimulate adenylyl cyclase activity (1). The adrenergic receptor subtypes are differentially distributed across various tissues, and tissue responses to epinephrine and norepinephrine are believed to be dependent upon the relative ratios of the various adrenergic receptors they express.Because ␤-and ␣ 2 -adrenergic receptors couple to G proteins with opposing actions on adenylyl cyclase activity, the two receptors might be expected to purely antagonize each other's signaling when they are co-stimulated in the same cell. However, it has been shown that ␣ 2 AR co-stimulation can in some cases paradoxically sensitize ␤-adrenergic signaling in brain tissue (2-4). Moreover, the pharmacological properties of ␤ARs in brain tissue are known to be regulated by ␣ 2 ARs (5, 6), and reciprocally the pharmacological properties of ␣ 2 ARs in brain tissue are known to regulated by ␤ARs (7,8). These examples of cross-talk and mutual regulation between ␤-and ␣ 2 -adrenergic receptors have been well known for more than 20 years, but the underlying molecular mechanisms remain unclear.GPCRs have traditionally been thought to exist as monomers, but recent studies (9) have revealed that they can exist in the plasma membrane as both homodimers and heterodimers. At present, a key question in this field is: how widespread is the phenomenon of receptor heterodimerization? The most clearcut case of the importance of GPCR heterodimerization comes from the GABA B receptor, a pharmacologically defined entity that is now known to be comprised of two distinct GPCRs, GABA B R1 and GABA B R2 (10). Because GABA B R1 and GAB-A B R2 are not functional when expressed by themselves, they represent a clear example of the physiological importance of receptor heterodimerization. Although other heptahelical receptors may not absolutely require heterodimerization to be functional in the same way that the GABA B receptor does, heterodimerization of other receptors may underlie some phenomena that are major question marks in our present understanding of neurotransmitter and hormone receptors, such as unexplained forms of cross-talk between different receptor subtypes.We wondered if the previously reported cross-talk between ␤ARs and ␣ 2 ARs in brain tissue might be due in part to a physical association between these two receptor types. Many early studies (11-13) of GPCR dimerization focused on the ␤ 2 AR. We have found recently (14) that the ␤ 1 AR also exhibits robust homodimerization in cells. Fu...

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Section: Discussionmentioning

confidence: 99%

Heterodimerization of α2A- and β1-Adrenergic Receptors

Castleberry

et al. 2003

Journal of Biological Chemistry

113

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“…Furthermore, rhabdomyolysis has been observed when simvastatin was combined with erythromycin or ritonavir (Williams and Feely 2002). Symptomatic hypotension may occur when mechanism-based CYP3A4 inhibitors are combined with some dihydropyridine calcium antagonists (Anderson and Nawarskas 2001), as well as with the phosphodiesterase inhibitor, sildenafil (Simonsen 2002). In addition, ataxia can occur when carbamazepine is coadministered with mechanism-based CYP3A4 inhibitors such as macrolide antibiotics, isoniazid, verapamil, or diltiazem (Spina et al 1996; Patsalos et al 2002).…”

Section: Clinical Outcomes Of Mechanism-based Inhibition Of Cyp3a4mentioning

confidence: 99%

Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4

Zhou¹,

Chan²,

Li³

et al. 2005

tcrm

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Abstract:Mechanism-based inhibition of cytochrome P450 (CYP) 3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The inactivation of CYP3A4 by drugs has important clinical significance as it metabolizes approximately 60% of therapeutic drugs, and its inhibition frequently causes unfavorable drug-drug interactions and toxicity. The clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs, and patients. Clinical professionals should adopt proper approaches when using drugs that are mechanism-based CYP3A4 inhibitors. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (eg, safe drug combination regimen, dose adjustment, or discontinuation of therapy when toxic drug interactions occur), therapeutic drug monitoring, and predicting the risks for potential drug-drug interactions. A good understanding of CYP3A4 inactivation and proper clinical management are needed by clinical professionals when these drugs are used.

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Section: Case Study 1: Statinsmentioning

confidence: 99%

“…36 Noncardioselective beta-blockers and cardioselective beta-blockers in larger doses can antagonize the effects of ␤-agonists and lead to bronchoconstriction. 36 ␤-blockers in combination with amiodarone (Cordarone), diltiazem, digoxin, and verapamil can have increased effects on heart rate and possibly lead to significant bradycardia. 36 Probably one of the most common and often unrecognized drug interactions in clinical practice is that between nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensives.…”

Section: Case Study 1: Statinsmentioning

confidence: 99%

“…36 ␤-blockers in combination with amiodarone (Cordarone), diltiazem, digoxin, and verapamil can have increased effects on heart rate and possibly lead to significant bradycardia. 36 Probably one of the most common and often unrecognized drug interactions in clinical practice is that between nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensives. The NSAIDs ibuprofen (Motrin) and naproxen (Naprosyn) are available by prescription as well as overthe-counter.…”

Section: Case Study 1: Statinsmentioning

confidence: 99%

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Common Drug Pathways and Interactions

Kroner¹

2002

Diabetes Spectrum

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In Brief This article focuses on common prescription drug interactions in the treatment of diabetes, dyslipidemia, hypertension, and erectile dysfunction. Mechanisms of the drug interactions and recommendations for clinical practice are highlighted. Because of concerns about potentially negative effects some prescription medications may have on glycemic control in people with diabetes, some of these drug-disease interactions are also addressed.

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Cardiovascular Drug-Drug Interactions

Cited by 31 publications

References 157 publications

Heterodimerization of α2A- and β1-Adrenergic Receptors

Heterodimerization of α2A- and β1-Adrenergic Receptors

Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4

Common Drug Pathways and Interactions

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