INTRODUCTION:

Treatment for patients with different types of heart failure often consists of a cocktail of medications, including diuretics, cardiac glycosides, and drainage agents¹. These techniques lessen symptoms, but it's unclear how they affect survival.

Digoxin and diuretics, for instance, have not been shown to have an impact on the overall mortality of heart failure patients². While beta-blockers have been shown to increase survival in certain patients, their usage in these patients is debatable and ambiguous³. However, it has been demonstrated that smaller medications, particularly nitrates, hydralazine, and angiotensin-converting enzyme inhibitors, can extend life. Cardiovascular events and cardiac arrhythmias are more common in patients with congestive heart failure and ventricular arrhythmias⁴. To increase survival, efforts have been made to lower ventricular arrhythmias with antiarrhythmic medications. Arrhythmia suppression with flecainide raises mortality in myocardial infarction patients, according to cardiac antiarrhythmic trials⁴.

Pharmacogenomics is the study of how a person's biology affects how their body responds to drugs. This term, which stands for the nexus of medicine and genetics, is derived from the words pharmacology and genomics. Pharmacogenomics holds the potential to customize prescription drugs daily according to a person's genetic composition⁵. A person's response to medication can be influenced by their environment, food, age, lifestyle, and health issues, but knowing their genetic composition can help develop safer and more effective personalized medicine. The main thing is useful. A person's drug response, both positive and negative, is a complicated characteristic that is controlled by a wide range of genes. Researchers have discovered that it is challenging to create genetic tests that can forecast a person's reaction to a certain medication if they do not yet know every gene linked to drug resistance⁵.

Amiodarone is an antiarrhythmic drug used to treat and prevent many types of irregular heartbeat⁶. Amiodarone was first developed in 1961, and clinical use began in 1962 for chest pain believed to be cardiac-related. It was withdrawn from the market in 1967 due to adverse effects. In 1974, it was found useful in arrhythmias^7,8. Amiodarone is used in the treatment of acute malignant arrhythmias and chronic pressure arrhythmias, and is used in supraventricular arrhythmias and ventricular arrhythmias^9,10. Amiodarone slows conduction velocity and prolongs the duration of SA and AV nodal reflexes. It also prolongs the duration of the ventricular reflex without affecting the conduction velocity of the Purkinje fibers. Amiodarone has been shown to prolong myocardial cell firing and reflex duration and is a noncompetitive adrenergic blocking agent^11,12.

Because of the potential adverse effects such as myocardial depression and proarrhythmic problems like bradycardia and atrial block, the concurrent use of metoprolol with amiodarone calls for greater therapeutic alertness. This theoretical error has been called into doubt, nevertheless, as prior research analysis suggests that this combination of drugs may offer further advantages¹³.

Metoprolol succinate is a beta blocker used to treat blood pressure arrhythmias. Metoprolol succinate has a biological half-life of 3-7 hours. Hydrochlorothiazide (HCT) is 6-chloro-3,4-dihydro-2H-1,2,4-benzodiathiazine-7-sulfanamide 1,1-dioxide. It has a diuretic effect, increases the renal excretion of sodium and chloride, and reduces the burden on the heart. Both of these drugs affect blood pressure. Several retrospective clinical trials have investigated the combination of metoprolol and amiodarone in contrast to experimental studies. Therefore, it is important to properly assess the risks associated with the combination of metoprolol and amiodarone ¹⁴.

The purpose of this study was to investigate the pharmacological effects of amiodarone and metoprolol on isolated cardiac specimens. Metoprolol and amiodarone together have been shown to have an impact on dependent variables, heart rate (HR), coronary blood flow (CF), myocardial compliance (dP / dt), and systolic pressure (SP)¹⁵.

Metoprolol Amiodarone

Figure 1: Metoprolol and Amiodarone [Scientific Image].

Drug-drug interaction:

In pharmacology, when several drugs are prescribed for one or more diseases, drug interactions cause unexpected side effects, toxic effects, or lack of clinical efficacy in individual organisms¹⁶. This is often considered in terms of two main categories of underlying mechanisms: Pharmacokinetics and pharmacodynamics¹⁷. The effects of one or both drugs can be enhanced or suppressed, or they can produce new and unexpected effects that can lead to fatal consequences¹⁸. Changes in pharmacokinetics, absorption, distribution, metabolism, and excretion (ADME cycle) may affect plasma concentrations and changes in drug bioavailability. Drug effects at the metabolic level can alter metabolic enzymes and alter drug activation or inactivation¹⁷. If metabolism is impaired, the drug can remain in the body for a long time and increase its concentration, potentially causing secondary toxicity. On the other hand, increased metabolism may decrease plasma concentration and thus bioavailability¹⁹.

Drug drug interaction (DDIs) is one of the most widely recognized reasons for ADR, and we note what is happening happens in the older because of polypharmacy²⁰. To be sure, poly pharmacy builds the intricacy of treatment the executives and in this manner expands the gamble of clinical medication co-operations that can prompt aftereffects and abatement or increment clinical effiacay²¹.

Figure 2: Drug Drug Interaction [biopharmaservices].

Addiction is the effect or effect of a drug that is changed or modified by interaction with one or more other drugs. Adverse drug reactions range from mild to toxic drug reactions such as hypersensitivity and anaphylaxis. Chemical or physical interaction between two or more laboratory conditions, drug incompatibility²³. There are three categories of drug action mechanisms, including drug interactions (in vitro), 6,7 pharmacokinetics, 8-10 and pharmacodynamics. Pharmacokinetic drug interactions involve the processes of absorption, distribution, metabolism, and excretion, all of which are related to treatment failure or toxicity²⁴.

Pharmacokinetic drug-drug interactions occur when drugs change the properties (absorption, distribution, metabolism, excretion) of the combined drug. Pharmacokinetic effect increases or decreases the plasma concentration of the drug. Although the strength of these changes varies, they can cause relative contraindications. Drug interactions in the distribution process involve three mechanisms: metabolic inhibition, metabolic induction, and changes in hepatic blood flow²⁵.

Effect of Amiodarone on Metoprolol Plasma Levels:

Bradycardia and atrioventricular (AV) block may arise from the combination of amiodarone's and metoprolol's beta-adrenergic blocking effects (lowering heart rate) and its calcium channel blocking effects (negative inotropy) concurrent usage of two medications²⁶.

Metoprolol concentrations were considerably greater in amiodarone-treated subjects than in non-treated participants, despite unadjusted findings showing no significant difference in plasma metoprolol concentrations between amiodarone users and nonusers. All adjusted analytical models showed a link between metoprolol concentration and amiodarone consumption, although this association became substantial when the metoprolol dose was changed. Even after accounting for the usage of strong and moderate CYP2D6 inhibitors, among other possible antagonists, this connection persisted to be significant²⁷.

Impact of metoprolol and amiodarone combination:

Since amiodarone's pharmacokinetics and pharmacodynamics of its interaction with metoprolol have also been established, it was included in this investigation. Subsequent investigations will examine whether these results apply to additional minor medication interactions or, more significantly, how these pharmacological, genetic, clinical, and demographic aspects manifest in clinical practice. Find out how they communicate. Take note of how you may use it to enhance your well-being. In this discipline, selection and management²⁸.

The usage of amiodarone was connected to a greater level of α-OH-metoprolol, which was an unexpected finding. The study revealed that CYP2D6 inhibitors have sufficient potency to forecast the decline in α-OH-metoprolol concentrations. Rather than CYP2D6 suppression, the higher concentration of α-OH-metoprolol in amiodarone users is caused by this metabolite's modification of amiodarone pharmacokinetics²⁹.

There have been multiple documented medication interactions with amiodarone. The expression of CYP2C8, CYP3A4, CYP1A2, CYP2C19, and CYP2D6 is slightly inhibited³⁰. The majority of the antiarrhythmic drug's inhibitory potential is attributed to DEA, the active metabolite of amiodarone²⁹. Additionally, amiodarone inhibits the ABCB1 P-glycoprotein (P-gp) membrane transporter system, which may interact with other medications³¹.

It might be challenging to explain the mechanisms underlying amiodarone and the rise in α-OH or metoprolol concentrations in humans for several reasons. First, metoprolol is metabolized by some CYPs into α-OH-metoprolol and other metabolites such as N-deisopropylmetoprolol and O-demethylmetoprolol³². Amiodarone inhibits CYP3A4 and CYP2D6 among these CYPs^28,29. It should be mentioned that the increase in the concentration of α-OH-metoprolol in amiodarone users can be explained by excessive suppression of the synthesis of metabolites other than α-OH, given the variety of pathways involved in the metabolism of metoprolol. Metoprolol is this. Secondly, it is challenging to identify potential pathways that could be implicated in this interaction due to the lack of knowledge regarding the distribution, metabolism, and excretion of α-OH-metoprolol metabolites. Research is necessary because of conflicting findings, although it has been proposed that renal function may be one of the methods by which metoprolol eliminates α-OH. Third, metoprolol's modest interactions are more challenging to evaluate due to the inhibitory qualities of amiodarone and its active metabolite, DEA. Fourth, amiodarone has a half-life of 40 to 50 days. DEA's active metabolites have protracted half-lives. As a result, care should be taken when extrapolating data from brief pharmacokinetic investigations³³.

Our population's ability to replicate a "real-world" patient population with a variety of disorders is a strength of our methodology. This is an intriguing discovery because people on amiodarone manage a variety of symptoms with various drugs. This has also been demonstrated in earlier papers and our study. Our study's continuous administration of amiodarone to patients is another strength. This is a significant benefit because oral amiodarone and DEA require many months to attain steady-state plasma concentrations^33-35.

Adverse effects:

Atrioventricular block, bradycardia, hypotension, and block intolerance are among the side effects that may occur more frequently when amiodarone and metoprolol interact³⁵.

PHARMACOGENOMICS IN CARDIOVASCULAR MEDICINES (METOPROLOL AND AMIODARONE):

Metoprolol (β-Blocker):

Two common pseudogene polymorphisms in the adrenergic β-1 receptor (ADBR1) gene, S49G (rs1801252) and R389G (rs1801253), have been associated with clear evidence of modulation of β-blocker activity³⁶. In vitro, G49 is more sensitive to agonist modulation than S49³⁷, and Clear evidence of regulation of β-blocker activity has been linked to two prevalent pseudogene polymorphisms in the adrenergic β-1 receptor (ADBR1) gene: S49G (rs1801252) and R389G (rs1801253)³⁶. R389 mutants bind G protein receptors more effectively than G389 mutants³⁸, and G49 is more responsive to agonist modulation than S49. In contrast to other genotypes, homozygous carriers of the R389 genotype demonstrated improved left ventricular function following beta-blocker (metoprolol) medication in an in vivo investigation³⁹. Better results were also noted for homozygotes of R389 in the Survival Evaluation Trial (BEST), a sizable investigation of metoprolol in heart failure patients^40,41. Lastly, a randomized controlled trial involving 3200 R389 individuals with heart disease was carried out to assess the safety and effectiveness of metoprolol. It has also been observed that homozygous R389 carriers respond more favorably to β-blockers in terms of antihypertensive effects⁴².

The ADBR2 gene encodes 22 adrenergic receptors. Agonist regulation is inhibited by two frequent polymorphisms in ADBR2: R16G (rs1042713) and Q27G (rs1042714). There have been reports, but no replications of associations between common ADRB2 polymorphisms and clinical cardiovascular outcomes⁴³.

CYP2D6 breaks down beta-blocking antiarrhythmic medications including popular beta-blockers like metoprolol. Numerous functional variations exist for this gene, and individuals with two faulty alleles in 7% of Caucasians and Africans have poor metabolism. Rarely, do some individuals with extensive metabolism and those with an ultra-rapid metabolism have a functioning variant of this gene. The greater metoprolol and propafenone metabolic concentrations in heavy metabolizers are linked to a higher risk of bradycardia and bronchospasm. Metoprolol's labeling has been updated by the FDA to reflect the possibility that impaired metabolism could be a risk factor for adverse drug reactions (ADRs)⁴⁴.

Beta-adrenergic receptors are regulated by G protein-coupled receptor kinases (GRKs). Compared to the (Q41Q) version of GRK5, the L41Q variant is linked to an increased risk of heart failure and impaired catecholamine sensitivity⁴⁵. Though it has numerous polymorphisms in numerous ancestries, L41 is more prevalent among Africans⁴⁶.

Amiodarone (Antiarrhythmia):

Drug-induced QT prolongation is frequently the cause of drug reversal or withdrawal and predicts lethal torsade de pointes (TDP) arrhythmias. Rarely do long QT syndrome cases have mutations in the genes linked to congenital long QT syndrome (CLQTS)⁴⁷. The D85N variation of the KCNE1 potassium channel subunit gene was linked nine to twelve times to this ADR, according to large-scale candidate gene research⁴⁸. Variants of the gene NOS1AP, which controls the early QT interval, were found to be a risk factor for amiodarone-induced TdP in a different investigation^49,50.

MECHANISM OF ACTION:

Amiodarone is viewed as a class III antiarrhythmic drug. It prevents the potassium influx that causes myocardial repolarization in the third phase of the cardiac action potential. Thus, amiodarone not just drags out the length of the activity potential, yet additionally delays the term of the viable obstruction of heart cells (myocytes). As a result, cardiomyocyte excitability decreases, which prevents and restores normal heart rhythms^51,52.

Amiodarone, in contrast to class III antiarrhythmic medications, inhibits sodium channels, calcium channels, and beta-adrenergic receptors. These effects may occasionally result in adverse effects such as bradycardia, hypotension, and torsade de pointes (TdP). Amiodarone can also cause liver or other organ fatty changes by increasing the activity of peroxisome-activated receptors. Finally, it was discovered that amiodarone can bind to thyroid receptors and cause hypothyroidism or amiodarone-induced thyrotoxicosis because of its iodine content^53,54.

Table 1: Several examples of pharmacogenetic interactions affecting cardiac drug effects have been reported^50,52-54.

Drugs/Drug Class	Genes with species associated with fertility.
Antiarrhythmic Drugs	Polymorphisms in KCN1, MiRP1, SCN5A gene mutations are associated with congenital LQTS
Beta-blockers (Metoprolol)	ACE β ₁AR, β ₂AR, α₂AR
ACE inhibitors	ACE Angiotensinogen ATI Bradykinin B2 receptor
Lipid-lowering drugs (statins, ±fibrates)	CETP Apolipoprotein E Hepatic lipoprotein Lipoprotein lipase Stromelysin-I β-Fibrinogen ACE LDL receptor
Diuretics (thiazides)	α-adducin G protein (β3-subunit)

CONCLUSION:

Metoprolol and amiodarone together can help patients with congestive heart failure (CHF) by enhancing immunity, lowering blood lipids and inflammatory markers, and improving heart function. A small interaction between these two medications can increase the concentration of metoprolol because amiodarone has myocardial and adrenergic blocking capabilities. This shows how the combination of amiodarone and metoprolol affects heart rate, myocardial compliance, and coronary blood flow. Atrial block and bradycardia could be prevalent.

The interpretation of certain findings, such as the evaluation of medication alterations over time and the pharmacodynamics of amiodarone and metoprolol interactions, is restricted by the cross-sectional design of our investigation. On the other hand, we discovered a steady relationship between metoprolol concentrations and amiodarone consumption. Another drawback is that we relied on the patients' good tolerance of metoprolol and amiodarone.

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Received on 22.05.2024 Revised on 07.11.2024

Accepted on 15.02.2025 Published on 28.02.2025

Available online from March 04, 2025

Asian Journal of Pharmaceutical Analysis. 2025;15(1):51-56.

DOI: 10.52711/2231-5675.2025.00009

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.