Therapeutics Fibrillation and Atrial Flutter

Questions: 1. Discuss digoxin and its place in therapy. Include in your answer (but not limited to) aspects that relate to how it works, what it is used for, therapeutic drug monitoring and patient specific information. 2. Choose one of the newer (novel) anticoagulant drugs (NOACS) and discuss its place in therapy. Make particular note of recent studies for evidence of safety and efficacy. 3. Discuss long acting beta agonists (LABAs) and their use. Include (but not limited to) aspects that relate to pharmaceutical care of patients that may be using these drugs as well as more specific information relating to the class of drug. Answers: 1. Digoxin primarily acts by inhibiting sodium-potassium adenosine triphosphatase (Na+/K+ ATPase) in the myocardium. By virtue of this inhibition, there is increase in the intracellular sodium levels which results in the reverse exchange of sodium and calcium through sodium-calcium exchanger. In normal condition, three sodium ions get imported for every one calcium ion exported out of the cell. After the reversal of exchange of ions, there is increased concentration of calcium ions in the cell for the contractile proteins like actin and myosin. Digoxin decreases heart rate by increasing intracellular calcium level which increase length of the phase 4 and phase 0 of the cardiac action potential (1). Digoxin is mainly useful in condition of irregular heart beat like atrial fibrillation and atrial flutter and occasionally it is useful for the treatment of heart failure. Due to high ventricular rate, there is the inadequate diastolic filling time. Digoxin reduce this ventricular rate by reducing the rate of conduction in AV node which leads to the increase in its refractory period. As a result there is the improvement in the pumping activity of the heart due to the improvement in the filling. Even tough digoxin is not the first choice in heart failure it can be used for heart failure. Therapeutic drug monitoring of digoxin is essential both for efficacy and toxicity because of its narrow therapeutic index. This narrow therapeutic index reflects there is large overlap between the drug concentration in the plasma and its therapeutic effect and toxic effect. Side effects of digoxin are concentration dependent. If plasma concentration of digoxin is more than 0.8 nanograms/mL, it exhibits its adverse effects (2). Digoxin should not be administered in patients with low potassium level. Digoxin usually competes with and share binding site of K+ for Na+/K+ ATPase pump. Hence, digoxin exhibits adverse effects in patients with low potassium level. Patients with other electrolyte imbalance conditions like hypomagnesemia, hypercalcemia and hypernatremia may reduce therapeutic effect of digoxin, even though its plasma concentration is adequate. Patients with hypothyroidism and with renal impairment may affect concentration of digoxin in the plasma. Hence, these patients should be closely monitored for plasma concentration of digoxin. Hypoxia and alkalosis caused due to the chronic lung disease may result in the adverse effects of digoxin (1, 2). 2.Dabigatran (Pradaxa) : Anticoagulant drugs are particularly useful for the thromboembolism. Dabigatran, a direct thrombin inhibitor was approved in 2010 and this is only drug available in the market in this class of direct thrombin inhibitor. Warfarin was used since long time as anticoagulant, however it was associated with very narrow therapeutic window and patient to patient variability is more and requires frequent drug monitoring. With novel oral anticoagulants, there is no need of frequent drug monitoring. Coagulation pathway involves multiple components and inhibition or alteration one component can also alter entire pathway. Direct thrombin inhibitors act on the last step by inhibiting thrombin. This last step of coagulation pathway involves conversion of prothrombin to thrombin. This thrombin facilitate conversion of fibrinogen to fibrin which results in the clot formation (3). RE-LY trial (Randomized Evaluation of Long Term Anticoagulant Therapy) with dabigatran conducted on 18,113 subjects with non-vascular atrial fibrillation (AF) with the dose of 110 mg twice daily exhibited superior effect in reduction of stroke as compared to warfarin. Also both the doses of dabigatran like 110 and 150 mg twice daily exhibited major, intracranial and total bleeding with lesser incidence as compared to the warfarin (4). In another study with 2782 asian patients, it has been shown that both the doses of dabigatran exhibited advantage over warfarin in CHADS score. This CHADS score is the good predictor of stroke and bleeding in anticoagulant therapy (5). In another trial with 149 patients in left atrial ablation for atrial fibrillation, dabigatran at the dose of 110 mg twice daily proved to be safe and effective as compared to the acenocoumarol (6). 3. Long acting beta agonists (LABAs) specifically 2 adrenergic receptor agonists are useful in moderate to severe asthma and also in patients with chronic obstructive pulmonary disease (COPD). This class of drugs include formoterol, arformoterol, bambuterol, clenbuterol, formoterol and salmeterol. This class of drugs have duration of action approximately 12 hours. However, other than formoterol other drugs of this class are not in routine use for acute exacerbations of asthma because of onset of action of these class of drugs is slower than short acting 2 agonist such as salbutamol. This class of drugs exhibits longer duration action because of addition of the long lipophilic side chain which binds and unbinds to the adrenergic receptors continuously. This class of medication is used as controller medication in case of asthma and it can be used once or twice a day (7). This class of medication can be used in combination with the inhaled steroids. Various health guidelines mentioned t hat, this class of medication should be prescribed in severe asthma instead of mild asthma. In recent studies, it is evident that there are more asthma exacerbations and deaths in patients with salmeterol group as compared to the placebo group. In this study, 26,000 people with asthma were recruited and salmeterol was given twice daily. Hence studies with large subjects should be conducted for combination of long acting 2 agonist along with corticosteroids to reduce these severe exacerbations of asthma. Long acting 2 agonist should not be used for immediate effect or to get rid of quick symptoms (8). In majority of the cases long acting 2 agonist should be used in combination with inhaled corticosteroids because there are chances of severe exacerbations of asthma without use of concomitant steroid. These exacerbations of asthma are due to the continuous augmentation of inflammation in the absence of steroids. In few cases, asthma seems to exacerbate during the use of 2 agonist, and this condition should be brought to the notice of doctor. Long acting 2 agonist should be given to children below 4 years with more care. Pregnant women should not use long acting 2 agonist (9). References: Ziff OJ, Kotecha D. Digoxin: The good and the bad. Trends Cardiovasc Med. 2016 Oct;26(7):585-95. MacLeod-Glover N, Mink M, Yarema M, Chuang R4. Digoxin toxicity: Case for retiring its use in elderly patients? Can Fam Physician. 2016 Mar; 62(3):223-8. Ageno W, Eikelboom J, Lip GY. Dabigatran in clinical practice: Contemporary overview of the evidence. Int J Cardiol. 2016 Oct 1; 220: 417-28. Hori M, Fukaya T, Kleine E, Reilly PA, Ezekowitz MD, Connolly SJ. Efficacy and Safety of Dabigatran Etexilate vs. Warfarin in Asian RE-LY Patients According to Baseline Renal Function or CHADS2 Score. Circ J. 2015; 79(10):2138-47. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 11391151 Efremidis M, Vlachos K, Letsas KP, Giannopoulos G, Lioni L, Georgopoulos S, Vadiaka M, Deftereos S, Sideris A. Low dose dabigatran versus uninterrupted acenocoumarol for peri-procedural anticoagulation in atrial fibrillation catheter ablation. J Electrocardiol. 2015 Sep-Oct;48(5):840-4.. Karbasi-Afshar R, Aslani J, Ghanei M. Efficacy and safety of conventional long acting 2- agonists: systematic review and meta-analysis. Caspian J Intern Med. 2016 Spring;7(2):64-70. Bacharier LB. Step-down therapy in asthma: a focus on treatment options for patients receiving inhaled corticosteroids and long-acting beta-agonist combination therapy. Allergy Asthma Proc. 2012 Jan-Feb; 33(1):13-8. Hernandez G, Avila M, Pont A, Garin O, Alonso J, Laforest L, Cates CJ, Ferrer M. Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies. Respiratory Research. 2014; 15:83 DOI:10.1186/1465-9921-15-83