Disease Overview And Pharmacological Basis Of Drug Therapies Biology Essay

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The prevalence of atrial fibrillation in the population increases with age as it affects 0.5% population in the aged range from 50-59 year-old and increasing to 8.8% in the age ranged from 80-89 year-old.1 It was also found that the risk of stroke is increased by 6-fold and is associated with a 2- fold increase in mortality. The prevalence of atrial fibrillation secondary to hyperthyroidism has been estimated to range from 5-15% 2 In another words, atrial fibrillation is developed in 5-15% of patients with hyperthyroidism.

Atrial Fibrillation is initiated by chaotic movement of electrical impulses across the atria causing atria to fibrillate at a rate as high as 300 to 600 beats per minute. This will then lead to insufficient filling and emptying of the atria. At the same time, ventricles lose their regular rhythm and begin to contract faster at rate of more than 100 beats per minute. This irregular beating will then result in insufficient blood supply to the body. In addition to that, the pooling of blood within the heart can lead to formation of blood clots and subsequently increases the risk of stroke.3 Underlying disease such as hyperthyroidism is linked to the shortening duration of action potential resulting in an increase in cardiac contractility subsequently triggering development of atrial fibrillation.4 This effect was shown in a study conducted by in which the duration of action potential is significantly lower in patients with hyperthyroidism.5 The thyroid hormone is structurally similar to catecholamines which accounts for alteration of the action potential duration, enhancement of automaticity and activity.5

Atrial fibrillation is diagnosed by electrocardiogram showing absence of P waves and irregular QRS complexes. 3 Urine and electrolyte test, thyroid function test and cardiac enzyme test are normally carried out too. Thyroid function tests are evaluated by measuring the level of thyroid stimulating hormone and free thyroxine (T3), triiodothyronine (T4) as high thyroid hormone level (hyperthyroidism) is one of the risks factor of AF. Therefore, a rise in T3, T4 and a reduction in TSH level indicates AF.4 The serum concentration of cardiac enzyme such as troponin I is measured to determine the degree of damage to heart. 3

In this case scenario, the patient was diagnosed with paroxysmal atrial fibrillation secondary to thyrotoxicosis. Paroxysmal atrial fibrillation is defined as recurrence of episode of AF which normally resolves in less than 7 days.6 The management of atrial fibrillation in this patient comprised of the use of warfarin for thromboprophylaxis and the use of anti thyroid drugs (carbimazole and polythiouracil) for treatment of underlying thyrotoxicosis. Warfarin is a vitamin K antagonist which acts by inhibiting enzymic reduction of vitamin K to its active hydroquinone form therefore interferes with the post translational γ- carboxylation of glutamic acid residues in clotting factors II, VII, IX and X leading to a deficiency in clotting factors in blood.6 Both carbimazole and polythiuracil are chemically related to thiourea and the thicarbamide group (S-C-N) accounts for anti thyroid activity. They act by inhibiting the thyroperoxidase-catalysed oxidation reactions by acting as substrates for the postulated peroxide-iodinium complex, therefore competitively inhibiting the interaction with tyrosine. It was found that propylthiouracil has additional effect of reducing the deionation of T4 to T3 in peripheral tissues.7

Evidence Based Studies

According to NICE guidelines, management of paroxysmal atrial fibrillation should be initiated with the aims of suppressing paroxysms of atrial fibrillation and maintain long-term sinus rhythm and to prevent the complications associated with paroxysmal AF such as stroke. 6First line drugs that are recommended are beta blocker such as atenolol but if patients are still experiencing symptoms of paroxysms, drugs from different drug class such as Class Ic antiarrhythmic drug (flecainide, propafenone) and Class III antiarrhythmic drug (sotalol, amiodarone) should be considered. Warfarin is used to reduce the occurrence of stroke. The appropriate and effective management of the underlying disease (thyrotoxicosis) is essential in this patient in order to reduce the frequency paroxysms.6

A study conducted by Steeds shown that both sotalol and atenolol had similar and significant efficacy in reduction symptomatic occurrence of paroxysmal atrial fibrillation. The dose used in this particular study was 80mg bd for sotalol and 50mg daily for atenolol.8 On the basis of results at 1 year, amiodarone would be preferred with respect to class I and other class III drugs, as it was more effective in preventing recurrences of atrial fibrillation, produced fewer withdrawals, no significant proarrhythmia, and caused no increase in all-cause mortality.

Two studies conducted by Kochiadakis GE and his colleges have shown that amiodarone was more effective in reducing the rate of atrial fibrillation recurrence and able to restore sinus rhythm more effectively compared to sotalol.9,10 In addition to that, low dose of amiodarone was found to be more effective than sotalol in restoring normal sinus rhythm. The efficacy of amidorone was further proven by a meta analysis condutced by Lafunte and his colleges. In this study, amiodarone (class III antiarrhythmic drug) was concluded to have higher efficacy over class Ia antiarrhythmic drug (disopyramide, quinidine), class Ic antiarrhythmic drug (flecainide and propafenone) and other class III drug (sotalol) in preventing the relapse of atrial fibrillation. In addition to that, it was shown that amiodarone resulted in fewer adverse effects compared with other drug class.11

Antithrombolytic therapy is important to minimise the risk of stroke. The main drug used is warfarin. In two studies comparing efficacy of warfarin against placebo concluded that warfarin was able to reduce the risk of ischaemic stroke significantly. 12,13 However, a meta analysis conducted by Aguilar and his colleges showed that the use of warfarin resulted in an increased risk of haemorrhage but overall mortality is not significantly different from those who are taking anti platelet agent such as aspirin.14 Similarly, this meta analysis also showed that warfarin was more efficacious than placebo for primary stroke prevention with moderate evidence of more major bleeding. This meta analysis included analysis of antiplatelet agent such as aspirin and its efficacy in reducing the risk of stroke and it was found that aspirin was more effective than placebo for primary stroke prevention (1.9% risk reduction for stroke) with evidence of major bleeding. By comparing warfarin and aspirin, it was found that the use of warfarin accounted for fewer case of stroke compared to patient on aspirin but with a higher risk of haemorrhage. This meta analysis also depicted that low dose warfarin or a combination of low dose warfarin and aspirin were less effective for stroke prevention than adjusted-dose warfarin.13,14 This finding is supported by another meta analysis conducted by HART. In the analysis, adjusted dose warfarin and antiplatelet (aspirin) was able to reduce incidence of stroke by 64% and 22% respectively. Another meta analysis justifies that adjusted dose warfarin is more advantageous in reducing the incidence of stroke in patient with atrial fibrillation when compared to efficacy of low dose or fixed dose warfarin with aspirin.12 However, there was no difference observed in terms of overall mortality, vascular or haemorrhagic death, or major haemorrhage between these two groups. Hence, it is reasonable to conclude that adjusted dose warfarin was more effective compared to antiplatelet in stroke risk reduction. 12 In addition to that, a study conducted by Van Walraven showed similar findings justifying that adjusted dose warfarin was able to produce a more predictable and significant reductions in stroke for patients with atrial fibrillation.15 The study conducted by Aguilar indicated that the use adjusted-dose warfarin to prolong INR ranged from 2 to 3 was able to reduce incidence of stroke death for patients with AF substantially and the haemorrhage side effects were not dominant as the patients were carefully monitored.14

The patient in this case scenario was diagnosed with atrial fibrillation secondary to thyrotoxicosis. As mentioned earlier, NICE guidelines state that appropriate management of underlying disease such as thyrotoxicosis is essential in reducing the frequency of paroxysms periods in another term a better control of atrial fibrillation.6 This patient was not given any types antiarrhythmic medication including beta blockers, Class Ic antiarrhythmic drug (flecainide, propafenone) and Class III antiarrhythmic drug (sotalol, amiodarone). These types of drugs were found to have significant therapeutic effect on patients with atrial fibrillation as explained previously. Appropriate management of thyrotoxicosis correlates with better management of atrial fibrillation as shown in this patient. In particular, her atrial fibrillation was well controlled with the use of anti thyroid agent as she only developed one episode of palpitation since the past two years which was relieved by rest. The antithyroid agents that were prescribed to the patient include carbimazole and polythiouracil.

The management of hyperthyroidism aims to lower the serum concentration of thyroid hormone in the body. There are three main treatments currently available for treatment of hyperthyroidism. These include the use of anti thyroid agents such as carbimazole, methimazole and polythiouracil, radioactive iodine and thyroid surgery.16,17 The use of anti thyroid agents in the management of hyperthyroidism is proven to be beneficial in managing atrial fibrillation. This statement is justified by a study conducted by Berker.D and his colleges. The study showed that both mehimazle and polythiouracil are effective in reducing P wave duration and dispersion. Prolonged P wave duration and dispersion was shown to be correlated with development of episodes of atrial fibrillation in patient with hyperthyroidism.4 Hence it is reasonable to conclude that shortened P wave duration and duration resulted from anti thyroid therapy plays a role in reducing negative effects of thyroid hormones on atrial electrophysiology.4 Relapses due to stopping of anti thyroid drug can be estimated in 40% to 60% in patients with hyperthyroidism (Graves’s disease in particular).18

Anti thyroid drug therapy can be divided into two distinctive drug regimens which include block-replace regimen and titration regimen. Block-replace regimen involves the use of high and fixed dose of anti thyroid drug to inhibit production of thyroid hormone followed by a replacement dose of thyroid hormone. Contrastingly, titration regimen involves reduction in dose of antithyroid drug by titrating treatment against thyroid hormone concentrations in the body. 19,20 A meta analysis conducted by Abraham.P and his college indicated comparison of these regimens in preventing relapse one year after stopping the therapy and optimal duration for both block-replace and titration regimen. 19 In this study, titration regimen with therapy duration of 18 months and 6 months were compared and it was shown that longer duration therapy resulted in lower incidence of relapses (37%) compared to 6 month therapy (58%). Similar comparison was made for block regimen therapy but results indicated that there is no significant difference between the efficacies of 6 month and 12 month block- replace regimens. When comparing the efficacy of both regimens in preventing relapses, it was found that both regimens had similar efficacy (54%). However, block-replace regimen was reported to cause more side effects leading to higher incidence of withdrawal compared to titration regimen. The most common side effect reported was rashes. In short, evidences showed that the optimal therapy duration for titration regimen ranged from 12-18 months and 12 months for block-replace regimen and noted that that titration regimen produces fewer side effects. 19 In this case scenario, patient had been taking carbimazole 20mg daily for 18 months but her thyroid levels were elevated upon withdrawing of carbimazole leading to atrial fibrillation. Relapse occurred and another drug, polythiouracil 100mg tds was prescribed to her. Her atrial fibrillation was well controlled (normal sinus rhythm) with the use of this anti thyroid drug. Evidence showed that carbimazole to be taken 20mg daily is more effective than dosing of 40mg daily. The use of lower dose is associated with fewer side effects lower risk in developing hypothyroidism.21 This is further supported by a study conducted on accessing the rationale of using carbimazole dose of 100mg daily and it was found that high dose carbimazole resulted in higher risk of side effects such agranulocytosis. 22


The patient in this case scenario was given appropriate management. According to NICE guidelines and relevant studies, it was found that management of underlying disease which is thyrotoxicosis in this circumstance is essential in reducing the frequency of atrial fibrillation episodes. Patient was admitted to hospital due to an elevation in thyroid hormone level triggering paroxysmal atrial fibrillation. The patient was then prescribed an anti thyroid drug and her atrial fibrillation was resolved over time. In addition to anti thyroid medication, patient was given warfarin for thromboprophylaxis as formation of blood clots in patients with atrial fibrillation is common. Warfarin was proven to be a better choice of anti coagulant as it has shown to reduce the risk of stroke significantly.