Antiarrítmicos Classe II (Betabloqueadores)

Estrutura Química e Farmacodinâmica

Definição

Os antiarrítmicos de classe II incluem betabloqueadores, que inibem competitivamente a ligação da epinefrina e da norepinefrina aos recetores beta-adrenérgicos nas células vasculares e cardíacas.

Estrutura química

• Contêm um anel aromático ou heteroaromático com um grupo amina
• O propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs é o fármaco padrão.
• A maioria dos betabloqueadores usados clinicamente são administrados como racematos, exceto o timolol Timolol A beta-adrenergic antagonist that is similar in action to propranolol; the levo-isomer is more active. Timolol has been proposed as an anti-hypertensive, anti-arrhythmic, anti-angina, and anti-glaucoma agent. It is also used in the treatment of migraine disorders and tremor. Class 2 Antiarrhythmic Drugs (Beta Blockers).

Mecanismo de ação

• Os betabloqueadores inibem competitivamente os recetores beta-adrenérgicos:
  • Agentes não seletivos que se ligam e induzem efeitos antagónicos nos recetores beta-1 (B1) e beta-2 (B2)
  • Os agentes cardiosseletivos só se ligam aos recetores B1.
• Localizações do recetor:
  • B1:
    • Nó sinoauricular (SA)
    • Nó auriculoventricular (AV)
    • Músculo auricular e ventricular
    • Rins
  • B2:
    • Vasos sanguíneos
    • Brônquios
    • Trato GI
    • Útero
    • Fígado
    • Trato urinário
• Ação nas células cardíacas:
  • Bloqueia a ligação das catecolaminas (epinefrina) aos recetores acoplados à proteína G (recetor B1) → inibe a ativação da adenilil ciclase
  • ↓ Conversão de ATP em cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors → ↓ ativação da proteína cinase A
  • Os canais de cálcio ( Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)) não são fosforilados → não se abrem → ↓ influxo de Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) nas células miocárdicas
  • Efeito nodal:
    • ↓ atividade do nó SA
    • ↑ Tempo de condução do nó AV e período refratário
    • ↓ Declive e fase 4 prolongada

Efeitos fisiológicos

• Efeitos antiarrítmicos:
  • Efeitos cronotrópicos negativos ( FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions)
  • Efeitos dromotrópicos negativos:
    • Atrasa a velocidade e a capacidade de iniciar um potencial de ação
    • ↓ Velocidade de condução
  • Período refratário prolongado
  • A atividade estabilizadora de membrana (AEM) e a atividade simpaticomimética intrínseca (ASI) não têm um grande impacto na potência antiarrítmica.
• Bloqueio de B1:
  • ↓ Necessidades de oxigénio:
    • ↓ FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions
    • ↓ Contratilidade
    • ↓ Pós-carga
    • ↓ Pressão arterial
  • ↑ Fornecimento de oxigénio (indiretamente):
    • Prolonga a diástole
    • Melhora a perfusão
• Bloqueio de B2:
  • Vasoconstrição
  • Broncoconstrição
• Bloqueio alfa-1 (A1):
  • Visto com o carvedilol Carvedilol A carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Mais MAIS Androgen Insensitivity Syndrome ↓ pós-carga devido a ↓ resistência vascular sistémica (RVS)
• Efeitos do ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG): prolongamento do intervalo PR

Tipos de recetores adrenérgicos e as suas propriedades

Propriedades adicionais dos betabloqueadores

Alguns betabloqueadores podem apresentar as seguintes propriedades e efeitos:

Classificação

Os antiarrítmicos de classe II podem ser classificados com base na seletividade do seu recetor beta:

• Betabloqueadores cardiosseletivos (recetores B1):
  • Acebutolol Acebutolol A cardioselective beta-1 adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm, as well as weak inherent sympathomimetic action. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Atenolol Atenolol A cardioselective beta-1 adrenergic blocker possessing properties and potency similar to propranolol, but without a negative inotropic effect. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Betaxolol Betaxolol A cardioselective beta-1-adrenergic antagonist with no partial agonist activity. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Bisoprolol Bisoprolol A cardioselective beta-1 adrenergic blocker. It is effective in the management of hypertension and angina pectoris. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Esmolol Esmolol Antiadrenergic Drugs
  • Metoprolol Metoprolol A selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias. Antiadrenergic Drugs
• Betabloqueadores não cardiosseletivos (recetores B1 e B2):
  • Nadolol Nadolol A non-selective beta-adrenergic antagonist with a long half-life, used in cardiovascular disease to treat arrhythmias, angina pectoris, and hypertension. Nadolol is also used for migraine disorders and for tremor. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs
  • Timolol Timolol A beta-adrenergic antagonist that is similar in action to propranolol; the levo-isomer is more active. Timolol has been proposed as an anti-hypertensive, anti-arrhythmic, anti-angina, and anti-glaucoma agent. It is also used in the treatment of migraine disorders and tremor. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Carvedilol Carvedilol A carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction. Class 2 Antiarrhythmic Drugs (Beta Blockers) (também tem atividade de bloqueio do recetor A1)

Farmacocinética

Absorção

• A maioria dos fármacos é rápida e completamente absorvida pelo trato GI.
• ↓ Taxa de absorção:
  • Idosos
  • Indivíduos com insuficiência renal

Distribuição

• Distribuição rápida dentro do corpo
• A ligação às proteínas é variável.
• Os agentes lipofílicos podem atravessar a barreira hematoencefálica.

Metabolismo

• A maioria dos agentes lipofílicos sofre metabolismo hepático de 1ª passagem significativo:
  • Carvedilol Carvedilol A carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction. Class 2 Antiarrhythmic Drugs (Beta Blockers)
  • Metoprolol Metoprolol A selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias. Antiadrenergic Drugs
  • Propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs
• Alguns fármacos são convertidos nos seus metabolitos ativos.
• Os compostos hidrofóbicos tendem a sofrer metabolismo hepático limitado.

Excreção

• Metabolismo hepático (agentes lipofílicos) → bílis
• Agentes hidrofílicos → excreção renal
• A diminuição da função hepática e renal pode ↓ taxa de eliminação

Indicações

Arritmia

Os antiarrítmicos de classe II são usados no tratamento de:

• Fibrilhação auricular
• Flutter auricular
• Taquicardias supraventriculares
• Arritmias ventriculares

Usos adicionais

Os betabloqueadores, como classe, estão aprovados pela FDA para o tratamento de:

• Doença cardíaca coronária:
  • Angina
  • Pós-EAM
• Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies essencial
• Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma ( timolol Timolol A beta-adrenergic antagonist that is similar in action to propranolol; the levo-isomer is more active. Timolol has been proposed as an anti-hypertensive, anti-arrhythmic, anti-angina, and anti-glaucoma agent. It is also used in the treatment of migraine disorders and tremor. Class 2 Antiarrhythmic Drugs (Beta Blockers))
• Insuficiência cardíaca com redução da fração de ejeção
• Hipertensão arterial
• Estenose subaórtica hipertrófica
• Profilaxia da enxaqueca
• Feocromocitoma; adjuvante
• Profilaxia de hemorragia varicosa

Indicações para fármacos antiarrítmicos classe II

Efeitos Adversos e Contraindicações

Efeitos adversos

• Cardiovascular:
  • Bradicardia
  • Hipotensão
  • Exacerbação da insuficiência cardíaca (com terapia inicial)
  • Abstinência com descontinuação que pode precipitar (pelo ↑ atividade simpática):
    • EAM (em indivíduos com doença arterial coronária)
    • Taquiarritmias ventriculares
    • Morte súbita cardíaca
• SNC:
  • Fadiga
  • Depressão
  • Sonhos vívidos
  • Disfunção sexual
• Respiratório: broncoconstrição
• Endócrino:
  • Hipoglicemia
  • Hiperglicemia (geralmente em indivíduos com diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus não insulino-dependente)
  • Dislipidemia
  • Aumento de peso
  • Retenção de fluidos
• Dermatológico: potencial exacerbação da psoríase

Contraindicações

• Insuficiência cardíaca descompensada
• Choque cardiogénico
• Hipotensão
• Bradicardia grave
• Bloqueio AV de 2º ou 3º grau
• Síndrome do seio doente (a menos que esteja presente um pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias)
• Doença reativa grave das vias aéreas
• Hipertensão pulmonar ( esmolol Esmolol Antiadrenergic Drugs)

Interações farmacológicas

• Potenciamento da bradicardia:
  • Bloqueadores de canais de Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)
  • Amiodarona
  • Agonistas A2
  • Digoxina
• Aumento da hipoglicemia:
  • Sulfonilureias
  • Insulina
• Vasoconstrição excessiva: alcaloides do ergot

Comparação de Classes de Fármacos Antiarrítmicos

A tabela a seguir compara as classes de antiarrítmicos I‒IV. A classe V não está incluída devido aos variados mecanismos de ação e efeitos.