Alupent Beta-2

1 What is Alupent Beta-2?

Brand: Alupent, Brethine, Proventil, Proventil Repetabs, Ventolin, Volmax, VoSpire ER, Apo-Salvent, Pms-Salbutamol

Generic: Beta-2 adrenergic agonists

Alupent Beta-2 adrenergic agonists are the drugs which cause smooth muscle relaxation acting on the beta-2 receptors resulting in bronchodilation, vasodilation in muscles and liver, relaxation of uterine muscle and increased insulin secretion. 

They are commonly used to treat certain lung diseases such as bronchial asthma and chronic obstructive pulmonary diseases including chronic bronchitis and emphysema

These are categorized into two groups based upon selectivity:

  • Non-selective: isoprenaline, adrenaline, noradrenaline etc.
  • Selective: salbutamol, terbutaline, ritodrine etc.

Depending upon duration of action, they are also divided into following groups:

  • Short-acting: isoprenaline, levosalbutamol, ritodrine, salbutamol, terbutaline etc.
  • Long-acting: formoterol, salmeterol etc.
  • Ultra-long-acting: abediterol, carmoterol etc.

2 What To Know Before Using

Before using Alupent Beta-2, you must know all about the risks and complications associated with it.

The actions of a particular beta-2 adrenergic agonist in most tissues have been clearly differentiated depending on its relative activity at the predominant receptor type present in a given tissue.

The overall actions are:

Heart

Adrenaline increases heart rate by increasing the slope of slow diastolic depolarization of cells in the SA node. It also activates latent pacemakers in A-V node and Purkinje fibres; arrhythmia can occur with high doses that raise blood pressure (BP) markedly. Raised BP reflexly depresses the SA node and unmasks the latent pacemakers. 

Certain anesthetics (chloroform, halothane) sensitize the heart to arrhythmic action of adrenaline. Idioventricular rate is increased in patients with complete heart block.

Force of cardiac contraction is increased. In addition, development of tension as well as relaxation is accelerated. Thus, systole is shortened more than diastole. Cardiac output (CO) and oxygen consumption of the heart are markedly enhanced.

Conduction velocity through AV node, bundle of His, atrial and ventricular fibres is increased; partial A-V block may be overcome. Refractory period (RP) of all types of cardiac cells is reduced. All cardiac actions are predominantly beta-1 receptor mediated.

When BP rises markedly, reflex bradycardia occurs due to stimulation of vagus – this is the usual response seen when NA is injected intravenously.

Blood vessels

Both vasoconstriction (alpha) and vasodilatation (beta-2) can occur depending on the drug, its dose and vascular bed. Constriction predominates in cutaneous, mucous membrane and renal beds. 

Vasoconstriction occurs through alpha-1 and alpha-2 receptors. On the contrary, dilatation predominates in skeletal muscles, liver and coronaries. 

The direct effect on cerebral vessels is not prominent – blood flow through this bed parallels change in BP.

The action is most marked on arterioles and precapillary sphincters; large arteries and veins are affected at higher doses.

Blood pressure

The effect depends on the amine, its dose and rate of administration. 

  1. Noradrenaline causes rise in systolic, diastolic and mean BP; it does not  cause vasodilatation (no beta-2 action), peripheral resistance increases consistently due to alpha action.
  2. Isoprenaline causes rise in systolic but marked fall in diastolic BP (beta-1: cardiac stimulation, beta-2: vasodilation). The mean BP generally falls.
  3. Adrenaline given by slow IV infusion or s.c. injection causes rise in systolic  but fall in diastolic BP; peripheral resistance decreases because vascular beta-2 receptors are more sensitive than alpha receptors. Mean BP generally rises and pulse pressure is increased.
  4. Rapid IV injection of adrenaline produces a marked increase in both systolic as well as diastolic BP. The BP returns to normal within a few minutes and a secondary fall in mean BP follows.

Respiration

Adrenaline and Isoprenaline, but not noradrenaline are potent bronchodilators (beta-2).This action is more marked when the bronchi are constricted. Adrenaline given by aerosol additionally decongests bronchial mucosa by alpha action. 

Adrenaline can directly stimulate respiratory center (RC) but this action is seldom manifest at clinically used doses. 

Rapid IV injection causes transient apnea due to reflex inhibition of RC. Toxic doses of adrenaline cause pulmonary edema by shifting blood from systemic  to pulmonary circulation.

Skeletal muscle

The direct effect on muscle fibers  is exerted through beta-2 receptors and differs according to the type of fibre. The active state is abbreviated and less tension is developed in the slow contracting red fibers. 

There is incomplete fusion of individual responses. This along with enhanced firing of muscle spindles is responsible for the tremors produced by beta-2 agonists.

Metabolic

Adrenaline causes glycogenolysis resulting in hyperglycemia, hyperlactaciademia (beta-2); lipolysis resulting in a rise in plasma free fatty acid and calorigenesis (beta-2 + beta-3). These are due to direct action on liver, muscle and adipose tissue cells. 

In addition, metabolic effects result from reduction of insulin (alpha-2) and augmentation of glucagon (beta-2) secretion. 

Transient hyperkalemia followed by hypokalemia occurs due to initial release of potassium from liver, and latter its enhanced uptake into skeletal muscles as well as in liver.  

3 Precautions To Take

Alupent Beta-2 activates membrane bound enzyme adenylyl cyclase through G proteins which cause ATP break down to cAMP at the inner face. This in turn phosphorylates a number of intracellular cAMP-dependent protein kinases and initiates a series of reactions:

  • In liver and muscle, glycogen phosphorylase is activated causing glycogenolysis while glycogen synthase is inhibited. Both actions result in hyperglycemia and hyperlactacidemia. Neoglucogenesis in liver adds to the response.Potassium is first released from liver which may cause hyperkalemia followed by more prolonged hypokalemia due to potassium uptake in muscle and later in liver itself.
  • In adipose tissue, triglyceride lipase is activated which results in increased plasma free fatty acids. Increased oxygen consumption and heat production result primarily by action on brown adipose tissue.
  • In heart, proteins like troponin and phospholamban are phosphorylated. The former results in increased interaction with calcium at the myofilaments which causes increased force of contraction; the latter causes the sequestration of calcium by sarcoplasmic reticulum resulting in more rapid relaxation. 

The activated G proteins, in addition, interact directly with the calcium channels in the membrane promoting influx of calcium which reinforce the positive inotropic action exerted through cAMP.

  • In the gut and bronchial muscle, relaxation accompanied with hyperpolarization is induced, but the intermediate steps have not been clearly delineated.  
  • In pancreatic islets, activation of beta-2 receptors on alpha cells increases glucagon secretion, and that on beta cells increases insulin secretion , both by raising intracellular cAMP. However, augmentation of insulin secretion is weak.
  • In bladder, detrusor is relaxed (beta) and trigone is constricted (alpha). Both actions tend to hinder micturition.
  • In uterus, adrenaline can both contract and relax uterine muscle, respectively through alpha and beta receptors. The overall effect varies with species, hormonal and gestational status. Human uterus is relaxed by adrenaline at term of pregnancy, but at other times, its concentrations are enhanced.

4 Potential Side Effects

  • Transient restlessness, headache, palpitation, anxiety, tremor and pallor may occur after s.c./i.m. injection of adrenaline.
  • Marked rise in BP leading to cerebral hemorrhage, ventricular tachycardia/fibrillation, angina, myocardial infarction are the hazards of large doses or inadvertent IV injection of adrenaline.
  • Adrenaline is contraindicated in hypertensive, hyperthyroid and angina patients.
  • Adrenaline should not be given during anesthesia with halothane because of risk of arrhythmias. 
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