Autonomic pharmacology

β-Adrenergic Receptor Antagonists

Pulmonary effects associated with ß antagonist administration:¹⁵²

Administration of ß-adrenergic receptor antagonists may alter bronchiolar smooth muscle tone.

Nonselective ß receptor antagonists, propranolol (Inderal) is the classical example, blocks ß₂ receptors associated with bronchial smooth muscle.
Although of limited consequence with respect to pulmonary function in normal individuals, individuals with chronic obstructive pulmonary disease (COPD) may experience serious bronchoconstriction.

Asthmatic patients may experience an increase in airway resistance following ß-receptor blockade, even if the agent is classified as a selective ß₁ antagonist.

Possibly newer agents, such as celiprolol which exhibits a combination of both ß₁ receptor selectivity and ß₂ receptor partial agonism may, following clinical evaluation, prove more appropriate in patients exhibiting bronchospastic disease.

Asthma: Differential Diagnosis

During presentation with acute episodic disease, the diagnosis of asthma is typically straightforward given the presence of wheezing and dyspnea.
- As part of the assessment, personal & family history indicative of allergic disease including eczema, urticaria, and rhinitis provides additional support. Asthma is often characterized by nocturnal awakening with wheezing and/or dyspnea.
  - Wheeze²⁵⁶
- If nocturnal awakening is not present, its absence is sufficient to cast doubt concerning the asthma diagnosis. Nevertheless, other conditions may make the asthma diagnosis problematic.
  - For example, airway obstruction caused by tumor or laryngeal edema constitute an alternative to the asthma diagnosis.
    - However, these patients will present with stridor with harsh respiratory sounds that appear localized to particular tracheal area.
    - That is, the more diffuse wheezing throughout the lung fields will be missing.
    - Bronchoscopy or laryngoscopy may be required to resolve the situation.
  - Glottic dysfunction can induce symptoms similar to asthma because these patients narrow their glottis while breathing causing occasional severe airway obstruction with periodic carbon dioxide retention.
    - In these cases, by contrast to asthma, arterial oxygen tension is maintained.
    - Furthermore with glottic narrowing, alveolar-arterial oxygen gradient is maintained in contrast to the alveolar-arterial oxygen gradient widening seen with lower airway obstruction (asthma).
    - Direct examination of the patient will symptoms are present is required to establish glottic narrowing diagnosis.
  - Alternative presentations may be seen in generalized endobronchial disease following foreign body aspiration, bronchial stenosis, or tumor presence. In these cases, persistent wheezing will tend to be quite localized in presented together with coughing paroxysms.
  - Occasionally, acute left ventricular heart failure exhibit some signs and symptoms consistent with asthma; however, gallop rhythms, blood-tinged sputum with basilar rales allow discrimination.
  - Bronchospasm secondary to carcinoid tumors, chronic bronchitis, and recurrent pulmonary emboli also present diagnostic alternatives.
    - With chronic bronchitis one would not expect persistent symptom-free periods; by contrast, in asthma there should be symptoms-free periods, although with chronic bronchitis acute wheezing may occur at this is on top of persistent coughing with sputum production.
    - On the other hand, pulmonary emboli symptoms may be quite close to those exhibited in asthma. For example, episodic breathlessness observed on exertion with wheezing may be common. Pulmonary function diagnostics also may reveal peripheral airway obstruction. Lung scans may be of normal. Differential diagnosis may be aided by patient response to bronchodilator medications and anticoagulant treatment; however, angiographic assessment would be the gold standard in establishing the definitive diagnosis.
- Diagnosis: Asthma must be demonstrated through documentation of reversible airway obstruction in which reversibility may be defined as a 15% or greater increase in FEV1 following two puffs about beta-adrenergic agonist (e.g. terbutaline). If the initial spirometry tests are normal, increased airway reactivity may be unmasked through the use of provocative agents such as methacholine, histamine, or by forcing the patient to hyperventilate cold air.
McFadden, E.R., Jr. "Asthma: Diseases of the Respiratory System" in Harrison's Principles of Internal Medicine, 15th Edition (Braunwald, E., Fauci, A.S., Kasper, D.L., Hauser, S.L, Longo, D.L. and Jameson, J. Larry, eds) pp. 1456-1463, McGraw-Hill Medical Pubishing, Division, New York, 2001
Kelley, H. William, "Asthma" in Pharmacotherapy: A Pathophysiologic Approach, (Dipiro, J.T., Talkbert, R.L. Yee, G.C., Matze, G.R., Wells, B.G. and Posey, L. Michael, eds.) pp 430-459. McGraw-Hill Medical Pubishing, Division, New York, 1999.
McFadden, Jr., E. R., Diseases of the Respiratory System: Asthma, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p 1422.

Metabolic effects associated with ß antagonist administration:¹⁵²
- Carbohydrate and lipid metabolism are altered by the ß-adrenergic receptor antagonists.
  - Normally, catecholamines promote glycogenolysis and favor glucose mobilization in response to hypoglycemia.
  - Non-selective ß-adrenergic receptor blockers may prolong recovery from hypoglycemia in type I diabetes (insulin-dependent); however, this effect is uncommonly noted in type II diabetes. ß-adrenergic receptor blockers can limit glycogenolysis and glucose mobilization responses to hypoglycemia.
- Systemic glucose balance, which aims to maintain a normal plasma glucose level, utilizes hormonal control, neuronal signals and substrate effects which regulate endogenous glucose production as well as glucose utilization.²⁵⁷
  - Insulin plays a dominant role in this regulation since, with declining plasma glucose levels, pancreatic ß cell insulin secretion decreases which in turn increases hepatic glycogenolysis and gluconeogenesis.
    - This analysis suggests that the first defense against hypoglycemia is a reduction in insulin secretion.
  - Should plasma glucose concentration decline somewhat below the physiological range, other hormones are released which would tend to elevate plasma glucose; these hormones are sometimes described as glucose counterregulatory hormones.
    - Prominent in this group is pancreatic α cell glucagon which promotes liver glycogenolysis.
    - Glucagon is considered a second offense against hypoglycemia.
  - In glucagon deficiency, adrenomedullary epinephrine becomes important in stimulation of hepatic gluconeogenesis and glycolysis (as well as renal gluconeogenesis)-so in this circumstance, epinephrine becomes the third line of defense against hypoglycemia.
  - Lastly, with prolonged hypoglycemia, cortisol and growth hormone can support glucose production while limiting glucose utilization.
- There are several manifestations of hypoglycemia, typically occurring as a result of lower levels of CNS glucose.²⁵⁷
  - Hypoglycemia²⁵⁸
  - The range of effects can include behavioral changes, confusion, fatigue, seizures, loss of consciousness and with severe, prolonged hypoglycemia conditions, death.
  - There are important autonomic symptoms of hypoglycemia which occur due to increased sympathoadrenal activity.
    - These symptoms are secondary to increased norepinephrine release from postganglionic sympathetic neurons and epinephrine release from the adrenal medulla.
      - Symptoms include:
        
        palpitations
        
        tremor, and
        
        anxiety (nervousness).
      - Such symptoms aid the diabetic individual in recognizing hypoglycemia; therefore, the masking of the symptoms due to the presence of ß-receptor antagonism can be dangerous.
        
        ß₁-receptor blockers are preferable to the nonspecific agents in that they may be less likely to impede recovery from hypoglycemia.¹⁵²
- Hypoglycemia is considered a limiting factor in glycemic management in diabetes as it causes both recurrent morbidity in most individuals with type I diabetes and recurrent morbidity in many type II diabetic patients.²⁵⁷
  - Additionally, hypoglycemia prevents maintenance of the euglycemic state and therefore limits the attainability of known glycemic control benefits.
  - Another challenge is that recurrent hypoglycemia disposes to hypoglycemia-associated autonomic failure-representing clinical symptoms of both impaired glucose counterregulation and hypoglycemia unawareness.
- Free fatty acids represent an important source of energy and their release is regulated in part by ß-adrenergic receptors.¹⁵²
  - Activation of these receptors promote fatty acid release; moreover, beta-adrenergic receptor antagonists diminish release.
  - Different ß receptor antagonist drugs exhibit different effects on plasma lipids.
    - For example, non-selective ß antagonists decrease HDL cholesterol while increasing both LDL cholesterol and triglycerides.
      - HDL Interactions²⁵⁹
    - On the other hand, ß₁-selective blockers may improve serum lipid profiles in certain patients who exhibit abnormal blood lipid levels.¹⁵²
      - ß₁-selective antagonists that may be helpful in the circumstance include celiprolol, carteolol, nebivolol, carvedilol and bevantolol.
      - Propranolol and atenolol are examples of ß-receptor antagonist that increase triglyceride levels; whereas, chronic celiprolol, carvedilol and carteolol administration appears to decreased plasma triglycerides.
    - As discussed above, administration of ß-adrenergic receptor antagonist medications may mask symptoms of hypoglycemia.¹⁵²
      - However, there are additional effects of ß-antagonists on insulin and insulin sensitivities.
      - Classical ß-blockers, e.g. propranolol, decrease insulin sensitivity.
        
        By contrast, "vasodilating" ß-receptor blockers including celiprolol, nipradilol, carteolol, dilevalol, and carvedilol increase insulin sensitivity and individuals exhibiting insulin resistance.
        
        The combination of improvement in insulin sensitivity through administration of the vasodilating ß-receptor blockers and their beneficial cardiac effects suggest some reduction in hazard associated with diabetes-caused lipid abnormalities.¹⁵²
      - ß-adrenergic receptor agonists affect K⁺ metabolism.¹⁵²
        
        Administration of ß-receptor agonists decreases K⁺ plasma levels, as these drugs favor transport of K⁺ into skeletal muscle.
        
        Epinephrine administration results in a measurable decline in plasma K⁺ concentration.
        
        Hypokalemia secondary to catecholamine release, provoked by stress for example, could be pro-arrhythmogenic.

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