Medical pharmacology: Autonomic pharmacology

Epinephrine

Metabolic Actions⁴

Free fatty acid concentration in blood is increased by epinephrine-mediated β-adrenergic receptor activation.

Consequently, an increase in triglyceride lipase activity is observed, facilitating triglyceride conversion to free fatty acids and glycerol.

**Triglyceride Lipase (Triacyl-glycerol acylhydrolase)**⁶⁶

Triglyceride lipases hydrolyze ester linkages of triglycerides.⁶⁷

An increase in oxygen consumption (20%-30%) is associated with this process, likely due to increased triglyceride breakdown in brown adipose tissue (brown fat).⁶⁸

Most of total body fat is categorized as either structural lipid (e.g., making up cellular membranes) and neutral fat, stored in adipose cells. Neutral fat may be mobilized by contrast to structural lipid.

Brown fat represents a small percentage of total body fat and, in adults, is mainly localized between the scapulas (at the nape of the neck) as well as along thoracic and abdominal great vessels.

**Brown Fat Cells (Left); White Fat Cells (Right)⁶⁹**

Brown fat (left) cells are polygonal and exhibit considerable cytoplasm and multiple lipid droplets. Nuclei are round and centrally-located.⁶⁹ By contrast, white fat cells have only a limited amount of cytoplasm surround the central, large lipid droplet. Nuclei are flattened and eccentric.⁶⁹

These fat cells (brown fat) have substantial sympathetic nerve innervations, in contrast to white fat deposits.
- Brown fat contains mitochondria (iron associated with mitochondria is responsible for the brown color) that not only support ATP generation but also an additional mechanism by which proton flux is uncoupled from ATP production. This latter mechanism, depending on an uncoupling protein (UCP1), favors heat generation.

Other Epinephrine Effects⁴
- An increase in circulating polymorphonuclear leukocytes.
- An increase in blood coagulation as well as promotion of fibrinolysis.
- A reduction of intraocular pressure, perhaps due to decreased aqueous humor production secondary to both vasoconstriction and increased outflow.
- Epinephrine facilitates neuromuscular transmission, especially following prolonged rapid motoneuronal stimulation.
  - Activation of α-adrenergic receptors by epinephrine promotes enhanced transmitter release from somatic motor neurons (an α₁-effect most likely).
  - This action may explain why an intra-arterial injection of epinephrine in myasthenic patients transiently increases strength of the injected limb.
- Epinephrine and some β₂-selective adrenergic agonists increase physiological tremor, perhaps due at least partially to β-adrenergic receptor mediated increases in muscle spindle discharge.
- Epinephrine causes a decrease in plasma K⁺, secondary to enhanced K⁺ uptake into cells, prominently skeletal muscle cells.
  - This effect on K⁺ is both likely mediated by β₂-adrenergic receptor activation and results in reduced renal K⁺ excretion.
  - Furthermore, activation of β₂-adrenergic receptors may facilitate management of hyperkalemic familial periodic paralysis which is characterized by episodic flaccid paralysis, skeletal muscle depolarization and hyperkalemia.
    - In hyperkalemic periodic paralysis, episodic, generalized weakness appears with a fairly rapid onset and is accompanied by an increase in serum K⁺.⁷⁰
      - Weakness often occurs following a period of rest that in turn followed exercise.
        
        This type of periodic paralysis was initially described in 1951 and within the subsequent decade additional families with this affliction had been identified.
        
        In many presentations minor degrees of myotonia were present and hyperkalemic periodic paralysis was considered in relation to paramyotonia congenita.
      - Hyperkalemic periodic paralysis appears related to a defect in the α-subunit of the sodium channel and there are distinct variants of this clinical disorder.
        
        A common feature is membrane hyperexcitability secondary to a delay in sodium channel inactivation following membrane depolarization.
    - Clinically, the inheritance pattern is autosomal dominant and the patient may exhibit an onset in infancy and childhood.⁷⁰
      - The likelihood of attacks of weakness appears increased before breakfast and later in the day (as noted before, during a rest period following exercise).
        
        The reader is directed to ref. 70 for more details concerning clinical presentation.
    - During the episode of weakness, serum K⁺ rises (not always) up to about 5-6 mmol/L.⁷⁰
      - This increase in K⁺ is also associated with an increase in ECG T wave amplitude and a reduction in serum Na⁺ levels (secondary to Na⁺ influx into muscle) increased urinary K⁺ excretion results in reduced serum K⁺ levels with termination of the episode.
      - Between the episodes, serum K⁺ is often normal or only slightly elevated.
      - Some agents that have been beneficial in management of hyperkalemic periodic paralysis include carbonic anhydrase inhibitors (acetazolamide) and the diuretic hydrochlorothiazide.
        
        In cases in which myotonia appears more problematic than weakness, mexilitine may be helpful. In management of acute and severe episodes, IV calcium gluconate may be beneficial; however, if this treatment is initially unsuccessful then IV glucose or glucose and insulin and hydrochlorothiazide may be helpful in reducing serum K⁺ levels.
  - β₂-selective agents, such as albuterol, reduces impairment in the ability of the skeletal muscle to both accumulate and retain K⁺.
- Larger repeated doses of epinephrine or other sympathomimetic amines in animal models damage the myocardium and arterial walls.
  - Myocardial damage appears very similar to that observed following myocardial infarction.
  - Antagonists to β- and α-receptors along with Ca²⁺ channel antagonists mitigate this pathological action.
  - Patients with pheochromocytoma, the catecholamine liberating tumor, or patients subjected to prolonged norepinephrine infusions may also exhibit similar myocardial and/or arterial wall pathologies.

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