Autonomic pharmacology

Epinephrine

Adrenal Medulla:⁵³

Epinephrine is one of several adrenal medullary catecholamines; other important vasoactive substances secreted by the adrenal medulla include norepinephrine and dopamine.

In humans, catecholamine output measured in the adrenal vein consists mainly of epinephrine.
The source for circulatory norepinephrine is norepinephrine released by adrenergic, sympathetic nerve terminals.
As noted earlier, hydroxylation and decarboxylation of tyrosine results in norepinephrine formation and an additional step, norepinephrine methylation, results in epinephrine. This last step is catalyzed by phenylethanolamine-N-methyltransferase (PNMT), an enzyme found prominently in the adrenal medulla and the brain.
- Epinephrine Biosynthesis

Adrenal medullary PNMT is regulated in part by glucocorticoids, which induce higher enzyme concentrations. Normal adrenal medullary development requires glucocorticoids; note that with 21β-hydroxylase deficiency which results in reduced fetal glucocorticoid secretion, the adrenal medulla is dysplastic. Furthermore, if untreated, 21β-hydroxylase deficiency results in low postnatal circulating catecholamine.

21-Hydroxylase Deficiency⁵⁴
21-hydroxylase deficiency (21-OHD) is the most frequent cause of congenital adrenal hyperplasia (CAH).⁵⁴ The incidence is between 1:10000 and 1:15000 and is also the most frequent reason for androgenization in chromosomal 46, XX females.⁵⁴ Individuals so affected are homozygous or compound heterozygous for serious mutations in the enzyme 21-hydroxylase (CYP21A2).⁵⁴ The consequence of the mutation is a blockade in adrenal glucocorticoid as well as mineralcorticoid synthesis, increasing 17-hydroxyprogesterone and channeling steroid precursors into the androgen synthesis pathway. Such glucocorticoid insufficiency induces a compensatory elevation in adrenocorticotropin (ACTH) causing adrenal hyperplasia with increased synthesis of steroid precursors prior to the enzyme blockade site. The increased androgen synthesis in utero results in androgenization of the female fetus during the first trimester. At birth, ambiguous genitalia including varying degrees of clitoral enlargement and labial fusion may be observed. In males with 21-OHD, excessive androgen production causes gonadotropin-independent precocious puberty. 21-OHD may be associated with "salt-wasting" due to severe combined mineralcorticoid and glucocorticoid deficiencies⁵⁴. This effect may appear between one week and three weeks of life and, since it is may be a life-threatening emergency, fluid resuscitation and steroid treatment must be promptly initiated. A newborn presenting with ambiguous genitalia with bilateral non-palpable gonads may be afflicted with 21-OHD. Male infants (46,XY) with 21-OHD present with no genital abnormalities at birth yet remain susceptible to adrenal insufficiency along with salt-losing crises. Females who exhibit "classic simple virilizing" form of 21-OHD will also exhibit genital ambiguity.⁵⁴ These patients present with impaired cortisol biosynthesis but are not at risk for salt loss. Patients with "nonclassic" 21-OHD will express normal cortisol and aldosterone levels while producing excess androgens. Most common presenting features include hirsutism (60%), oligomenorrhea (50%), and acne (30%). This syndrome represents one of the most frequent human recessive disorders with an associated incidence of about 1:100-1:500 and higher incidences and certain groups. Acute salt-wasting associated with 21-hydroxylase deficiency is characterized by hyperglycemia, hyponatremia, hyperkalemia, low cortisol and aldosterone with elevated 17-hydroxyprogesterone, ACTH, and plasma renin activity.⁵⁴ Neonatal screening tests for increased 17-hydroxyprogesterone allows for presymptomatic diagnosis of classic 21-OHD. Usually, in this circumstance, 17-hydroxyprogesterone is clearly elevated. In adult patients, ACTH stimulation (with 0.25 mg cosyntropin IV), with subsequent assays for 17-hydroxyprogesterone at zero and 30 min. may be helpful in detecting nonclassic 21-OHD and heterozygotes. Patient management:⁵⁴ Acute salt-wasting crises necessitate several steps: fluid resuscitation, correction of hyperglycemia, and IV hydrocortisone. Following patient stabilization, cortical insufficiency should be corrected by administering glucocorticoids; glucocorticoids also suppress ACTH stimulation and as a consequence, prevent further virilization, rapid skeletal maturation, and the development of polycystic ovaries. The treatment approach should likely utilize the lowest glucocorticoid dose that is sufficient to suppress adrenal androgen production while not resulting in indication of glucocorticoid excess (e.g. obesity and impaired growth). Salt-wasting conditions are treated with mineralcorticoid replacement. Infants require typically salt supplements up to the first year of life. Monitoring of mineralcorticoid replacement is based on plasma renin activity and electrolyte assessment. Older adolescents and adults may be treated with prednisolone or dexamethasone at night, providing more complete ACTH suppression. Careful selection of steroid doses and subsequent adjustment on an individual basis limit the likelihood of weight gain, hypertension, and effects on bone turnover. see reference 54 for more detailed discussions.

About 70% of plasma epinephrine is conjugated to sulfate. The sulfate conjugates are biologically inactive. Epinephrine is primarily synthesized in the adrenal medulla and epinephrine localized elsewhere appears most likely due to absorption from the blood rather than local synthesis. However, following bilateral adrenalectomy, low epinephrine levels in the circulation appear; the source of this epinephrine, possibly cardiac adrenergic cells, has not been definitively determined.
Adrenal medullary epinephrine is stored in granules along with ATP and chromagranin A.
Epinephrine secretion occurs following preganglionic neuronal acetylcholine release; these neurons innervate the secretory cells. Acetylcholine increases Ca²⁺ channel conductance thus allowing increased intracellular Ca²⁺. Ca²⁺ influx is an important event in promoting granular exocytosis.
Adrenal medullary epinephrine-containing cells also secrete opioid peptides with most of the circulating met-enkephalin (the precursor molecule is preproenkephalin) derived from the adrenal medulla.
- Lastly, adrenomedullin, a polypeptide that promotes vasodepressor responses is localized in the adrenal medulla.

Epinephrine: Target Organ Effects

Cardiovascular effects of epinephrine are represented in the table below. These effects take into account both activation of β- and α- receptors as appropriate. Epinephrine effects are compared to those of norepinephrine, both following IV administration.

Epinephrine and Norepinephrine Effects on the Heart^4,55
Cardiac Effects	Epinephrine	Norepinephrine
Heart Rate		(following atropine)
Stroke Volume
Cardiac Output		no change,
Coronary Blood Flow
Arrhythmias

= increase
= decrease
infusion: 0.1 to 0.4 μg/kg/min

Epinephrine and Norepinephrine Effects on Blood Pressure^4,55
Blood Pressure Effects	Epinephrine	Norepinephrine
Systolic Arterial pressure
Mean Arterial
Diastolic Arterial pressure	, no change,
Mean Pulmonary Pressure

= increase
= decrease
infusion: 0.1 to 0.4 μg/kg/min

Epinephrine is a potent vasopressor

Systolic pressure increases to a greater extent than diastolic (diastolic pressure may decrease)
- pulse pressure widens
Epinephrine increases blood pressure by:
1. enhancing cardiac contractility (positive inotropic effect): β₁-receptor effects
2. increasing heart rate (positive chronotropic effect): β₁-receptor effects.
3. vasoconstriction α₁ receptor effects
  - precapillary resistance vessels of the skin, kidney, and mucosa
  - veins
If epinphrine is administered relatively rapidly, the elevation of systolic pressure is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate.
- At lower epinephrine doses a reduced effect on systolic pressure is observed.
- Diastolic pressures may decrease as peripheral resistance is reduced. A decrease in peripheral resistance is a result of ß₂-adrenergic receptor activation.

Reflex Control of Arterial Blood Pressure
A principal mechanism for arterial blood pressure control is the baroreceptor reflex. The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck. A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch. As pressure rises and especially for rapid increases in pressure: baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in vasodilatation of the veins and arterioles in the peripheral vascular beds. negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

Epinephrine and Norepinephrine Effects on Peripheral Circulation^4,55
Peripheral Circulation Effects	Epinephrine	Norepinephrine
Total Peripheral Resistance
Cerebral Blood Flow		no change,
Muscle Blood Flow		no change,
Cutaneous Blood Flow
Renal Blood Flow
Splanchnic Blood Flow		no change,

= increase
= decrease
infusion: 0.1 to 0.4 μg/kg/min

Cardiac Effects⁴

Epinephrine exerts a number of cardiac stimulatory effects.
Epinephrine is a primary agonist at β₁ adrenergic receptors influencing both myocardial and specialized conducting tissue and pacemaker cells. α- and other β-adrenergic receptor subtypes are also present.
Epinephrine administration results in an increase in heart rate and changes in cardiac rhythm.
- Increased myocardial work and associated oxygen consumption are increased in accord with enhanced contractility with shortened cardiac systole.
- Myocardial mechanical changes subsequent to epinephrine include:
  - increased rate of rise of isometric tension
  - increased relaxation rate
  - reduced time to peak tension
  - increased excitability (which may predispose to arrhythmias)
  - increased rate of pacemaker cell activity (i.e., increased slope of phase 4 depolarization)
  - increased likelihood of automaticity in some cardiac regions
  - and increases contractile force.
- Epinephrine-induced positive chronotropism (increase in rate) is associated mainly with reduced systole with preservation of diastolic duration.
  - Duration of diastole is important in ensuring sufficient myocardial filling time.
- With epinephrine, the pacemaker cells of the sinoatrial (SA) node reach threshold potential more quickly; this effect occurs because of an increased slope of membrane depolarization towards threshold (phase 4 depolarization).
  - Cardiac Electrical Conduction System⁵⁷
  - Normal Pacemaker Cell Electrophysiological Behavior: Note that the resting membrane potential (Phase 4) is not stable.⁵⁶
  - Action potential amplitude and maximal depolarization rate (phase 0) are also increased. Increased automaticity associated with epinephrine may lead to changes in which SA nodal cells pace the heart, as "latent" pacemakers may emerge.⁴
    - Cells which exhibit spontaneous resting depolarization may be latent pacemakers; however, normally, SA nodal cells reach threshold first.
    - Since epinephrine will accelerate diastolic depolarization in Purkinje fibers, pacemaker activity in these fibers is enhanced. Phase 4 (diastolic) membrane potentials tend to be stable in normal atrial and ventricular muscle fibers with epinephrine usually exhibiting minimal effect.
      - However, at high epinephrine doses, premature ventricular contractions may occur suggesting the possibility that more serious arrhythmias may ensue.
      - If the myocardium has been "sensitized", an effect which has been associated with prior administration of some anesthetics, circulating catecholamines may be sufficient to induce serious ventricular arrhythmias ranging from extrasystoles to fibrillation.
    - In some circumstances conduction velocities through the Purkinje system may be low, secondary to reduced membrane potentials (more positive).
    - Conduction velocity is closely coupled to the value of the membrane potential of the time of depolarization.
      - With reduced membrane potentials (more positive), fewer inward depolarizing channels are activated synchronously; therefore, both the magnitude of the depolarizing effect is less and the rate of rise is reduced.
      - Less inward current flowing translates directly to reduced rate of action potential propagation.
      - Epinephrine tends to increase the membrane potential in Purkinje cells and mitigate or reverse slow action potential propagation due to pre-existing reduced membrane potentials.
Epinephrine decreases the human atrial ventricular (AV nodal) refractory period; however, if the dosage of epinephrine is sufficient to induce a compensatory, vagal (parasympathetic) response, an opposing effect at the AV node would occur (a lengthening of the refractive period).⁴
- This reflex response is another example of the compensatory action inherent in the autonomic nervous system. In this example, an increase in blood pressure due to epinephrine results in an increase in vagal tone, which not only reduces heart rate and contractility but also acts in opposition to the epinephrine effect on the AV nodal refractory period.
- The interplay between sympathetic and parasympathetic tone may predispose to ventricular arrhythmias in view of the epinephrine proarrhythmic action being mitigated in part by blockade of reflex vagal responses.
- Epinephrine-induced arrhythmias are likely due to increases in cardiac automaticity. β-adrenergic receptor antagonists such as propranolol (Inderal) exerts a protective effect against epinephrine-induced arrhythmias.
  - Accidental intravenous epinephrine administration (intended subcutaneous injection) can result in PVCs (premature ventricular contractions) as well as more serious arrhythmias. Epinephrine administration can induce changes in the ECG, particularly T-wave changes.
- Reduced T-wave amplitude and ST segment changes may be observed. ST segmental changes seen following epinephrine appear similar to those observed in angina pectoris.

Epinephrine in management of cardiac arrest^58,58a

Epinephrine is the drug of choice for treating patients in cardiac arrest.⁵⁸
- Vasopressin may be considered if arrest continues following the first dose of epinephrine and vasopressin is considered a possible option to epinephrine.
  - Vasopressin
- In patients presenting with persistent ventricular fibrillation, amiodarone is likely the antiarrhythmic agent of choice, although its administration should be preceded by at least one epinephrine dose.
- Epinephrine activates both α- and β-adrenergic receptors; however, the important epinephrine actions in this context appear mediated by α-receptor activation.
Mechanism of Action: The mechanism of action is based on epinephrine-mediated increases in systemic vascular resistance which secondarily improves both coronary and cerebral perfusion. Epinephrine administration along with β-adrenergic receptor antagonists proved helpful in resuscitation; whereas, epinephrine coadministration with α-receptor blockers were not helpful.⁵⁸
2005 Guidelines indicate: "It is appropriate to administer a 1-mg dose of epinephrine (IV/IO (intraosseous) every 3 to 5 min during adult cardiac arrest (Class IIb). Higher doses may be indicated to treat specific problems, such as β-blocker or calcium channel blocker overdose."^58a
- β-adrenergic effects associated with epinephrine may precipitate, with repeated doses, recurrent ventricular arrhythmias; as a result, intravenous β-adrenergic receptor antagonists might be ineffective antiarrhythmic intervention during resuscitation should several epinephrine doses be administered.
- High-dose epinephrine is not recommended.
Concerning vasopressin: this nonadrenergic peripheral vasoconstrictor has been recommended for use during cardiac arrest, although in two randomized clinical trials no increase in Return of Spontaneous Circulation (ROSC) was noted, when vasopressin was compared to 1 mg epinephrine.⁵⁸

The 2005 Guidelines in its Advance Cardiac Life Support (ACLS) pulseless arrest algorithm notes that single vasopressin does may be substituted for the first 1 of 2 epinephrine doses.⁵⁸^,^58a
- The International Consensus Conference stated that there was insufficient evidence either to refute or support vasopressin uses an alternative to or in combination with epinephrine in any cardiac arrest rhythm.⁵⁸

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