Medical Pharmacology: Adrenenergic Autonomic pharmacology

Epinephrine undergoes rapid oxidation and conjugation in the liver following oral administration.
Therefore, for clinical effectiveness, other routes of administration must be utilized.
α-adrenergic receptor agonist properties of epinephrine cause localized vasoconstriction, which limits subcutaneous epinephrine absorption.
- Improved absorption can be obtained by intramuscular administration.
Both subcutaneous and intramuscular epinephrine injection are utilized for treatment of anaphylaxis.⁷¹
- The subcutaneous route is often favored for "mild" reactions.

In the initial treatment of anaphylaxis, research findings suggest intramuscular epinephrine injection into the thigh is preferable compared to upper arm intramuscular or subcutaneous routes of administration. This conclusion was reached because peak plasma epinephrine concentration was higher following thigh administration (see figure below).⁷¹

**Mean plasma epinephrine concentrations vs time following administration of 0.3 mg dose of epinephrine by i.m or s.c injection⁷¹**

"Mean plasma epinephrine concentrations versus time are shown after administration of an identical 0.3-mg (0.3-mL) dose of epinephrine by IM or SC injection in 2 different sites. T, Thigh; A, upper arm. Mean endogenous plasma epinephrine concentrations are shown after IM or SC injection of 0.9% saline solution (0.3 mL) in the upper arm. The plasma epinephrine concentrations shown were calculated by averaging (mean ± SEM) the epinephrine concentrations at each sampling time for each route and each site of injection."⁷¹

Metabolism:

Epinephrine undergoes rapid metabolism which results in its inactivation.
The hepatic enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are particularly important in epinephrine inactivation.

Monoamine oxidase catalyzes monoamine oxidative deamination. In a reaction that consumes oxygen, an amine group is removed forming the corresponding aldehyde and ammonia.

Monoamine oxidase enzymes contain a covalently linked cofactor FAD (flavin adenine dinucleotide) and therefore described as flavoproteins. The form of the reaction is shown below:⁷²
MAO/FAD catalyzed monoamine deamination reaction⁷²

**Flavin Adenine Dinucleotide (FAD): Ball & Stick Model (top) and Space Filling Model (Bottom)**⁷²

Ribbon diagram of a monomer of human MAO-A, with FAD and clorgiline bound, oriented as if attached to the outer mitochondrial membrane⁷²

Inactivation of epinephrine and catecholamine neurotransmitters such as dopamine and norepinephrine also involves catechol-O-methyltransferase (COMT), an enzyme discoverd by Julius Axelrod in 1957.⁷³

Methyltransferase enzymes catalyze methyl (CH₃)-group transfers with the methyl group in this case provided by S-adenosyl-methionine (SAM).

**Catechol-O-methyl transferase^77,77a**

COMT complex with 3,5-dintrocatechol (dark blue) and S-adenosyl-methionine (yellow), created using PyMol and GIMP.^77,77a

COMT inhibitors such as tocapone (Tasmar, administered in combination with levodopa and carbidopa (Sinemet) and entacapone (Comtan, administered in combination with levodopa and carbidopa ) are used in management of Parkinson's disease. Entacapone does not exhibit anti-Parkinson's effects on its own.
- In August 2010 the FDA notified healthcare professionals that evaluation of clinical trial data indicating patients taking a combination of carbidopa/levodopa and entacapone (the combination drug was Stalevo) might be an increased risk for cardiovascular events including heart attack, stroke, and cardiovascular death, compared to patients taking the combination product Sinemet (carbidopa + levodopa), was undertaken. It is suggested that the reader follow-up on the current status of this FDA evaluation.⁷⁴
Dopamine Degradation⁷⁵
Norepinephrine Degradation⁷⁶

Formulation and stability⁴
- Various epinephrine formulations are available to accommodate differing routes of administration and/or clinical indications.
  - Epinephrine administration may involve:
    - Subcutaneous injection
    - Intramuscular injection
    - Intravenous infusion
    - Topical application
    - Inhalation.
  - The intravenous route provides immediate effect and is administered cautiously with adequate dilution and slow injection.
  - Epinephrine suspensions are available to slow subcutaneous absorption and this preparation should not be injected intravenously.
  - Furthermore, the 1% (10 mg/ml; 1:100) formulation for use by inhalation must not be confused with the 1:1000 solution appropriate for parenteral use.
    - Possible fatal consequences can ensue if 1:100 epinephrine solution is administered parenterally.
  - Epinephrine is well known to be unstable and alkaline solution if exposed to air or light. Oxidation of epinephrine is indicated by a pink color (adrenochrome); subsequent polymer formation results in a brown appearance.

Some clinical applications⁴

A major clinical use for epinephrine is in prompt management of hypersensitivity reactions to drugs and other allergens. Indications include treatment of anaphylaxis.⁴
Cardiac uses include helping to restore normal cardiac rhythm in patients in cardiac arrest..⁴
- Epinephrine is the drug of choice for treating patients in cardiac arrest.^4,58
  - 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
  - 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.
  - 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
Vasocontrictors added to local anesthetic solutions⁷⁸
- Purpose of adding epinephrine to a local anesthetic solution: Increased duration: addition of epinephrine (1:2000,000 or 5 μg/ml) to cause vasoconstriction
  - Reduced systemic absorption
  - Higher anesthetic concentration near nerve fibers
  - Prolongation of conduction blockade (about 50% longer)
  - Reduced systemic absorption (by about 33%)
- Factors influencing the effectiveness of epinephrine on local anesthesia: Dependencies --
  - Which anesthetic is used:
    - Reduced effect of epinephrine on duration of conduction blockade and systemic absorption comparing mepivacaine (Carbocaine) and etidocaine (Duranest) [these are more lipophilic] with lidocaine (Xylocaine), which is less lipophilic
      - More lipophilic local anesthetics will tend on their own to associate strongly with tissues
  - Level of sensory blockade needed for spinal or epidural anesthesia
    - Duration of lower extremity sensory anesthesia extended by epinephrine or phenylephrine (Neo-Synephrine); this effect is not observed for abdominal region anesthesia
      - Conditions: epinephrine (0.2 mg) or phenylephrine (Neo-Synephrine) (2 mg) added to mepivacaine (Carbocaine) or lidocaine (Xylocaine), placed in subarachnoid spaces
  - Spinal anesthesia - tetracaine (pontocaine): duration of action extended by vasoconstrictors
    - Condition 1: epinephrine plus tetracaine (pontocaine) (6 mg, low-dose)- result: increase in spinal anesthesia success rate
    - Condition 2: epinephrine plus tetracaine (pontocaine) (10 mg, higher dose)- result: no increase in spinal anesthesia success rate
- Prolongation of local anesthetic action (no effect by epinephrine on time-to-onset): Mechanisms --
  - Decreased systemic absorption
  - Increased local anesthetic concentration in the vicinity of sensory nerves
  - Increased uptake of the local anesthetic
- Advantages of reduced local anesthetic systemic absorption:
  - Local anesthetic absorption rate more likely to match metabolic rate resulting in less local anesthetic systemic toxicity
- Toxicities associated with systemic epinephrine absorption:
  - Local anesthetic + epinephrine: increased cardiac irritability which may cause an increased risk of cardiac arrhythmias
  - Increased possibility of hypertensive response in susceptible patients
- Other agents which may be added to local anesthetics that affect duration of action
  - Dextran (low-molecular-weight) when added to local anesthetic solutions result in increased peripheral nerve block anesthesia duration (probably due to a reduction in local anesthetic systemic absorption)
Powerful vasoconstrictive actions of epinephrine, mediated by α₁-adrenergic receptor activation, is the basis for effectiveness as a topical hemostatic agent.
- Bleeding surfaces in the mouth or bleeding peptic ulcers (visualized endoscopically) may be managed by epinephrine.

**Some Contraindications to Vasoconstrictor Use and/or Local Anesthetic Drugs**⁷⁹
Recent myocardial infarction (heart attack) (<1 month or symptomatic) Presence of "high-risk" arrhythmia Uncontrolled or severe hypertension Unstable angina Patients receiving digitalis glycosides (e.g. digoxin) Uncontrolled diabetes Uncontrolled hyperthyroidism Moderate to severe asthma (avoid sulfite-containing local anesthetic preparations) Documented "allergy" to anesthetic or vasoconstrictor drug Pheochromocytoma Drug abuse--cocaine, methamphetamine, amphetamine (known use within prior 6-24 hour minimum, depending on agent ingested

**Some Relative Contraindications to Vasoconstrictor Use and/or Local Anesthetic Drugs**⁷⁹
Disease or Drug Issue	Selection Consideration
Stroke history	limit vasoconstrictor
Cardiovascular conditions; and/or patient taking nonselective beta antagonists, antihypertensive drugs.	limit vasoconstrictor
Hypoglycemic agents, insulin	limit vasoconstrictor
Hyperthyroidism	limit vasoconstrictor
Monoamine oxidase inhibitors (MAO inhibitors)	limit vasoconstrictor
Anticonvulsants, e.g. phenytoin	limit vasoconstrictor

Epinephrine inhalation may be helpful in management of post-intubation and infectious croup.⁴

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