Synthesis of norepinephrine

Storage

Release

Termination:

A-Active reuptake:


1-Reuptake into the nerve terminal: this occurs by norepinephrine transporter (NET) which carries NE and similar molecules back into the
cell cytoplasm from the synaptic cleft, called reuptake 1. 


B-Enzymatic metabolism:
NE and epinephrine can be metabolized by several enzymes.
Metabolism is not the primary mechanism for termination of action of NE physiologically released from noradrenergic nerves.
Two enzymes are important:-
1-Monoamine oxidase (MAO) enzyme
2-Catechol-O-methyltransferase (COMT) enzyme

Structure of sympathomimetic:
A-Catecholamines:
They contain catechol nucleus in their structure, 
1-Endogenous: occur naturally in the body
-Epinephrine.
-Nor-epinephrine.
-Dopamine
2- Non-endogenous:
-Non-selective β agonist: Isopreterenol.
-Selective β1 agonist: Dobutamine.


B-Non-catecholamines: Where no catechol nucleus in their structure.
Include the other sympathomimetic drugs.

types of Sympathomimetic Drugs:

A. Direct-acting sympathomimetic drugs:  eg, norepinephrine and epinephrine.
B. Indirect acting sympathomimetic drugs:These indirect agents may have either of two different mechanisms:

(1) They may displace stored catecholamines from the adrenergic nerve ending eg, tyramine


(2) They may decrease the degradation of released norepinephrine either by
(a)Inhibiting reuptake of catecholamines already released eg, cocaine and tricyclic antidepressants.
(b)Preventing the enzymatic metabolism of norepinephrine by: -Monoamine oxidase (MAO) e.g., pargyline which inhibits MAO enzyme. -Catechol- O-methyltransferase (COMT) e.g., entacapone which inhibits COMT enzyme.


C. Mixed acting sympathomimetic drugs: Some drugs have both direct and indirect actions:
e.g. Ephedrine.


Epinephrine

Pharmacological action:
1-Cardio vascular system:
a-Heart: Epinephrine is a powerful cardiac stimulant. 
b-Blood Pressure (B.P)
Epinephrine is one of the most potent vasopressor drugs known. 
C-Vascular effect:
 Biphasic response of epinephrine.
 *Epinephrine reversal:

 -Increase renal vasoconstriction and reduce renal blood flow 

-Direct pulmonary vasoconstriction occurs. 

-Coronary blood flow is enhanced by epinephrine, 

2-GIT: epinephrine produces relaxation of smooth muscle of GIT

3-Urinary bladder: Epinephrine relaxes the detrusor muscle of the bladder 

4-Respiratory tract: -Epinephrine has a powerful bronchodilator action (β2 receptor);

5- Uterus: the response to epinephrine varies with species,

6-CNS: epinephrine cannot cross the BBB, so its effects on CNS are limited.

7-Metabolic Effects: -It elevates the blood glucose (hyperglycemia) 

8-Eyes: Mydriasis is seen during physiological sympathetic stimulation but not when epinephrine is instilled into the conjunctival sac of normal eyes. 

9-Miscellaneous Effects -It increases plasma protein concentration and accelerates blood coagulation by increasing the activity of factor V.

Pharmacokinetic:

1-Absorption: -Epinephrine is not effective after oral administration

2-Fate: Epinephrine is rapidly inactivated in liver by both COMT and MAO enzymes. The drug and its metabolites are excreted in the urine. 

Therapeutic Uses

1-In the past, the most common use of epinephrine was to relieve bronchospasm in cases of bronchial asthma; but now β2-selective agonists are preferred.

2-It provides rapid relief of hypersensitivity reactions,

3-Used to prolong the action of local anesthetics.

4 -Epinephrine is applied topically in nasal packs to stop bleeding (as in epistaxis).

5-It restores the cardiac rhythm in patients with cardiac arrest.

6-It is used to decrease I.O.P in open angle glaucoma.

7-Inhalation of epinephrine is useful in the treatment of post-intubation and infectious croup (laryngotracheobronchitis).

Toxicity, Adverse Effects, and Contraindications:
1-It causes restlessness, headache, tremor, and palpitations.

2- cerebral hemorrhage from the sharp rise in blood pressure.

3-Tachycardia and ventricular fibrillation.

-Precautions for epinephrine use: Hypertension, angina pectoris, hyperthyroidism, diabetes mellitus and heart failure.

-The use of epinephrine is contraindicated in patients receiving non-selective β receptor antagonists,