6/5/13

Epinephrine

Epinephrine [ep-i-NEF-rin] is one of four catecholamines—epinephrine, norepinephrine, dopamine, and dobutamine— commonly used in therapy. The first three catecholamines occur naturally in the body as neurotransmitters; the latter is a synthetic compound. Epinephrine is synthesized from tyrosine in the adrenal medulla and released, along with small quantities of norepinephrine, into the bloodstream. Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are strongest.


1. Actions:

 a. Cardiovascular:
The major actions of epinephrine are on the cardiovascular system. Epinephrine strengthens the contractility of the myocardium (positive inotropic: β1 action) and increases its rate of contraction (positive chronotropic: β1 action). Cardiac output therefore increases. With these effects comes increased oxygen demands on the myocardium. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects). Renal blood flow is decreased. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure. 

Figure: Cardiovascular effects of intravenous infusion of low doses of epinephrine.



b. Respiratory: 
Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action). This action relieves all known allergic- or histamine-induced bronchoconstriction. In the case of anaphylactic shock, this can be lifesaving. In individuals suffering from an acute asthmatic attack, epinephrine rapidly relieves the dyspnea (labored breathing) and increases the tidal volume (volume of gases inspired and expired). Epinephrine also inhibits the release of allergy mediators such as histamines from mast cells

c. Hyperglycemia:
Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect). These effects are mediated via the cAMP mechanism. d. Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue, which upon stimulation activate adenylyl cyclase to increase cAMP levels. Cyclic AMP stimulates a hormone-sensitive lipase, which hydrolyzes triacylglycerols to free fatty acids and glycerol.4 2. Biotransformations: Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO, and COMT, which has S-adenosylmethionine as a cofactor . The final metabolites found in the urine are metanephrine and vanillylmandelic acid. [Note: Urine also contains normetanephrine, a product of norepinephrine metabolism.]



 3. Therapeutic uses

a. Bronchospasm:
Epinephrine is the primary drug used in the emergency treatment of any condition of the respiratory tract when bronchoconstriction has resulted in diminished respiratory exchange. Thus, in treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice; within a few minutes after subcutaneous administration, greatly improved respiratory exchange is observed. Administration may be repeated after a few hours. However, selective β2 agonists, such as albuterol, are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect.

b. Glaucoma:
In ophthalmology, a two-percent epinephrine solution may be used topically to reduce intraocular pressure in open-angle glaucoma. It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels. c. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. 

d. Cardiac arrest:
Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause. 

e. Anesthetics:
Local anesthetic solutions usually contain 1:100,000 parts epinephrine. The effect of the drug is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the injection site before being absorbed into the circulation and metabolized. Very weak solutions of epinephrine (1:100,000) can also be used topically to vasoconstrict mucous membranes to control oozing of capillary blood. 


4. Pharmacokinetics: 

Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). In emergency situations, epinephrine is given intravenously for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, by inhalation, or topically to the eye 


Figure :Pharmacokinetics of epinephrine.


Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only metabolites are excreted in the urine


5. Adverse effects:

a. CNS disturbances: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor.
 b. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure.
c. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving digitalis.
d. Pulmonary edema: Epinephrine can induce pulmonary edema. 



6. Interactions: 

a. Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in patients with hyperthyroidism. If epinephrine is required in such an individual, the dose must be reduced. The mechanism appears to involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response. 

b. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron; thus, like norepinephrine, epinephrine remains at the receptor site for longer periods of time




Figure  Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)



c. Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. 

d. β-Blockers: These agents prevent epinephrine's effects on b receptorsA. Ephedrine and pseudoephedrine Ephedrine [e-FED-rin], and pseudoephedrine [soo-doe-e-FED-rin] are plant alkaloids, that are now made synthetically. These drugs are mixed-action adrenergic agents. They not only release stored norepinephrine from nerve endings



but also directly stimulate both α and β receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS; however, pseudoephedrine has fewer CNS effects. Ephedrine is eliminated largely unchanged in the urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in the urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation.

Ephedrine produces bronchodilation, but it is less potent than epinephrine or isoproterenol in this regard and produces its action more slowly. It is therefore sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather than to treat the acute attack. Ephedrine enhances contractility and improves motor function in myasthenia gravis, particularly when used in conjunction with anticholinesterases .Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance.

Ephedrine has been used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to raise blood pressure. Pseudoephedrine is primarily used to treat nasal and sinus congestion or congestion of the eustachian tubes. [Note: The clinical use of ephedrine is declining due to the availability of better, more potent agents that cause fewer adverse effects. Ephedrine-containing herbal supplements (mainly ephedra-containing products) were banned by the U.S. Food and Drug Administration in April 2004 because of lifethreatening cardiovascular reactions. Pseudoephedrine has been illegally converted to methamphetamine. Thus, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter.] 


e. Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the effects of epinephrine, which may lead to tachycardia.




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1 comment:

  1. One of the most interesting drugs for pharmacology practicals.
    So much one can do with it! :-)

    ReplyDelete