• Actions of epinephrine:Actions of epinephrine:1- Cardiovascular:1- Cardiovascular:

• The The major actions of epinephrine major actions of epinephrine are are on the on the cardiovascular system.cardiovascular system.

• Epinephrine strengthens the Epinephrine strengthens the contractilitycontractility of of the the myocardiummyocardium (positive inotropic: (positive inotropic: ββ11 action) action)

and increases its and increases its rate of contraction rate of contraction (positive (positive chronotropicchronotropic: : ββ11 action). Cardiac output action). Cardiac output

therefore increases. therefore increases.

•With these effects comes increased With these effects comes increased oxygen oxygen demandsdemands on the on the myocardium. myocardium.

• Epinephrine Epinephrine constrictsconstricts arterioles arterioles in in the the skin, mucous membranes, and skin, mucous membranes, and viscera viscera ((αα effects), and it effects), and it dilates dilates vesselsvessels going to the going to the liver and skeletal liver and skeletal muscle (muscle (ββ22 effects). effects).

–RenalRenal blood flow is blood flow is decreaseddecreased. . Therefore, the cumulative effect is an Therefore, the cumulative effect is an increaseincrease in in systolic blood pressuresystolic blood pressure, , coupled with a coupled with a slight decrease slight decrease in in diastolic pressure .diastolic pressure .

2- 2- Respiratory:Respiratory:• Epinephrine causes powerful bronchodilator by Epinephrine causes powerful bronchodilator by acting directly on acting directly on bronchial smooth muscle (bronchial smooth muscle (ββ22

action). action).

•This action relieves all known This action relieves all known allergic or allergic or histamine-induced bronchoconstriction. histamine-induced bronchoconstriction.

•In the case of In the case of anaphylactic shockanaphylactic shock, this can be , this can be lifesaving.lifesaving.

•epinephrine rapidly relieves epinephrine rapidly relieves the the dyspneadyspnea and and increases volume of increases volume of gases inspired and expired.gases inspired and expired.

•EpinephrineEpinephrine also also inhibitsinhibits the the releaserelease of of allergy allergy mediators such as histamines mediators such as histamines from mast cells.from mast cells.

3- Hyperglycemia:3- Hyperglycemia:

•Epinephrine has a Epinephrine has a significant significant hyperglycemic hyperglycemic effect because of :effect because of :A- A- increase glycogenolysis increase glycogenolysis in the liver (in the liver (ββ22 effect). effect).

B- B- increasedincreased release of release of gglucagonlucagon ((ββ22 effect). effect).

C- C- decreased decreased release of release of insulin insulin ((αα22 effect). effect).

These effects are mediated via the cAMP These effects are mediated via the cAMP

mechanismmechanism..

4- Lipolysis:4- Lipolysis:

•Epinephrine Epinephrine initiates lipolysis initiates lipolysis through through its agonist activity on the its agonist activity on the ββ receptors of receptors of adipose tissue, which stimulation a adipose tissue, which stimulation a hormone-sensitive lipase,hormone-sensitive lipase, which which hydrolyzes hydrolyzes triacylglycerols to triacylglycerols to free fatty free fatty acids and glycerol.acids and glycerol.

• Biotransformations:Biotransformations:• Epinephrine, like the other Epinephrine, like the other

catecholamines, is metabolized by two catecholamines, is metabolized by two enzymatic pathways:enzymatic pathways:

• 1- MAO 1- MAO • 2- COMT, 2- COMT, • The final metabolites found in the urine .The final metabolites found in the urine .

• Therapeutic usesTherapeutic uses1- In Bronchospasm:1- In Bronchospasm:

•EpinephrineEpinephrine is the primary drug used in is the primary drug used in the emergency in treatment of acute the emergency in treatment of acute asthma and anaphylactic shock. asthma and anaphylactic shock.

•epinephrine is the epinephrine is the drug of choicedrug of choice; ; within a few minutes after within a few minutes after subcutaneous subcutaneous administrationadministration, greatly improved , greatly improved respiration. respiration.

• Administration may be repeated after a Administration may be repeated after a few hours. few hours.

• However, selective However, selective ββ22 agonists, such as agonists, such as

AlbuterolAlbuterol are favored in the are favored in the chronic chronic treatment of asthma treatment of asthma because:because:

1- 1- longer durationlonger duration of action of action

2- 2- minimal cardiac minimal cardiac stimulatory effect.stimulatory effect.

2- Glaucoma: 2- Glaucoma:

•In ophthalmology, 2% epinephrine In ophthalmology, 2% epinephrine solution may be used topically to solution may be used topically to reduce reduce intraocular pressure in open-intraocular pressure in open-angle glaucoma. angle glaucoma.

•It It reduces the production of reduces the production of aqueous humor aqueous humor by by vasoconstriction vasoconstriction of the of the ciliary body ciliary body blood vessels.blood vessels.

3- Anaphylactic shock: 3- Anaphylactic shock:

Epinephrine is the drug of choice for the Epinephrine is the drug of choice for the treatment of treatment of Type I hypersensitivity Type I hypersensitivity reactions reactions in response to allergens.in response to allergens.

4- Cardiac arrest:4- Cardiac arrest:

Epinephrine may be used to Epinephrine may be used to restore restore cardiac rhythmcardiac rhythm in patients with in patients with cardiac cardiac arrestarrest..

5- With local anesthesia 5- With local anesthesia

•Local anesthetic solutions usually contain 1:100,000 Local anesthetic solutions usually contain 1:100,000 parts epinephrine. parts epinephrine.

•The effect of the drug is to:The effect of the drug is to:

• 1-1-increase the duration of the local anesthesiaincrease the duration of the local anesthesia by by producing producing vasoconstriction at the site of injectionvasoconstriction at the site of injection, ,

thereby thereby allowingallowing the local anesthetic the local anesthetic to persist to persist at at the injection site the injection site before being absorbed before being absorbed into the into the circulation and metabolized. circulation and metabolized.

•2-Very weak solutions of epinephrine (1:100,000) 2-Very weak solutions of epinephrine (1:100,000) can also be used can also be used topically to vasoconstrict mucous topically to vasoconstrict mucous membranes to control membranes to control oozingoozing of capillary blood. of capillary blood.

Adverse effectsAdverse effects1- CNS disturbances: 1- CNS disturbances: Epinephrine can produce Epinephrine can produce

adverse CNS effects that include anxiety, fear, adverse CNS effects that include anxiety, fear,

tension, headache, and tremor.tension, headache, and tremor.

2-Cerebral hemorrhage: 2-Cerebral hemorrhage: The drug may induce The drug may induce

cerebral hemorrhage as a result of cerebral hemorrhage as a result of elevation blood elevation blood

pressure.pressure.

3- Cardiac arrhythmias: 3- Cardiac arrhythmias: Epinephrine can trigger Epinephrine can trigger

cardiac cardiac arrhythmias.arrhythmias.4- Pulmonary edema: 4- Pulmonary edema: Epinephrine can induce pulmonary Epinephrine can induce pulmonary

edema.edema.

InteractionsInteractions::1-Hyperthyroidism:1-Hyperthyroidism:

•EpinephrineEpinephrine enhancedenhanced cardiovascularcardiovascular actions actions in patients with in patients with hyperthyroidism. hyperthyroidism.

•If If epinephrine is requiredepinephrine is required in such an in such an individual, individual, the dose must be reduced. the dose must be reduced. •The mechanism appears to involve The mechanism appears to involve increased increased production production of adrenergic of adrenergic receptorsreceptors on the on the vasculature of the hyperthyroid individualvasculature of the hyperthyroid individual, , leading to a leading to a hypersensitivehypersensitive response. response.

2-Cocaine:2-Cocaine:•In the presence of In the presence of cocainecocaine, epinephrine , epinephrine produces produces exaggerated cardiovascular exaggerated cardiovascular actions. actions.

•This is due to the ability of cocaine to This is due to the ability of cocaine to prevent prevent reuptake reuptake of catecholamines of catecholamines into into the adrenergic neuron; the adrenergic neuron; thus, like thus, like norepinephrine,norepinephrine, epinephrine remains at epinephrine remains at the receptor site for the receptor site for longer periods of longer periods of time.time.

3- Diabetes:3- Diabetes:

•Epinephrine increases the release Epinephrine increases the release of endogenous of endogenous stores of stores of glucoseglucose. In . In the diabetic, the diabetic, dosages of insulin dosages of insulin administration administration may have to be may have to be increased.increased.

4- 4- ββ-Blockers: -Blockers:

These agents (These agents (ββ-Blockers-Blockers) ) prevent prevent epinephrine's epinephrine's effects on effects on ββ receptors receptors, leaving , leaving αα- receptor - receptor stimulation. stimulation.

This may lead to an This may lead to an increase in peripheral increase in peripheral resistance resistance and an and an increase in blood pressureincrease in blood pressure..

5- Inhalation anesthetics:5- Inhalation anesthetics:

• Inhalational anesthetics Inhalational anesthetics sensitize the heart to sensitize the heart to the effects of epinephrinethe effects of epinephrine, which may lead to , which may lead to tachycardia.tachycardia.

B. NorepinephrineB. NorepinephrineBecause norepinephrine is the Because norepinephrine is the

neuromediator of adrenergic nerves, neuromediator of adrenergic nerves, it should it should theoreticallytheoretically stimulate stimulate all all types of adrenergic receptorstypes of adrenergic receptors. .

In practice, when the drug is given in In practice, when the drug is given in

therapeutic doses to humans, therapeutic doses to humans, the the αα--adrenergic receptor is most adrenergic receptor is most affectedaffected..

• Cardiovascular actions:Cardiovascular actions:

• Vasoconstriction:Vasoconstriction:

• Norepinephrine causes a rise in Norepinephrine causes a rise in peripheral resistance peripheral resistance due to intense due to intense vasoconstriction of most vascularvasoconstriction of most vascular beds, beds, including the including the kidneykidney ( (αα11 effect). effect).

• Both Both systolic and diastolic systolic and diastolic blood blood pressures increase.pressures increase.

• NorepinephrineNorepinephrine causes greater causes greater vasoconstrictionvasoconstriction than than epinephrineepinephrine, , because : it does not induce because : it does not induce vasodilation vasodilation via via ββ22 receptors on blood vessels receptors on blood vessels

supplying skeletal supplying skeletal muscles.muscles.

• The The weak weak ββ22 activity of norepinephrine activity of norepinephrine

also explains why it is not useful in the also explains why it is not useful in the treatment of treatment of asthma.asthma.]]

Therapeutic usesTherapeutic uses : :1- Norepinephrine is used to treat 1- Norepinephrine is used to treat

shockshock, because it , because it increases vascular increases vascular

resistanceresistance and, therefore, and, therefore, increases increases

blood pressure.blood pressure.•Other actions of norepinephrine are not considered to be Other actions of norepinephrine are not considered to be clinically significant.clinically significant.

• It is It is nevernever used for used for asthmaasthma or in combination with or in combination with local local anesthetics.anesthetics.

•

• Norepinephrine is a potent Norepinephrine is a potent vasoconstrictor vasoconstrictor and will cause and will cause extravasationextravasation (discharge of (discharge of blood blood from vessel into tissues)from vessel into tissues) along the along the injection site. injection site.

PharmacokineticsPharmacokinetics:: • Norepinephrine may be Norepinephrine may be given IV given IV for for rapid rapid

onset onset of action.of action.• The The duration duration of action is of action is 1 to 2 1 to 2 minutes minutes

following the following the end of the infusion periodend of the infusion period..• It is poorly absorbed after It is poorly absorbed after subcutaneous subcutaneous

injectioninjection..• and is and is destroyed in the gut destroyed in the gut if administered if administered

orally. orally. • Metabolism Metabolism is similar to that of epinephrine.is similar to that of epinephrine.

• Adverse effects: Adverse effects: • These are similar to those of These are similar to those of epinephrine.epinephrine.

In addition, norepinephrine may In addition, norepinephrine may cause cause blanching and sloughingblanching and sloughing of skin along of skin along injected injected vein(due to extreme vasoconstriction).vein(due to extreme vasoconstriction).

C-IsoproterenolC-Isoproterenol

Isoproterenol is a Isoproterenol is a direct-acting synthetic direct-acting synthetic catecholamine that predominantly catecholamine that predominantly stimulates both stimulates both ββ11- and - and ββ22-adrenergic -adrenergic

receptors. receptors. Its non selectivity Its non selectivity is one of the reason is one of the reason

why it is why it is rarely used therapeutically.rarely used therapeutically. Its action on Its action on αα receptors is receptors is insignificant.insignificant.

• Actions:Actions:• Cardiovascular:Cardiovascular:

• IIsoproterenolsoproterenol produces produces intense intense stimulationstimulation of the of the heart heart to increase its to increase its rate rate and force of contractionand force of contraction, causing , causing increased increased cardiac output .cardiac output .

• It is It is as active as epinephrine as active as epinephrine in this action in this action and, therefore, is useful in the treatment of and, therefore, is useful in the treatment of atrioventricular block or cardiac arrest.atrioventricular block or cardiac arrest.

•

IsoproterenoIsoproterenol also l also dilates the dilates the arterioles of skeletal muscle arterioles of skeletal muscle ((ββ22

effect), resulting in effect), resulting in decreased decreased peripheral resistance. peripheral resistance.

• Pulmonary: Pulmonary: • A A profound and rapid bronchodilation profound and rapid bronchodilation

is produced by the drug (is produced by the drug (ββ2 2 action).action).

• Isoproterenol is as active as epinephrine Isoproterenol is as active as epinephrine and rapidly and rapidly alleviates an acute attack alleviates an acute attack of asthmaof asthma when taken by when taken by inhalationinhalation (which is the recommended route). (which is the recommended route).

• This action lasts about This action lasts about 1 hour 1 hour and may and may be repeated by subsequent doses.be repeated by subsequent doses.

• Other effects: Other effects:

• Other actions on Other actions on ββ receptors, such as receptors, such as increased blood sugar and increased increased blood sugar and increased lipolysis, can be demonstrated but are lipolysis, can be demonstrated but are not clinically significant.not clinically significant.

• Therapeutic uses: Therapeutic uses: • IsoproterenolIsoproterenol is now is now rarely rarely used as a used as a

bronchodilator in asthma. bronchodilator in asthma. • It can be employed to It can be employed to stimulate the stimulate the

heart in emergency situationsheart in emergency situations..

• Pharmacokinetics: Pharmacokinetics: • Isoproterenol can be absorbed Isoproterenol can be absorbed

systemically by the systemically by the sublingual mucosa sublingual mucosa but is morebut is more absorbed when given absorbed when given parenterallyparenterally or as an or as an inhaled aerosolinhaled aerosol..

• It is a marginal substrate for COMT and It is a marginal substrate for COMT and is stable to MAO action.is stable to MAO action.

• Adverse effects: Adverse effects: • The adverse effects of isoproterenol are The adverse effects of isoproterenol are

similar to those of epinephrine.similar to those of epinephrine.

D. DopamineD. Dopamine The The immediate metabolic precursor immediate metabolic precursor of of

norepinephrine, occurs naturally in the norepinephrine, occurs naturally in the CNSCNS functions as a neurotransmitter, as functions as a neurotransmitter, as well as in the well as in the adrenal medulla.adrenal medulla.

Dopamine can activate Dopamine can activate αα- and - and ββ--adrenergic receptorsadrenergic receptors. For example, at . For example, at higher doseshigher doses, , it can it can cause vasoconstriction cause vasoconstriction

by activating by activating αα11 receptors, whereas at receptors, whereas at

lower doseslower doses, , it it stimulates stimulates ββ11 cardiac receptors cardiac receptors. .

In addition, In addition, DD11 and D and D22 dopaminergic dopaminergic

receptors, occur in the receptors, occur in the peripheral mesenteric peripheral mesenteric and renal vascular beds, and renal vascular beds, where binding of where binding of dopamine produces dopamine produces vasodilationvasodilation. .

• Actions:Actions:

• Cardiovascular:Cardiovascular:

• Dopamine Dopamine exerts a exerts a stimulatory effect stimulatory effect on on the the ββ11 receptors receptors of the heart, having both of the heart, having both

inotropic and chronotropic effects.inotropic and chronotropic effects.

• At very At very high doses, high doses, dopamine activates dopamine activates

α α 11 receptors receptors on the vasculature, on the vasculature, resulting in resulting in

vasoconstriction.vasoconstriction.

• Renal and visceral:Renal and visceral:• Dopamine Dopamine dilates renal and splanchnic dilates renal and splanchnic

arterioles arterioles by activating by activating dopaminergic dopaminergic receptorsreceptors, thus , thus increasing blood flow increasing blood flow to to the kidneys and other viscera .the kidneys and other viscera .

• Therefore, Therefore, dopamine is clinically useful in dopamine is clinically useful in the treatment of shockthe treatment of shock,. ,.

Therapeutic usesTherapeutic uses::

• 1- Dopamine is the drug of choice for 1- Dopamine is the drug of choice for shock and is given by continuous shock and is given by continuous infusion.infusion.

2- 2- It It raises the blood pressure raises the blood pressure by by stimulating:stimulating:

• A- A- ββ11 receptors on the heart receptors on the heart to increase to increase

• cardiac output,cardiac output,• B- B- αα11 receptors receptors on blood vessels to on blood vessels to

• increase total peripheral resistance. increase total peripheral resistance.

• 3- 3- enhances perfusion enhances perfusion to the to the kidney and kidney and splanchnic splanchnic areas.areas.

• An An increased blood flow increased blood flow to the kidney to the kidney enhances the glomerular filtration rate and enhances the glomerular filtration rate and causes causes sodium diuresis. sodium diuresis.

• Adverse effects:Adverse effects:• An overdose of dopamine produces the An overdose of dopamine produces the

same effects as sympathetic stimulation.same effects as sympathetic stimulation.• Dopamine is rapidly metabolized by MAO Dopamine is rapidly metabolized by MAO

or COMT.or COMT.• adverse effectsadverse effects • (nausea, hypertension, arrhythmias)(nausea, hypertension, arrhythmias)

DobutamineDobutamine•Actions: •Dobutamine is a synthetic, direct-acting catecholamine that is a β1-receptor agonist. • It increases cardiac rate and output with few vascular effects.

•Therapeutic uses:• Dobutamine is used to increase cardiac output in congestive heart failure as well as for inotropic support after cardiac surgery.