Copyright © 2001. W. B. Saunders Company. All Rights Reserved.

Adrenergic AgonistsAdrenergic Agonists

• Produce their effects by activating adrenergic receptors

• Adrenergic receptors are

– Alpha 1

– Alpha 2

– Beta 1

– Beta 2

– Dopamine

• Produce their effects by activating adrenergic receptors

• Adrenergic receptors are

– Alpha 1

– Alpha 2

– Beta 1

– Beta 2

– Dopamine

Adrenergic receptors (adrenoceptors)Adrenergic receptors (adrenoceptors) Two families of receptors: Two families of receptors: αα and and ββ, were , were

identified on the basis of their responses to the identified on the basis of their responses to the adrenergic agonists: adrenergic agonists: epinephrine, epinephrine, norepinephrine, and isoproterenol. norepinephrine, and isoproterenol.

• α α receptor divided to : receptor divided to : αα11 and and αα22 Receptors Receptors. .

• The The αα-adrenoceptors : a -adrenoceptors : a weak response weak response to the to the synthetic synthetic agonist agonist isoproterenolisoproterenol, but they are , but they are responsive to the responsive to the naturally occurring naturally occurring catecholamines (catecholamines (epinephrine and norepinephrineepinephrine and norepinephrine).).

• For For αα receptors, receptors, the rank order of potency the rank order of potency is is epinephrine epinephrine >> norepinephrine >> isoproterenol. norepinephrine >> isoproterenol.

• The The αα-adrenoceptors are subdivided into two -adrenoceptors are subdivided into two subgroups, subgroups, αα11 and and αα22, , based on their based on their affinities affinities

for for αα agonists and antagonist agonists and antagonist drugs.drugs.• For example, the For example, the αα11 receptors receptors have a higher have a higher

affinity for affinity for phenylephrinephenylephrine than than αα22 receptors. receptors.

• Conversely, Conversely, the drug the drug clonidineclonidine selectively selectively binds to binds to αα22 receptors and has less effect receptors and has less effect on on αα11

receptors.receptors.

αα11 Receptors: Receptors: These receptors are present on the These receptors are present on the postsynapticpostsynaptic

membrane membrane of the of the effector organseffector organs

Activation of Activation of αα11 receptors receptors initiatesinitiates a series of a series of

reactions through a reactions through a G protein activation G protein activation of of phospholipase C, resulting in the phospholipase C, resulting in the generation of generation of inositol trisphosphate (IPinositol trisphosphate (IP33) ) and diacylglycerol and diacylglycerol

(DAG) (DAG) from phosphatidylinositol. from phosphatidylinositol.

IPIP33 initiates the initiates the release of Carelease of Ca2+2+ from the from the

endoplasmic reticulum into the cytosol, and endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell.DAG turns on other proteins within the cell.

MCMP 407

NH3

COOH

Gq

Phospho-lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways

1 adrenergic

receptor

HO

HO CH

OH

CH2 NH2

Norepinephrine

αα22 Receptors: Receptors: These receptors, located on These receptors, located on presynaptic nerve presynaptic nerve

endings endings and on other cells, such as the and on other cells, such as the ββ cell cell of the pancreas, and on certain vascular of the pancreas, and on certain vascular smooth muscle cells. smooth muscle cells.

When a sympathetic adrenergic nerve is When a sympathetic adrenergic nerve is stimulated, the released stimulated, the released norepinephrinenorepinephrine in the in the synaptic cleft and interacts with the synaptic cleft and interacts with the αα11 receptors. receptors.

A portion of the released A portion of the released norepinephrine norepinephrine (circles back) and reacts with (circles back) and reacts with αα22 receptors on receptors on

the neuronal membrane .the neuronal membrane .

The stimulation of the The stimulation of the αα22 receptor causes receptor causes feedback feedback

inhibitioninhibition the the release of norepinephrine from the release of norepinephrine from the stimulated adrenergic neuron.stimulated adrenergic neuron.

This inhibitory action This inhibitory action decreases further output decreases further output from the adrenergic neuron and serves as a local from the adrenergic neuron and serves as a local modulating mechanism for reducing modulating mechanism for reducing sympathetic neuromediator sympathetic neuromediator output when there is output when there is high sympathetic activity. high sympathetic activity.

[Note: In this instance these receptors are acting as [Note: In this instance these receptors are acting as inhibitory autoreceptors.]inhibitory autoreceptors.]

αα22 Receptors are also found on presynpatic Receptors are also found on presynpatic

parasympathetic neurons. parasympathetic neurons. NorepinephrineNorepinephrine released from released from a a presynapticpresynaptic

sympatheticsympathetic neuron can neuron can diffuse to and diffuse to and interact with these (receptorsinteract with these (receptors α α2)2) Receptors Receptors, ,

inhibiting acetylcholine release .inhibiting acetylcholine release . This is another local modulating mechanism to control This is another local modulating mechanism to control

autonomic activity in a given area.autonomic activity in a given area.

In contrast to In contrast to αα11 receptors, the effects of receptors, the effects of

binding at binding at αα22 receptors are mediated by receptors are mediated by

inhibition of adenylyl cyclase and a fall in the inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.levels of intracellular cAMP.

ββ Receptors: Receptors: These are characterized by a These are characterized by a strong response strong response

to to isoproterenol, isoproterenol, with with lessless sensitivity to sensitivity to epinephrine and norepinephrine.epinephrine and norepinephrine.

For For ββ receptors, the rank order of receptors, the rank order of potency is :potency is :

isoproterenol > epinephrine > norepinephrine. isoproterenol > epinephrine > norepinephrine. The The β β -adrenoceptors can be subdivided into -adrenoceptors can be subdivided into

major subgroups major subgroups ββ11 and and ββ22 based on their based on their

affinities for adrenergic agonists and affinities for adrenergic agonists and antagonists.antagonists.

ββ11 Receptors have approximately Receptors have approximately equalequal

affinities for epinephrine and norepinephrineaffinities for epinephrine and norepinephrine, , whereas whereas ββ22 receptors have a receptors have a higher higher

affinity for affinity for epinephrineepinephrine than for than for norepinephrine. norepinephrine.

Thus, tissues with a predominance of Thus, tissues with a predominance of ββ22

receptors (such as receptors (such as the vasculature of the vasculature of skeletal muscleskeletal muscle) ) are particularly are particularly responsive to the hormonal effects of responsive to the hormonal effects of circulating circulating epinephrine epinephrine released by the released by the adrenal medullaadrenal medulla. .

Binding of a neurotransmitter at any Binding of a neurotransmitter at any of of β β rereceptors ceptors results in activation results in activation of adenylyl cyclase and, therefore, of adenylyl cyclase and, therefore, increased concentrations of cAMP increased concentrations of cAMP within the cell.within the cell.

Copyright © 2001. W. B. Saunders Company. All Rights Reserved.

Dopamine Receptor ActivationDopamine Receptor Activation

Dopamine receptors are located in the kidney Stimulated by dopamine

Causes dilation of the following blood vessels, resulting in increased blood flow Renal Mesenteric Coronary Cerebral.

• Therapeutic uses

– Dilates renal vasculature

– Enhances cardiac performance

Dopamine receptors are located in the kidney Stimulated by dopamine

Causes dilation of the following blood vessels, resulting in increased blood flow Renal Mesenteric Coronary Cerebral.

• Therapeutic uses

– Dilates renal vasculature

– Enhances cardiac performance

• Distribution of receptors:Distribution of receptors:• Tissues such as the Tissues such as the vasculature to vasculature to

skeletalskeletal muscle have both muscle have both αα11 and and ββ22

receptors, but the receptors, but the ββ22 receptors receptors

predominate.predominate.• The The heart contains heart contains predominantly predominantly ββ11

receptors.receptors.

• Characteristic responses mediated Characteristic responses mediated by adrenoceptors: by adrenoceptors:

• As a generalization, stimulation of As a generalization, stimulation of αα11

receptors receptors produces vasoconstriction produces vasoconstriction (particularly in skin and abdominal (particularly in skin and abdominal viscera) viscera) and an increase in total and an increase in total peripheral resistance and blood peripheral resistance and blood pressure. pressure.

• Conversely, stimulation of Conversely, stimulation of ββ11 receptors receptors

characteristically causes characteristically causes cardiac cardiac stimulationstimulation, ,

• whereas stimulation ofwhereas stimulation of ββ22 receptors receptors

produces vasodilationproduces vasodilation (in skeletal (in skeletal vascular beds) and vascular beds) and bronchiolar bronchiolar relaxation.relaxation.

• Desensitization of receptors:Desensitization of receptors:• Prolonged exposure Prolonged exposure to the to the catecholaminescatecholamines

reduces the responsiveness of these receptors, reduces the responsiveness of these receptors, a phenomenon known a phenomenon known as desensitization. as desensitization.

• Three mechanisms have been suggested to Three mechanisms have been suggested to explain this phenomenon: explain this phenomenon:

• 1) 1) sequestrationsequestration of the receptors so that they of the receptors so that they are are unavailableunavailable for interaction for interaction with the ligand. with the ligand.

• 2) 2) down-regulationdown-regulation, that is, a disappearance , that is, a disappearance of the receptors either by of the receptors either by destruction or destruction or decreased synthesis.decreased synthesis.

• 3) 3) Inability to couple to G proteinInability to couple to G protein, , because the because the receptor receptor has been has been phosphorylated phosphorylated on the cytoplasmic side.on the cytoplasmic side.

Characteristics of Adrenergic AgonistsCharacteristics of Adrenergic Agonists

CatecholaminesCatecholamines Sympathomimetic amines :Sympathomimetic amines : (such as epinephrine, norepinephrine, (such as epinephrine, norepinephrine,

isoproterenol, and dopamine) are called isoproterenol, and dopamine) are called catecholamines. catecholamines.

These compounds have the following properties:These compounds have the following properties:

1- High potency: 1- High potency: Drugs that are Drugs that are catechol catechol derivatives show the derivatives show the highest potency highest potency in in directly activating directly activating αα or or ββ receptors. receptors.

2- 2- Rapid inactivation: Rapid inactivation: •The catecholamines are metabolized by The catecholamines are metabolized by COMTCOMT postsynaptically and by postsynaptically and by MAO MAO intraneuronallyintraneuronally, , they are also metabolized they are also metabolized in other tissues. in other tissues. •For example, For example, COMTCOMT is in the is in the gut wallgut wall, and MAO is , and MAO is in the in the liver and gut wall. liver and gut wall. •Thus, catecholamines have only a Thus, catecholamines have only a brief period of brief period of action action when when given parenterallygiven parenterally, , •and they are and they are ineffective when administered orally ineffective when administered orally because of inactivation.because of inactivation.

3- Poor penetration into the CNS:3- Poor penetration into the CNS:• Catecholamines Catecholamines are polar are polar and, and, therefore, do not readily penetrate into the therefore, do not readily penetrate into the CNS. CNS.

NoncatecholaminesNoncatecholamines Compounds Compounds lacking the catechol lacking the catechol

hydroxyl groups,hydroxyl groups, have longer half-lives, because they are have longer half-lives, because they are

not inactivated by COMT. not inactivated by COMT. These include These include phenylephrine, ephedrine, phenylephrine, ephedrine,

and amphetamine. and amphetamine.

These are These are poor substrates for MAO poor substrates for MAO and, and, thus, show a prolonged thus, show a prolonged duration of duration of actionaction, because MAO is an important , because MAO is an important route of detoxification. route of detoxification.

Increased lipid solubility of many of the Increased lipid solubility of many of the noncatecholamines noncatecholamines permits greater permits greater access to the CNS. access to the CNS.

Copyright © 2001. W. B. Saunders Company. All Rights Reserved.

Adrenergic AgonistsAdrenergic Agonists

• Differences in

– catecholamines and non-catecholamines

– Cannot use orally Can use orally

– Cannot cross blood-brain barrier Can cross blood-brain barrier

– Short-half live Longer half life

Examples:

– Norepinephrine Ephedrine

– Epinephrine Phenulephrine

– Isoproteronol Terbutaline

– Dopamine

– Dobutamine

• Differences in

– catecholamines and non-catecholamines

– Cannot use orally Can use orally

– Cannot cross blood-brain barrier Can cross blood-brain barrier

– Short-half live Longer half life

Examples:

– Norepinephrine Ephedrine

– Epinephrine Phenulephrine

– Isoproteronol Terbutaline

– Dopamine

– Dobutamine Menu B F F

Copyright © 2001. W. B. Saunders Company. All Rights Reserved.

Basic Mechanisms of AdrenergicReceptor ActivationBasic Mechanisms of AdrenergicReceptor Activation

• Direct receptor binding

• Promotion of norepinephrine release

• Blockage of norepinephrine reuptake

• Inhibition of norepinephrine inactivation

• Direct receptor binding

• Promotion of norepinephrine release

• Blockage of norepinephrine reuptake

• Inhibition of norepinephrine inactivation

Mechanism of action of the adrenergic Mechanism of action of the adrenergic agonistsagonists

• Direct-acting agonists: Direct-acting agonists: • These drugs act directly on These drugs act directly on αα or or ββ receptors, receptors,

producing effects similar to those that occur producing effects similar to those that occur following following stimulation of sympathetic nerves stimulation of sympathetic nerves or or release of the release of the hormone epinephrine from the hormone epinephrine from the adrenal medulla .adrenal medulla .

• Examples of direct-acting agonists include Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and epinephrine, norepinephrine, isoproterenol, and phenylephrine.phenylephrine.

ANS - Adrenergic DrugsResponse to Direct-Acting

Sympathomimetics

• Indirect-acting agonists: Indirect-acting agonists: • These agents, which include These agents, which include

amphetamine, cocaine and tyramine,amphetamine, cocaine and tyramine, may may block the uptake of block the uptake of norepinephrine norepinephrine (uptake blockers) (uptake blockers)

• or are or are taken up taken up into the presynaptic into the presynaptic neuron and neuron and cause the release of cause the release of norepinephrine from the cytoplasmic norepinephrine from the cytoplasmic pools or vesiclespools or vesicles of the adrenergic of the adrenergic neuron .neuron .

• As with neuronal stimulation, the As with neuronal stimulation, the norepinephrine then traverses the norepinephrine then traverses the synapse and binds to the synapse and binds to the αα or or ββ receptors. receptors.

• Examples of Examples of uptake blockers is uptake blockers is (cocaine(cocaine ) and agents that cause ) and agents that cause norepinephrine release is norepinephrine release is (amphetamines)(amphetamines)..

ANS - Adrenergic DrugsIndirect-acting

sympathomimetic

• Mixed-action agonists:Mixed-action agonists:

• Some agonists, such as Some agonists, such as ephedrine, ephedrine, pseudoephedrine and metaraminol, pseudoephedrine and metaraminol, have the capacity both to stimulate have the capacity both to stimulate adrenoceptors directly adrenoceptors directly and and to release to release norepinephrine from the adrenergic norepinephrine from the adrenergic neuron .neuron .

11--Direct-Acting Adrenergic AgonistsDirect-Acting Adrenergic Agonists

Direct-acting agonists Direct-acting agonists bind to adrenergic bind to adrenergic receptorsreceptors without interacting with without interacting with the the presynaptic neuronpresynaptic neuron. .

The activated The activated receptor initiates receptor initiates synthesis of synthesis of second messengers and subsequent second messengers and subsequent intracellular signalsintracellular signals. .

As a group, these agents are As a group, these agents are widely used widely used clinically.clinically.

A-EpinephrineA-Epinephrine Epinephrine is one of four catecholamines , Epinephrine is one of four catecholamines ,

(epinephrine, norepinephrine, dopamine(epinephrine, norepinephrine, dopamine, , and and dobutamine dobutamine ), commonly used in ), commonly used in therapy. therapy.

The first three catecholamines occur naturally The first three catecholamines occur naturally in the body as neurotransmitters; the in the body as neurotransmitters; the latter is a latter is a synthetic compound. synthetic compound.

EpinephrineEpinephrine is synthesized is synthesized from from tyrosinetyrosine in the in the adrenal medulla and adrenal medulla and releasedreleased, while small quantities of , while small quantities of norepinephrine, norepinephrine, into the bloodstream. into the bloodstream.

EpinephrineEpinephrine interacts with both interacts with both αα and and ββ receptors. receptors.

At low doses, At low doses, ββ effects (vasodilation) on effects (vasodilation) on the vascular system predominate, whereas the vascular system predominate, whereas at high doses, at high doses, αα effects (vasoconstriction) effects (vasoconstriction) are strongest.are strongest.