Adrenergic agonists Adrenergic agonists

Samuel Aguazim (Samuel Aguazim (MDMD))

What are adrenergic agonistWhat are adrenergic agonist

Drugs that mimic the effects of Drugs that mimic the effects of adrenergic nerve stimulation (or adrenergic nerve stimulation (or stimulation of the adrenal medulla)stimulation of the adrenal medulla)

Mimic the effects of norepinephrine or Mimic the effects of norepinephrine or epinephrineepinephrine

These drugs are known as These drugs are known as adrenomimetics or sympathomimeticsadrenomimetics or sympathomimetics

Remember the actions of the SNS Remember the actions of the SNS are mediated through alpha and are mediated through alpha and beta receptors.beta receptors.

RememberRemember

Alpha 1Alpha 1: most vascular smooth : most vascular smooth muscle, agonist contractmuscle, agonist contract

Beta 1Beta 1: heart, agonist increase rate: heart, agonist increase rate Beta 2Beta 2: respiratory and uterine : respiratory and uterine

smooth muscle, agonists relax.smooth muscle, agonists relax.

Name alpha selective direct – Name alpha selective direct – acting agonistsacting agonists

PhenylephrinePhenylephrine MethoxamineMethoxamine ClonidineClonidine methyldopamethyldopa

Identify the major beta Identify the major beta selective direct-acting agonistselective direct-acting agonist

DobutamineDobutamine IsoproterenolIsoproterenol AlbuterolAlbuterol MetaproterenolMetaproterenol TerbutalineTerbutaline

List the major alpha and beta List the major alpha and beta direct-acting agonistsdirect-acting agonists

EpinephrineEpinephrine NorepinephrineNorepinephrine dopaminedopamine

Direct- acting agonists Direct- acting agonists considered catecholaminesconsidered catecholamines

EpinephrineEpinephrine NorepinephrineNorepinephrine IsoproterenolIsoproterenol DopamineDopamine DobutamineDobutamine

The direct acting drugs bind to the The direct acting drugs bind to the receptors. So specificity of action is a receptors. So specificity of action is a possibility.possibility.

INDIRECT ACTINGINDIRECT ACTING

The indirect-acting sympathomimetic The indirect-acting sympathomimetic agents acts by releasing previously agents acts by releasing previously stored norepinephrines, their effects stored norepinephrines, their effects are widespread and non specific are widespread and non specific

AmphetamineAmphetamine TyramineTyramine

TWO MIXED AGONISTSTWO MIXED AGONISTS

DIRECT & INDIRECT ACTINGDIRECT & INDIRECT ACTING EphedrineEphedrine MetaraminolMetaraminol

Where are alpha 1 and alpha 2 Where are alpha 1 and alpha 2 receptors locatedreceptors located

Alpha 1 Alpha 1 receptors are located on the receptors are located on the effector organ’s postsynaptic effector organ’s postsynaptic membrane.membrane.

Alpha 2Alpha 2 receptors are predominantly receptors are predominantly located on the presynaptic located on the presynaptic membrane.membrane.

Postsynaptic alpha 2 receptors are Postsynaptic alpha 2 receptors are limited to the CNS and blood vesselslimited to the CNS and blood vessels

RESPONSES ASSOCIATED WITH RESPONSES ASSOCIATED WITH TYPES OF ADRENOCEPTORSTYPES OF ADRENOCEPTORS

Alpha1 Alpha1 Stimulation leads to release of intracellular Stimulation leads to release of intracellular

calcium from the endoplasmic reticulum calcium from the endoplasmic reticulum via inositol triphosphate (IP3 ). This leads via inositol triphosphate (IP3 ). This leads toto

Arterial and arteriolar constriction Arterial and arteriolar constriction (cutaneous, visceral, skeletal & pulmonary)(cutaneous, visceral, skeletal & pulmonary)

Venous constriction Venous constriction Uterine contraction Uterine contraction Pupillary dilation ( mydriasis )Pupillary dilation ( mydriasis ) (contraction of radial smooth muscle of iris)(contraction of radial smooth muscle of iris) Contraction of ureterContraction of ureter Contraction of pilomotor musclesContraction of pilomotor muscles

Alpha 2Alpha 2When alpha 2 presynaptic membrane receptors When alpha 2 presynaptic membrane receptors

are stimulated, intracellular cyclic adenosine are stimulated, intracellular cyclic adenosine monophosphate ( c CAMP ) production is monophosphate ( c CAMP ) production is inhibited.inhibited.

Inhibition of NE releaseInhibition of NE release Inhibition of ganglionic transmissionInhibition of ganglionic transmission Reduction of BP and heart rateReduction of BP and heart rate VasoconstrictionVasoconstriction (quantitatively less important (quantitatively less important

than than αα1)1) Decrease insulin secretionDecrease insulin secretion Platelet aggregationPlatelet aggregation

Name the direct-acting agonists that Name the direct-acting agonists that are selective for are selective for αα1 and 1 and αα2 2

adrenergic receptorsadrenergic receptors Alpha 1 receptors- Alpha 1 receptors- phenylephrine and methoxaminephenylephrine and methoxamine Alpha 2 receptors- Alpha 2 receptors- clonidine and clonidine and

methyldopamethyldopa

Phenylephrine Phenylephrine

Physiologic action( Physiologic action( alpha 1 agonistalpha 1 agonist)) Primarily vasoconstrictionPrimarily vasoconstriction Therapeutic usesTherapeutic uses Nasal decongestant**Nasal decongestant** Treat hypotensionTreat hypotension For ocular examinations( mydriasis)For ocular examinations( mydriasis) To terminate episodes of To terminate episodes of paroxysmal atrial paroxysmal atrial

tachycardiatachycardia( PAT)( PAT)

SE: SE: REBOUND MUCOSAL SWELLING AND REBOUND MUCOSAL SWELLING AND HYPERTENSIVE HEADACHEHYPERTENSIVE HEADACHE

METHOXAMINEMETHOXAMINE

THERAPEUTIC USES:THERAPEUTIC USES: Treatment of hypotension and Treatment of hypotension and

paroxysmal atrial tachycardiaparoxysmal atrial tachycardia

( PAT)( PAT) Adverse effect: similar to those of Adverse effect: similar to those of

phenylephrinephenylephrine

Alpha 2 selective agonistsAlpha 2 selective agonists Clonidine Clonidine --- it activates alpha 2 in the CNS to --- it activates alpha 2 in the CNS to

reduce sympathetic stimulation to the heart and reduce sympathetic stimulation to the heart and activates presynaptic alpha 2 receptors on the activates presynaptic alpha 2 receptors on the peripheral nerve endings to inhibit the release of peripheral nerve endings to inhibit the release of norepinephrinenorepinephrine

Therapeutic use – Therapeutic use – treat essential HTN, withdrawal treat essential HTN, withdrawal from benzodiazepines and opiates, treatment of from benzodiazepines and opiates, treatment of diarrhea in diabetic patients who have autonomic diarrhea in diabetic patients who have autonomic neuropathiesneuropathies

Adverse Effects: Adverse Effects: • dry mouth dry mouth • sedation sedation • sexual dysfunction sexual dysfunction

Direct – acting beta selective Direct – acting beta selective agonistsagonists

LOCATION:LOCATION: ββ11 receptors are primarily located on receptors are primarily located on

the postsynaptic membrane.the postsynaptic membrane. ββ22 receptors are found on both the receptors are found on both the

pre and postsynaptic membranespre and postsynaptic membranes

Beta 1Beta 1

Beta 1Beta 1 stimulation activates adenylate cyclase, stimulation activates adenylate cyclase, which opens calcium channels leading to: which opens calcium channels leading to: cardiac stimulation with both increasedcardiac stimulation with both increased chronotropic(HR), inotropic( contraction), chronotropic(HR), inotropic( contraction), dromotropic(conduction) effects.dromotropic(conduction) effects.

stimulation of lipolysis stimulation of lipolysis stimulation of renin secretionstimulation of renin secretion

Beta 2Beta 2 Beta 2Beta 2 receptors work via adenylate cyclase receptors work via adenylate cyclase

stimulation as well.stimulation as well. In this case, howeverIn this case, however, bronchial smooth muscle , bronchial smooth muscle

as well as skeletal muscle vasculature are as well as skeletal muscle vasculature are dilated.dilated.

The uterus, ciliary and detrusor muscles are The uterus, ciliary and detrusor muscles are relaxed and glucagon release is increased. relaxed and glucagon release is increased.

Both beta 1 and beta 2 receptors produce Both beta 1 and beta 2 receptors produce decreased intestinal tone and motility.decreased intestinal tone and motility.

DOBUTAMINEDOBUTAMINE

A dopamine analogue that A dopamine analogue that acts primarily on beta 1 acts primarily on beta 1 but it does have some action on beta 2 receptors as but it does have some action on beta 2 receptors as well.well.

Physiologic effects: Physiologic effects: increased heart rate and increased heart rate and contractility (contractility (ββ1) and smooth muscle relaxation 1) and smooth muscle relaxation ((ββ2)2)

Uses: treatment of unstable CHF and shockUses: treatment of unstable CHF and shock Route: ivRoute: iv Adverse effects: arrthymias, headache, hypertension, Adverse effects: arrthymias, headache, hypertension,

palpitation, angina and nauseapalpitation, angina and nausea

IsoproterenolIsoproterenol

Activates ßActivates ß adrenergic receptors (both ßadrenergic receptors (both ß11 - - and ßand ß22 -receptor subtypes) -receptor subtypes)

Activation of cardiac ßActivation of cardiac ß11 - adrenergic - adrenergic receptorsreceptors: : increased contractility and increased contractility and heart rate. heart rate.

Activation of ßActivation of ß22 - adrenergic receptors: - adrenergic receptors: Bronchial and GI smooth muscle relaxationBronchial and GI smooth muscle relaxation

Isoproterenol: Limited Isoproterenol: Limited therapeutic usestherapeutic uses

Emergency settings to treat heart Emergency settings to treat heart block or severe bradycardia block or severe bradycardia

Management of Management of torsade de pointes torsade de pointes (a (a ventricular arrhythmia)ventricular arrhythmia)

Drugs used as medication Drugs used as medication for broncho-dilation due to smooth for broncho-dilation due to smooth muscle dilatationmuscle dilatation

1. 1. AlbuterolAlbuterol2. Salmeterol – long acting with late onset2. Salmeterol – long acting with late onset3. Metaproterenol3. Metaproterenol4. Terbutaline4. TerbutalineTherapeutic uses: Therapeutic uses: rx of bronchospasm/asthmarx of bronchospasm/asthmaCOPD, bronchitis.COPD, bronchitis.Adverse effect: arrhythmias, tachycardia, headache and vomitingAdverse effect: arrhythmias, tachycardia, headache and vomiting

Beta 2 selective agonistsBeta 2 selective agonists

NOR EPINEPHRINE(NE)NOR EPINEPHRINE(NE) Through stimulation of Through stimulation of alpha alpha

receptorsreceptors, NE causes , NE causes constrictionconstriction of of all major vascular beds.all major vascular beds.

This, in turn, causes This, in turn, causes an increase in an increase in resistance and pressureresistance and pressure. .

The The increase in blood pressure increase in blood pressure causes a reflex increase in causes a reflex increase in parasympathetic output to the heartparasympathetic output to the heart, , which acts to slow the heart downwhich acts to slow the heart down

NOR EPINEPHRINENOR EPINEPHRINE

Activates alpha and beta 1 receptorsActivates alpha and beta 1 receptors physiologic effects: vasoconstriction physiologic effects: vasoconstriction

and reflex bradycardiaand reflex bradycardiaTherapeutic uses Therapeutic uses Shock Shock Never used for asthmaNever used for asthma SE: TISSUE HYPOXIASE: TISSUE HYPOXIA DECREASED PERFUSION TO KIDNEYDECREASED PERFUSION TO KIDNEY TISSUE NECROSISTISSUE NECROSIS

Catecholamines

Drug 

Receptors

Epinephrine 

alpha1, alpha2 ß1, ß2

Norepinephrine  

alpha1, alpha2, ß1

Isoproterenol  

ß1, ß2

Dobutamine  

ß1 (alpha1)

Dopamine  

(alpha1 and ß1 at high doses)

   

Direct- acting alpha and beta Direct- acting alpha and beta agonistagonist

EPINEPHRINEEPINEPHRINE

Epinephrine is a Epinephrine is a potent activator of potent activator of alpha and ß adrenergic receptors alpha and ß adrenergic receptors

Prominent Cardiovascular Effects Prominent Cardiovascular Effects

Cardiac effectsCardiac effects

Heart rate increases Heart rate increases

Cardiac output increases Cardiac output increases

Oxygen consumption increasesOxygen consumption increases

Vascular effectsVascular effects

Over renal system Over renal system – – decreased blood flowdecreased blood flow Renin – releaseRenin – release Respiratory system-Respiratory system-Broncho - dilatation -- Broncho - dilatation --

Beta 2Beta 2 Decreased secretionsDecreased secretions Metabolic- increased glycogenolysis and release Metabolic- increased glycogenolysis and release

glucagon and a decreased release of insulin glucagon and a decreased release of insulin results in hyperglycemiaresults in hyperglycemia

Epinephrine Epinephrine Used mainly for bronchospasmUsed mainly for bronchospasm Acute asthmaAcute asthma Anaphylactic shockAnaphylactic shock Open angle glaucomaOpen angle glaucoma Increase the duration of local anesthesia Increase the duration of local anesthesia SE: Cardiac arrhythmias, hypertension, SE: Cardiac arrhythmias, hypertension,

palpitations, dizziness, anxiety, headache palpitations, dizziness, anxiety, headache and tremor. etcand tremor. etc

DopamineDopamine

DopamineDopamine is the immediate precursor of is the immediate precursor of norepinephrine. norepinephrine.

It is synthesized in the CNS, sympathetic It is synthesized in the CNS, sympathetic ganglia and adrenal medullaganglia and adrenal medulla

acts on alpha 1, beta 1 and beta 2 and acts on alpha 1, beta 1 and beta 2 and dopamine ( D1&D2) receptorsdopamine ( D1&D2) receptors

At high doses dopamine acts much At high doses dopamine acts much epinephrineepinephrine

Cardiovascular Effects (Dopamine)Cardiovascular Effects (Dopamine)

Treatment of shock- Treatment of shock- raises BP by raises BP by stimulating the beta 1 receptors of the stimulating the beta 1 receptors of the heartheart

Acute renal failure to increase renal blood Acute renal failure to increase renal blood flowflow

Treatment of acute CHFTreatment of acute CHF

Therapeutic use (Dopamine)Therapeutic use (Dopamine)

Drug of choice for shock Drug of choice for shock

Both cardiogenic and hypovolemic shockBoth cardiogenic and hypovolemic shock..

Continuous infusion to be given.Continuous infusion to be given.

Dopamine Dopamine increases heart rate and cardiac increases heart rate and cardiac output output while simultaneously while simultaneously dilating the dilating the renal and coronary arteries.renal and coronary arteries.

Adverse effectsAdverse effects

palpitations palpitations

tachycardia tachycardia

arrhythmias arrhythmias

coronary insufficiency coronary insufficiency

alpha methyl DOPA

very effective alpha 2 agonist, and so prevents the release of NE.

· It is used as an antihypertensive

OTHER ADRENERGIC OTHER ADRENERGIC DRUGSDRUGS

EphedrineEphedrine – – alpha , beta and CNS alpha , beta and CNS Mainly used for treatment of asthma Mainly used for treatment of asthma

and nasal decongestant.and nasal decongestant.

PhenylpropanolaminePhenylpropanolamine – – nasal nasal decongestant and bronchodilatordecongestant and bronchodilator

TetrahydrozolineTetrahydrozoline – – related to related to ephedrine used as topical nasal and ephedrine used as topical nasal and conjunctival decongestant.conjunctival decongestant.

NaphazolineNaphazoline - - used as topical used as topical vasoconstrictor.vasoconstrictor.

OxymetazolineOxymetazoline – – to reduce to reduce congestion and swelling of the nasal congestion and swelling of the nasal mucosa.mucosa.

XylometazolineXylometazoline -- -- nasal nasal decongestant. decongestant.

Indirectly Acting SympathomimeticsIndirectly Acting Sympathomimetics

-act by releasing NE --act by releasing NE -Pharmacological Pharmacological

Effects Effects Vasoconstriction Vasoconstriction Bronchodilation Bronchodilation CNS effects: CNS effects:

stimulationstimulation

anorexigenicanorexigenic

ApplicationsApplications

Nasal decongestionNasal decongestion AsthmaAsthma NarcolepsyNarcolepsy Hyperkinetic Hyperkinetic

SyndromeSyndrome ObesityObesity

Indirectly Acting drugsIndirectly Acting drugs

AmphetamineAmphetamine

TyramineTyramine

AmphetamineAmphetamine

Alpha, beta . It releases stores NE Alpha, beta . It releases stores NE and dopamine. It can enter CNSand dopamine. It can enter CNS

Used as Used as CNS stimulant in treatment CNS stimulant in treatment of children with attention deficit of children with attention deficit syndrome.syndrome.

(hyperactivity is the feature)(hyperactivity is the feature) Narcolepsy Narcolepsy Obesity Obesity

Side effectsSide effects

Headache, palpitations, dysphoria Headache, palpitations, dysphoria

Appetite suppression Appetite suppression

Weight loss due to decrease food intake Weight loss due to decrease food intake

Psychological tolerance/dependence Psychological tolerance/dependence

TYRAMINETYRAMINE

It is a by-product of tyrosine metabolism; It is a by-product of tyrosine metabolism; tyrosine is a precursor to dopamine, tyrosine is a precursor to dopamine, epinephrine and norepinephrineepinephrine and norepinephrine

MOAMOA: tyramine is taken up by : tyramine is taken up by sympathetic neurons, which causes a sympathetic neurons, which causes a release of catecholamines.release of catecholamines.

Is there a therapeutic use: NOIs there a therapeutic use: NO

What are tyramine’s adverse What are tyramine’s adverse effects ?effects ?

It can cause a hypertensive emergency in It can cause a hypertensive emergency in patients who take patients who take monoamine oxidase monoamine oxidase (MAO) inhibiting drugs since MAO is (MAO) inhibiting drugs since MAO is responsible for metabolism of tyramine.responsible for metabolism of tyramine.

It is important to warn patients who are It is important to warn patients who are taking MAO inhibitors not to eat foods with taking MAO inhibitors not to eat foods with high tyramine concentrations, such as high tyramine concentrations, such as red red wine, beer, chocolate and cheesewine, beer, chocolate and cheese..

Drugs used as inhalation medication for broncho Drugs used as inhalation medication for broncho dilation aredilation are

1.Epinephrine – short acting1.Epinephrine – short acting2. Isoproterenol2. Isoproterenol3. Albuterol3. Albuterol4. Salmeterol – long acting with late onset4. Salmeterol – long acting with late onset5. Metaproterenol5. Metaproterenol6. Terbutaline6. Terbutaline

Mixed action adrenergic agonistsMixed action adrenergic agonists EphedrineEphedrine Stimulates both alpha and beta Stimulates both alpha and beta

receptorsreceptors Plant alkaloid now made Plant alkaloid now made

syntheticallysynthetically Used in asthmaUsed in asthma Nasal decongestantNasal decongestant