Adrenergic Drugs

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 Background

• Sympathomimetics or Adrenergic agonists.

• Sympatholytics or adrenergic antagonists.

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THE ADRENERGIC NEURON

• Neurons that secretes NE both centrally and

periphrally.

• Site of action for adrenergic drugs.

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Neurotransmission at adrenergic neurons

Involves the following steps:

1. Synthesis.
2. Storage.
3. Release.
4. Binding.
5. Metabolism.
6. and reuptake

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1. Synthesis of NE:

• Tyrosine is transported by a carrier into the

adrenergic neuron.

• Hydroxylated to DOPA by tyrosine

hydroxylase.

• Then decarboxylated by DOPA decarboxylase

to dopamine (DA).

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2. Storage of NE in vesicles:

• Dopamine then transported into vesicles by an

amine transporter system (VMAT).
(vesicular monoamine transporter)
• Dopamine is then hydroxylated to NE by DA β-
hydroxylase.

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3. Release of NE:
• Action potential and Ca2+ influx storage
vesicles to fuse with cell membrane
exocytosis and release

4. Binding to receptors:
• Released NE binds to postsynaptic or
presynaptic receptors (Auto regulatory).
• Triggers a cascade of events resulting in the
formation of intracellular second messengers –
action (c AMP and IP3).

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• 5. Removal of NE:
• Diffuse out and enter the systemic circulation.

• Metabolized by catechol O methyl transferase

(COMT). >> Normetanephrine

• Undergo reuptake back into the neuron using

Na+ and Cl- dependent transporters, the action
that could be inhibited by TCAs (tricyclic antidepressants)
SSRIs (selective serotonin reuptake inhibitors) or cocaine.

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6. Fate of recaptured NE:

• NE reuptake - taken up into synaptic vesicles

and be sequestered for release by another action
potential .

• NE can be oxidized by MAO in neuronal

mitochondria.

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Adrenergic receptors (adrenoceptors)

α1 Receptors
• Postsynaptic receptors.

• Activation contraction of smooth via

generation of IP3 and DAG.

• IP3 initiates the release of Ca2+ from the

endoplasmic reticulum into the cytosol.

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 α2 Receptors
• Presynaptic auto regulatory receptors that
control the release NE.

• Activation leads to inhibition of NE release.

• α2 receptors are also found on presynaptic Para

sympathetic neurons and inhibits the release of
Ach.

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 β- Adrenoceptors

• Β1 mainly in the heart.

• Β2 in the lungs and blood vessels of the skeletal

muscles.

• Β3 in the adipose tissues mediating lipolysis.

• Binding to B receptors activates adenylyl

cyclase and accumilates cAMP.
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 Receptors Distribution
• Predominance receptors
Blood vessels of skeletal muscles have both (α1
and β2) but β2 predominate.

• Other tissues may have one type

heart only β1 receptors.

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Characteristic responses mediated by
adrenoceptors
In general:
• Stimulation of α1 receptors produces
vasoconstriction (particularly in skin and
abdominal viscera)An increase in total PR and
BP.

• Stimulation of β1 increases HR and FC.

• Stimulation of β2 causes vasodilatation (in

skeletal muscles vessels) and skeletal muscles
relaxation 16
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 Desensitization of receptors
Prolonged exposure to the catecholamine results
in receptor desensitization.

Three suggested mechanisms:

1. Sequestration of the receptors.

2. Down-regulation, that is, a disappearance of

the receptors.

3. An inability to couple to G protein.

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 Adrenergic Agonists
1. Direct-acting agonists:
• Act directly on α or β receptors(Epi, NE, isoproterenol, and
phenylephrine).

2. Indirect-acting agonists:
• Block the reuptake of NE(cocaine).
• Cause the release of NE from vesicles( amphetamines).

3. Mixed-action agonists:
• Ephedrine, pseudoephedrine
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 DIRECT-ACTING ADRENERGIC AGONISTS
1. Epinephrine

• Methylation of NE in the adrenal medulla.

• The adrenal medulla releases about 80%
Epinephrine and 20% NE.
• Epinephrine interacts with both α and β
receptors.
• At low dose β effects (vasodilation).
• At high dose α effects (vasoconstriction).

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 Actions

1. CVS
• Positive inotropic and chronotropic effect (β1 ).

• Activates β1 on kidney and renin release

Angiotensin II (vasoconstrictor) Renal blood flow is
decreased.

• Constricts arterioles in the skin, mucous

membranes, and viscera (α).
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• Dilates vessels going to the liver and skeletal
muscles (β2).

• Increased SBP and a slight decrease in DBP

(β2).

2. Respiratory
bronchodilation (β2)
Inhibits histamine release (mast cells)

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3. Hyperglycemia
– Increases glycogenolysis in the liver (β2),
glucagon (β2 effect), and decreased release
of insulin (α2 effect).

4. Lipolysis
Initiates lipolysis (β of adipose tissue).

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Therapeutic uses

1. Bronchospasm
Selective β2 agonists (albuterol) are favored for the
management of COPD and athma with less cardiac
effects.

2. Anaphylactic shock
Drug of choice for type I hypersensitivity reaction.

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3. Cardiac arrest
Used to restore cardiac rhythm

4. Combined to local Anesthetics

Applied topically Increases the duration LA
(vasoconstriction).

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Pharmacokinetics
• Rapid onset.

• The preferred route is IM but inhalation and SC

are possible routes.

• In emergency IV

• It is rapidly metabolized by MAO and COMT.

• Excreted in urine
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4. Adverse effects & interactions:

• Anxiety, fear, tension, headache, and tremor.

• Cardiac arrhythmias ( when combined with

digoxin).

• Pulmonary edema.

• Hyperthyroidic patients (hypersensitive) at risk

of cardio vascular events.

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• Inhalation anesthetics sensitivity of the
cardiac muscles to adrenaline.

• Epinephrine increases blood glucose so for

diabetic patients there must be insulin dose
adjustment.

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2. NE
Actions
The α- receptor is most affected

CVS:
a. Vasoconstriction:

– A rise in Pulse rate and blood pressure. (α1

effect).

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Baroreceptor reflex
Increased BP stimulates the baroreceptors and
vagal activity that leads to reflex bradycardia

2. Therapeutic uses
Only to treat shock.

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3. Pharmacokinetics

• Is given IV for rapid onset.

• The duration 1 to 2 min.

• Is rapidly metabolized by MAO and COMT.

• Excreted in the urine

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4. Adverse effects

• Are similar to epinephrine.

• May cause blanching of skin along an injected

vein.

• May cause tissue necrosis

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3. Isoproterenol

• Stimulates both β1 and β2 with insignificant α

effect.

• Produces intense stimulation of HR, FC, CO.

• Dilates arterioles of skeletal muscles (β2).

• Decreases PR and diastolic BP.

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• Isoproterenol is a potent bronchodilator (β2).

• Its use has largely been replaced with other

drugs.

• It may be useful in AV block.

• Its adverse effects are similar to epinephrine.

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4. Dopamine

• Occurs naturally in basal ganglia and adrenal

medulla.

• Can activate α- and β receptors.

• At high dose vasoconstriction (α1).

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• At low dose (β1).

• D1 and D2 receptors occur in the peripheral

mesenteric and renal vascular beds
(vasodilation).

• D2 receptors are also found on presynaptic

adrenergic neurons inhibit NE release.

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1. Actions

a. Cardiovascular:
• Positive inotropic and chronotropic (β1)
• At HDs vasoconstriction (α1).

b. Renal and visceral

• Dopamine dilates renal and splanchnic
arterioles increasing blood flow.

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2. Therapeutic uses

Of choice for cardiogenic and septic shock (by

continuous infusion)

It raises BP(β1),increases CO and PR (α1), It

enhances perfusion to the kidney and
splanchnic areas and Increase of blood flow to
kidney enhances GFR
– Sodium diuresis
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3. Adverse effects

• Nausea, HTN, arrhythmias.

• DA overdose same effects as symp stimulation.

• Is rapidly metabolized by MAO or COMT.

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5. Dobutamine
• Is a β1 receptor agonist.

• It increases HR and CO and does not

significantly elevate oxygen demands a major
advantage over other sympathomimetics.

• Is used in acute HF and inotropic support after

cardiac surgery.

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• Should be used with caution in atrial
fibrillation (increases AV conduction).

• Tolerance may develop with prolonged use.

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6. Fenoldopam
• Is an agonist of peripheral D1 receptors.

• Is used as a rapid-acting vasodilator to treat severe

HTN (acting on coronary, kidney and mesenteric
arteries).

• Subject to first -pass metabolism10 min half-life

(after IV infusion).

• Headache, flushing, dizziness, nausea, vomiting, and

tachycardia (due to vasodilation)
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7. Oxymetazoline

• Stimulates both α1- and α2-receptors.

• As OTC Short -term nasal spray decongestants.

• Ophthalmic drops to remove redness of the eyes

associated with swimming, colds, and contact lenses
through direct stimulation of α receptors on blood
vessels supplying the nasal mucosa and conjunctiva.

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8. Phenylephrine

• Binds primarily to α1 receptors.

• Raises both SBP and DBP.

• Induces reflex bradycardia when given

parenterally.

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• Is used to treat hypotension in hospitalized or
surgical patients (especially those with a rapid
heart rate).

• HDs can cause hypertensive headache and

cardiac irregularities.

• Can be used as nasal decongestant.

• Has replaced pseudoephedrine.

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9. Clonidine

• Is an α2 agonist used for management of HTN.

• In withdrawal from opiates, tobacco smoking,

and BNZs.

• Clonidine acts centrally on presynaptic α2

receptors Inhibits sympathetic vasomotor
centers decreasing the sympathetic outflow to
the periphery.

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• The most common side effects are Lethargy,
sedation, constipation, and xerostomia.

• Abrupt discontinuance leads rebound HTN.

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10. Albuterol and terbutaline

• Are short-acting β2 agonists.

• Used primarily as bronchodilators (a metered

dose inhaler).

• Albuterol (salbutamol) of choice for the

management of acute asthma.

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• Terbutaline off –label use to prevent premature
labor.

• SEs: restlessness, apprehension, and anxiety,

tachycardia or arrhythmia (β1).

• MAOIs increase the risk of adverse CV effects

so should avoid concomitant use

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11. Salmeterol and formoterol:

• Long -acting β2-agonists over 12 hrs.

• Salmeterol has delayed onset.

• Combined with a corticosteroid.

• For nocturnal asthma

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