Basic and Clinical Pharmacology

C9 ADRENOCEPTOR AGONISTS & SYMPATHOMIMETIC DRUGS

A.Q. Sangalang, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

• Important regulator of activities of the heart and peripheral vasculature

o Stress
• Adrenal medulla also secretes epinephrine
o Adrenomimetics
o Constitute a group of drugs used for
Ø Cardiovascular
Ø Respiratory
Ø Other conditions

ADRENOMIMETIC AGONISTS
Direct-acting Indirect-acting
Beta agonist Releasers Reuptake inhibitors
Alpha agonist
Beta2-selective
Beta1-selective
Nonselective
Alpha2-selective
Alpha1-selective
Nonselective

• Subdivided into
o Mode of action
Ø Direct-acting
Ø Indirect-acting
o Spectrum of action
Ø Alpha
Ø Beta
Ø Dopamine receptor affinity

A. MODE OF ACTION
• DIRECT-ACTING SYMPATHOMIMETICS
o Bind to and activate the adrenoceptors
o Result to sympathetic stimulation
• INDIRECT-ACTING SYMPATHOMIMETICS
o Displacement of stored cathecolamines in the synapse
o Releasers
Ø Tyramine, amphetamine
o Inhibit the reuptake of cathecolamines by nerve terminals
o Reuptake inhibitors
Ø Cocaine, tricyclic antidepressants
B. SPECTRUM OF ACTION
• Classified as
o ALPHA
o Further subdivided into subgroups as
Ø Alpha1
Ø Alpha2

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 o BETA
o Further subdivided into subgroups as
Ø Beta1
Ø Beta2
Ø Beta3
o DOPAMINE
Ø Constitute a third class of adrenoceptors
Ø Drugs mentioned have little effect on dopamine receptors
Ø May act as a potent dopamine receptor agonist itself
Ø Intermediate doses activate beta receptors
Ø Large doses activate alpha receptors
Ø D1-D5 receptor subtypes
Ø D1- renal vasculature
Ø D2-brain

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 • RECEPTOR SELECTIVITY
o Drug preferentially binds to one subgroup of receptors at
concentrations too low to interact with another receptor

C. CHEMISTRY AND PHARMACOKINETICS

• PHENYLETHYLAMINE
o Parent compound
o Consists of
Ø Benzene ring
Ø Ethylamine side chain
Ø Alpha carbon
Ø Beta carbon
Ø Terminal amino group
• Modifications on the compound changes the affinity of the drug for alpha or beta
receptors
1. Substitution on the amino group
• Increasing the size of alkyl substituents
o Increases beta receptor activity
o Lowers alpha receptor activity
• Methyl substitution on NE yields epinephrine
o Enhanced activity for beta 2 receptors
• Isopropyl substitution on NE yields isoproterenol
o Synthetic catecholamine
2. Substitution on the benzene ring
• -OH groups at the C3 and C4 positions yield cathecolamines
o Norepinephrine epinephrine, and dopamine
o Endogenous adrenoceptor agonists
o Rapidly metabolized by COMT and MAO
o Inactive when given by the oral route
o Short duration of action
o When given IV, they do not enter the CNS In significant amounts
• Absence of one or both –OH group
o Increases bioavailability after oral administration

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 o COMT resistant
o Increase distribution to the CNS
o Amphetamine and ephedrine
3. Substitution on the alpha carbon
• Add methyl group
o MAO resistant
o Amphetamine and ephedrine
o Phenylisopropylamines
o Enhanced ability to displace cathecolamines from storage
o Indirect-acting sympathomimetics
4. Substitution on the beta carbon
• Add OH group
o Facilitates activation of adrenoceptors
o For storage of cathecolamines
o Direct-acting sympathomimetics
o Dopamine does not contain beta-OH group

ALPHA RECEPTOR ACTIVATION

Epinephrine > NE > isoproterenol

• Alpha1
o Increase in phosphatidyl inositol (IP3)
o Release of calcium
• Alpha2
o Decrease cAMP

BETA RECEPTOR ACTIVATION

Isoproterenol > epinephrine > NE

• Beta1, beta2, beta3
o Increase cAMP

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DOPAMINE RECEPTOR ACTIVATION
• D1
o Decrease cAMP
• D2
o More important in the brain

ORGAN SYSTEM EFFECTS

A. CNS
• Do not enter the CNS effectively
• Amphetamine
• Penetrates the CNS producing stimulant effects
• Mild altering or reduction of fatigue, progressing to anorexia, euphoria, and
insomnia
• Very high doses
o Marked anxiety or aggressiveness, paranoia and rarely convulsions

B. EYE
• Pupillary dilator responds with mydriasis
• Accommodation is not significantly affected
• Alpha agonists reduce intraocular pressure by increasing outflow of aqueous
humor
• Beta agonist have little effect
• Beta antagonists decrease production of aqueous humor
C. BRONCHI
• Marked relaxation of the smooth muscles of the bronchi
• Most efficacious and reliable for reversing bronchospasm
D. GIT
• Well-endowed with both alpha and beta receptors
• Located on the smooth muscles and neurons of the enteric nervous system
• Activation of either receptors leads to the relaxation of the smooth muscles
E. GUT
• Contains alpha receptors in the bladder trigone and sphincter area
• Bladder relaxation and sphincter contraction
• Beta2 agonist causes uterine relaxation in pregnancy
F. VASCULAR SYSTEM
• Alpha1 agonists
o Vasoconstriction
• Alpha2 agonists
o When given IV or topically (nasal)
o Vasoconstriction
o When given oral
Ø Reduces sympathetic outflow and BP
• Beta agonists
o Beta2 can reduce PVR and BP
o Beta1 has little effect
o Dopamine causes vasodilatation in the splanchnic and renal vascular beds
G. HEART
• Well supplied with beta1 and beta2 receptors

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 • Beta1 predominate in some parts of the heart
• Both mediate increase heart rate and contraction
• Increase blood pressure
H. METABOLIC AND HORMONAL EFFECTS
• Beta1 increases renin secretion
• Beta2 increases insulin secretion (gluconeogenesis)
• Increases glycogenolysis in the liver and the resulting hyperglycemia is countered
by insulin levels
• Stimulate lipolysis

CLINICAL USES
A. ANAPHYLAXIS
EPINEPHRINE
• Drug of choice for the immediate treatment of anaphylactic shock
• Rapid acting
• Pressor agent
• Used for cardiac arrest

B. CNS
PHENYLISOPROPYLAMINES (AMPHETAMINES)
• Narcolepsy
• Attention deficit disorder
• With appropriate control, weight reduction
C. EYE
PHENYLEPHRINE
• Used topically to produce mydriasis
• Used to reduce conjunctival itching and congestion caused by irritation
and allergy
D. BRONCHI
TERBUTALINE, ALBUTEROL, METAPROTERENOL
• Drugs of choice in the treatment of acute asthmatic attacks
SALMETEROL
• Long-acting
• Recommended for prophylaxis
E. CVS
1. Conditions in which an increase in blood flow Is desired
• Beta1 agonists maybe useful in situations like
o Acute cardiac failure
o Some types of shock
2. Conditions in which a decrease in blood flow or increase in BP is desired
• Alpha1 agonists are useful in situations in which vasoconstriction is needed
• Local hemostatic
• Decongestant effects
• In spinal shock in which temporary maintenance of BP may help perfuse the
brain, heart and the kidneys
F. GUT
RITODRINE, TERBUTALINE
• Used to suppress premature labor
• Cardiac stimulant effect may be hazardous to both mother and fetus

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 EPHEDRINE
• Long-acting oral sympathomimetic used to improve urinary incontinence in
children and the elderly with enuresis
• Mediated by the alpha receptors in the trigone of the bladder

CATHECOLAMINES
EPINEPHRINE
• Pressor agent
• Cardiac arrest
• Anaphylactic shock
NOREPINEPHRINE
• Pressor agent
ISOPROTERENOL
• Potent vasodilator
DOBUTAMINE
• Congestive heart failure
• Inotropic effect
DOPAMINE
• Inotropic effect
• Lower doses cause renal vasodilation
• Higher doses cause vasoconstriction

NON-CATHECOLAMINES
PHENYLEPHRINE
• Pressor agent
• Mydriatic
• Decongestant
METHOXAMINE
• Pressor agent, limited clinical application
• IV form only
MIDODRINE
• Pressor agent
• Orthostatic hypotension
OXYMETAZOLINE, XYLOMETAZOLINE
• DRIXINE (brand name)
• Topical decongestants
TERBUTALINE
• Bronchial asthma
RITODRINE
• Inhibits premature labor
COCAINE
• Local vasoconstrictive
• Anesthetic effect
TYRAMINE
• Byproduct of tyrosine
• Increase BP
• Found in fermented food
o Cheese and wine
o Not advised for patients taking MAO inhibitors

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TOXICITY
• Limited penetration to the brain
• Little CNS toxicity when given systemically
• In the periphery
o Excessive vasoconstriction
o Cardiac arrhythmias
o Myocardial infarction
o Pulmonary edema or hemorrhage
• Alpha agonists cause hypertension
• Beta1 agonists cause sinus tachycardia and serious arrhythmia
• Beta 2 agonists cause skeletal muscle tremor