Transcript Chapter 10 . Adrenoceptor Agonists

Adrenoceptor Agonists
definition
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Drugs that mimic the actions of
epinephrine or norepinephrine
Sympathomimetic drugs
Classification
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Depend on the affinity for
different groups of receptor
α-adrenoceptor agonists
β-adrenoceptor agonists
α, β-adrenoceptor agonists
Chemistry
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Parent compound: phenylethylamine
Change the affinity for α or β
receptors
Change pharmacokinetics properties
Chemistry and pharmacokinetics
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Substitutions
On the terminal amino group:
increase β receptors activity
 On the benzene ring: increase
bioavailability and prolongs the
duration of action; increase the
distribution of molecule to CNS
 On the alpha or beta carbons:
block oxidation by MAO
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α-adrenoceptor agonists
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Norepinephrine
Metaraminol
α 1 -adrenoceptor agonists:
phenylephrine and methoxamine
Norepinephrine
Potent effect of α receptor
 Relative little effect on β1
receptor
 Little effect on β2 receptor
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Pharmacological Effects
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Blood vessels: constrict (skin
vessels, renal vessels); coronary
artery dilate
Heart: pacemaker activity,
conduction velocity, and intrinsic
contractility increase. HR
decrease by a reflex response.
Pharmacological Effects
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Blood pressure: systolic
pressure increase at low
concentration; at high
concentration both systolic and
diastolic pressure increase
pharmacokinetics
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i.v. drip.
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Be uptake and metabolized quickly
Therapeutic Uses
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neurogenic shock, cardiogenic
shock
Hypotension
hemorrhage of upper digestive
tract
Adverse reaction
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Avascular necrosis
Acute renal failure
Contraindication: hypertension,
atherosclerosis, cardiopathy
Metaraminol
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excite α-R
replace the NA in vesicles，increase
NA release from vesicles directly
More stable to MAO, prolong the
action
Acute tolerance
Pharmacological Effects
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similar to NA in its action, but less
potent
increase systolic and diastolic blood
pressure
its major therapeutic use is in the
treatment of hypotensive state
Phenylephrine, Methoxamine
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α1-R agonists
similar to those of NA, but less
potent and has a longer duration of
action
vasoconstriction, increase arterial
pressure, and reflex bradycardia
Clinical Uses
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hypotension state;
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supraventricular paraxosmal
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pupil mydriasis
α、β-R agonist
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Adrenaline
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Dopamine
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ephedrine
Adrenaline
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At low concentration ,β effects
predominate; at high concentration ,
α effects predominate.
β2-R are more sensitive to Adr
than the α-R.
pharmacokinetics
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Adr- absorption is poor with
oral administration
can be given iv or im
Pharmacological Effects
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Heart
 a direct effect on β1-R ;
increase in heart rate , and
increase cardiac output;
 a propensity toward arrhythmias
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coronary artery dilate
Pharmacological Effects
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Blood vessel
Constrict (skin vessels, renal
vessels)
 Dilate: vessels in skeletal muscle ,
hepatic vessels
 coronary blood flow
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Pharmacological Effects
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blood pressure
At low concentration: systolic
pressure increase
 At high concentration: both
systolic and diastolic pressure
increase
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Pharmacological Effects
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Smooth muscle:
Bronchiolar smooth muscle relaxes
 blood vessel constrict
 Block the release of histamine
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Pharmacological Effects
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Metabolic effects
increase in glucoses and lactate
production via glycogenolysis
 inhibition of insulin secretion
(αR)
 increase in free fatty acid and
oxygen consumption .
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Therapeutic Uses
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cardiac arrest
acute or severe hypersensitivity
reaction , it is primary
treatment for anaphylactic
shock , asthma
prolong the duration of local
anesthesia
Adverse Effects
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Palpitation, BP
Hypertension, diabetes mellitus,
hyperthyroidism
Dopamine
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activate α、β1 and dopa-receptor
Be metabolized by MAO and COMT
quickly
No effect on CNS
Dopamine
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heart: positive inotropic effect on
the myocardium, increase cardiac
output
blood vessels
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At low or intermediate concentration:
act on D1 receptor, dilate
At high concentration : act on αreceptor, constrict
Pharmacological Effects
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Kidney
At low or intermediate
concentration: reduce arterial
resistance in the mesentery and
kidney
 At high concentration: cause
vasoconstriction with consequent
reduction in renal function
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Clinical uses
Shock
 Acute renal failure
 Adverse reaction: arrhythmia,
reduction in renal function
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Ephedrine
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absorbed when taken orally
resistant to COMT and MAO, so
that its action is prolonged
CNS effects may occur: such as
insomnia, nervousness, nausea and
agitation
Acute tolerance
pharmacological Effects
increase cardiac output,
increase blood pressure
 Relax smooth muscle
 CNS: excitement
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Clinical Uses
bronchial asthma
 nasal decongestant
 hypotension without crisis
 Adverse reactions: CNS
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β-R agonist
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β1 and β2-R agonist
Isoprenaline: lower selectivity
to both β1 and β2-R, little
effect on α-R
pharmacological Effects
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heart: positive inotropic
effect ,increase the heart rate and
conduction, cardiac output increase
blood vessels : reduction of
peripheral vascular resistance in
skeletal muscle, renal and
mesenteric vascular beds;
pharmacological Effects
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blood pressure: diastolic blood
pressure falls , systolic blood
pressure may increase
Relax both bronchial and
gastrointestinal smooth muscle
Metabolic effects
pharmacokinetics
Resistance to MAO
 less be uptaken
 aerosol
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Clinical uses
bronchial asthma
 Atrioventricular block
 cardiac arrest
 Infectious shock
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Adverse Effects
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palpitation; dizziness
overdosage by inhalation can
produce fatal ventricular
arrhythmia
Contraindication:
myocarditis ,coronary heart
disease; hyperthyroidism
β1-R agonist
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β1 reaction is more potent
thanβ2 reaction
Dobutamine
Dobutamine
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direct β1-R agonist
greater inotropic effect than
chronotropic effect
little effects on peripheral vascular
resistance.
Clinical uses: improve myocardial
function in congestive heart failure .
Adverse reactions
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BP , palpitation
Contraindication: IHSS, atrial
fibrillation
β2-R agonist
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bronchial asthma