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Agonists
Antagonists
The adrenergic neuron
Adrenergic neurons release Norepinephrine (NE) as the
neurotransmitter.
These neurons are found in the CNS, and also in the SNS
Neurotransmission at adrenergic neurons
The process involves five steps:
synthesis,
storage,
release, and
receptor binding of NE, followed by removal of the
neurotransmitter from the synaptic gap
The adrenergic receptors are located either
presynaptically on the neuron or
post-synaptically on the effector organs
Biosynthesis of catecholamines
Drug intervention -- Adrenergic transmission
: Stimulatory Tyrosine
: Inhibitory
Solid: Agonistic (Rate-limiting) TH Metyrosine
Dotted: Antagonistic
DopaDA
Reserpine
Adrenergic antagonists
Vesicle (DANE)
Phentolamine (a-blocker)
Propranolol (b-blocker) Amphetamine, tyramine,
ephedrine
Release
Adrenergic agonists Bretylium, guanethidine
(direct acting)
Cocaine
Isoproterenol Tricyclic antidepressants
Albuterol
NE (e.g. imipramine)
Receptor Recapture
+ action by Uptake-1
Adrenergic receptors (adrenoceptors)
Two families of receptors, designated and
were identified on the basis of their response to the
adrenergic agonist epinephrine, norepinephrine, &
isoproterenol (synthetic agonist)
for receptor the rank order of potency
epinephrine nor epinephrine > isoproterenol
-receptors:- isoproterenol > epinephrine >
norepinephrine
CH3
OH CH3
CH3 OH H
OH C OH N OH N
N H H
OH OH H H
OH H
H H
(-) Epinephrine
OH
(Adrenalin)
(-) Norepinephrine
(-) Isoproterenol Binds and activates both (Arterenol)
Binds and activates a- and b-adrenoceptors
b-adrenoceptors selectively
Cont...
The -adrenoceptors are subdivided into two groups
1 and 2 based on their affinity for agonists
phenylephrine (agonist) => 1 has greater affinity than 2
Clonidine (agonist) => 2 has greater affinity than 1
1 Receptors: present post synaptically on the
membrane of effector organs
2 receptors: located primarily on pre-synaptic nerve
endings and on other cells, such as -cell of the
pancreas
Stimulation of 2-receptor causes feedback inhibition
of the ongoing release of NE when there is high
sympathetic activity.
Cont...
G.Albuterol (Salbutamol)
Is a selective 2 agonist with properties similar to those of
terbutaline.
The drug widely used as an inhalant to relieve
bronchospasm
Onset and duration of bronchodilation effects of inhaled adrenergic agonists
2. Indirect acting adrenergic agonists
Cause NE release from presynpatic terminals
Amphetamine
Marked central stimulatory action is often mistaken
by drug abusers as its only action.
However, the drug can increase blood pressure
Its actions are mediated primary through the cellular
release of stored catecholamines
Effects include-euphoria (feeling of happiness),
postponement of sleep, suppress apetite, decrease
the feeling of fatigue.
Uses- Narcolepsy, obesity reduction
3. Mixed-action adrenergic agonists
Induce the release of nor-epinephrine from presynaptic terminals
and activate adrenergic receptors on post synaptic memberane
Ephedrine
A plant alkaloid, is now made synthetically
It releases stored norepinephrine from nerve endings and directly
stimulate both and receptors (direct + indirect)
Ephedrine is not a catechol and is poor substrate for COMT and
MAO; thus, the drug has a long duration of action but less potent
Has excellent absorption orally and penetrates in to the CNS
It raises blood pressure by vasoconstriction and cardiac stimulation
It produces bronchodilation, but it is less potent than epinephrine
or isoproternol & produce its action more slowly
Ephedrine has been used to treat asthma, as nasal decongestant,
and to raise blood pressure
The clinical use of ephedrine is declining due to availability of
better, more potent agents which cause fewer site effects
Adrenergic Antagonists
Adrenergic Antagonists
The adrenergic antagonists
(also called blockers) bind to
adrenoceptors
but donot trigger the
usual receptor mediated
intracellular effect
They are classified according
to their relative affinity for
or receptors
-adrenergic blocking agents
adrenoceptor blockers profoundly affect BP
They decrease peripheral vascular resistance
induces a reflex tachycardia resulting from the lowered BP.
A.Phenoxybenzamineboth 1 and 2 ;
noncompetitive
Not successful for hypertension. Why?
Block 1 , reflex tachycaria plus 2 blockade means increased SNS
outflow => increased CO
B.Phentolaminecompetitive block of both 1 and
2
C. Prazosin, terazosin & doxazosin
1 selective blockers
decrease peripheral vascular resistance
These drugs, unlike phenoxybenzamine and
phentolamine, cause minimal changes in CO? Why?
Yohimbine
selective competitive 2 blocker.
component of the bark of the yohimbe tree
-adrenergic Blocking Agents
All the clinically available -blockers are competitive
antagonists
Non-selective -blockers act on both 1 and 2
receptors;
whereas cardioselective antagonists primarily block 1 -
receptors
The names of all -blockers end in olol
except for labetalol and carvedilol
they do not induce postural hypotension,
because the -adrenoceptors remain functional
-blockers are effective in treating:
hypertension, angina, cardiac arrhythmias, myocardial
infarction, congestive heart failure, hyperthyroidism,
and glaucoma
-blockers
Propranolol: a prototype
non-selective -antagonist
(blocks both 1 and 2
receptors)