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Adrenergic agonists
Sympathomimetic drugs
ANS Pharmacology
Lecture 4
Dr. Hiwa K. Saaed
College of Pharmacy/University of Sulaimani
2017-2018
12 May 2018 2
The adrenergic drugs affect receptors that are
stimulated by norepinephrine or epinephrine.
Adrenergic drugs act on adrenergic receptors, located
either presynaptically on the neuron or
postsynaptically on the effector organ
NEP & EP are modulate the
• Rate and force of contraction of heart.
• Resistance (constriction and dilation) of blood vessels and
bronchioles.
• Release of insulin,
• breakdown of fat (lipolysis).
Therefore, they are frontline therapies for hypertension,
depression, shock, asthma, angina & etc.
Adrenergic agonists
12 May 2018 3
Neurotransmission at adrenergic
neurons
synthesis, storage, release, binding, removal
(reuptake) of the neurotransmitter
1. Synthesis of norepinephrine:
• Tyrosine is transported by a carrier into
the adrenergic neuron,
• Tyrosine hydroxylated by tyrosine
hydroxylase to dihydroxyphenylalanine
(DOPA).
This is the rate-limiting step in the formation
of norepinephrine.
• DOPA is then decarboxylated by the
enzyme aromatic I-amino acid
decarboxylase to form dopamine in the
presynaptic neuron.
• Synthesis and Storage of norepinephrine in vesicles: Dopamine is then
transported into synaptic vesicles by an amine transporter system. This carrier
system is blocked by reserpine. Dopamine is next hydroxylated to form
norepinephrine by the enzyme dopamine β-hydroxylase.
• Release of norepinephrine: An action potential arriving at the nerve junction
triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of
the neuron.
• The increase in calcium causes synaptic vesicles to fuse with the cell membrane
and to undergo exocytosis to expel their contents into the synapse. Drugs such as
guanethidine block this release.
• Binding to receptors: Norepinephrine binds to postsynaptic receptors or to
presynaptic receptors. Adrenergic receptors use both the cAMP second
messenger system and the phosphatidylinositol cycle to transduce the signal into
an effect.
Neurotransmission at adrenergic neurons & drugs target:
• Removal of norepinephrine:
1. diffuse out of the synaptic space and enter the systemic circulation;
2. be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the
synaptic space; or
3. undergo reuptake back into the neuron. Reuptake of norepinephrine into the
presynaptic neuron is the primary mechanism for termination of its effects.
The reuptake by the neuronal membrane involves a sodium-chloride (Na+/Cl-)-dependent
norepinephrine transporter (NET) that can be inhibited by tricyclic antidepressants (TCAs),
such as imipramine, by serotonin–norepinephrine reuptake inhibitors such as duloxetine, or
by cocaine.
Potential fates of recaptured norepinephrine:
• it may be taken up into synaptic vesicles via the amine transporter system and be sequestered for
release by another action potential,
• or it may persist in a protected pool in the cytoplasm.
• Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal
mitochondria.
Neurotransmission at adrenergic neurons & drugs target:
12 May 2018 6
• Tyrosine hydroxylase can be inhibited by methyl-p-tyrosine.
• MAO: inhibitors of MAO (e.g., phenelzine, tranylcypromine)
• The mobile pool; many indirect-acting sympathomimetics (e.g., amphetamine,
ephedrine, tyramine) can displace NE from the mobile pool
• Uptake: some indirect-acting sympathomimetics (cocaine, TCA).
• Presynaptic α2-receptors: (e.g., clonidine, alpha methyldopa) cause inhibition of NE
release.
• Granular uptake of NE: blocker of granular uptake of NE (e.g., reserpine) .
• NE release from granules: blockers (e.g., guanethidine).
• Postsynaptic receptors: can be activated or blocked.
Neurotransmission at adrenergic neurons & drugs target:
Divided into subgroups on the basis of their
Direct acting:
I. α agonists:
• Non selective,
• α1-selective,
• α2-selective
II. β agonists:
• Non selective,
• β1-selective,
• Β2-selective
Indirect acting
↑ CAO in the synapse:
• Releaser: Amphetamine, tyramine
Potentiate by MAOI, COMT blocker. Why?
• Reuptake inhibitor: Cocaine, TCA
Spectrum of action: α, β, or dopamine receptor affinity
Mode of action: Direct, Indirect or both (Mix)
Mixed acting
Ephedrine, metaraminol
12 May 2018 8
Adrenoceptors
• Selective for NE & EP.
• dopamine can also activate some adrenoceptors at very high
‘supraphysiologic’ concentrations.
• Divided into two main classes:
• α & β adrenoceptors
• All are members of GPCR superfamily.
12 May 2018 9
α-receptors:
EP≥NE>>Isoproterenol
β-receptors:
Isop>EP>NE
12 May 2018 10
• α-receptors are subdivided into two subgroups α1 & α2,
e.g., α1 receptors have a higher affinity for phenylephrine
than do α2 receptors. Conversely, clonidine selectively
binds to α2 receptors and has less effect on α1 receptors.
• α1 Are present on the postsynaptic membrane
• α2 Located primarily on presynaptic nerve endings.
The stimulation of α2 receptors causes feedback
inhibition of the ongoing release of NE;
• α2 Located on other cells such as the β-cell of the
pancreas control insulin output.
α-adrenoceptors (α1 & α2)
12 May 2018 11
β-receptors:
• Subdivided to β1, β2 and β3-receptors
• β1-receptors have ~equal affinities for both EP & NE.,
• β2-receptors have higher affinity for EP than for NE.
thus tissue with a predominance of β2-receptors (vasculature of skeletal
muscle) are particularly responsive to hormonal effects of circulating EP
released by adrenal medulla.
Mechanism of action:
• binding of neurotransmitter at the β1 or β2-receptor→ result in
activation of AC→↑cAMP concentrations within the cell.
12 May 2018 12
Mechanisms of action of adrenergic receptors :
12 May 2018 13
Mechanisms of action of adrenergic receptors :
12 May 2018 14
Desensitization of receptors:
• Prolonged exposure to the CAO reduces the responsiveness of the
receptors due to:
1. Sequestration of the receptors
2. Down-regulation (destruction, or decreased synthesis)
3. An inability to couple to G-protein
Properties of Catecholamines& Noncatecholamines
Catecholamines
• High potency in activating α & β
receptors
• Rapid inactivation by:
1. COMT postsynaptically, gut wall,
2. MAO intraneuronally, liver or gut
Thus, CAO have only a brief duration of
action when given parenterally, and are
ineffective when administered orally
because of inactivation.
• Poor penetration into the CNS (polar)
Noncatecholamines
• phenylephrine, ephedrine,
amphetamine
• Have longer t1/2 because they are
not inactivated by COMT, and they
are poor substrate for MAO
• Increased lipid solubility permits
the greater access to the CNS
12 May 2018 16
Major effects mediated by adrenoceptors
Stimulation of 1 receptors characteristically produces vasoconstriction (particularly in skin and
abdominal viscera) and an increase in total peripheral resistance and blood pressure.
Stimulation of 1 receptors characteristically causes cardiac stimulation (increase in heart rate and
contractility),
whereas stimulation of 2 receptors produces vasodilation (in skeletal muscle vascular beds) and
smooth muscle relaxation.
12 May 2018 17
SITE OF ACTION
12 May 2018 18
SITE OF ACTION

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L4 ans pharmacology 17 18

  • 1. Adrenergic agonists Sympathomimetic drugs ANS Pharmacology Lecture 4 Dr. Hiwa K. Saaed College of Pharmacy/University of Sulaimani 2017-2018
  • 2. 12 May 2018 2 The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Adrenergic drugs act on adrenergic receptors, located either presynaptically on the neuron or postsynaptically on the effector organ NEP & EP are modulate the • Rate and force of contraction of heart. • Resistance (constriction and dilation) of blood vessels and bronchioles. • Release of insulin, • breakdown of fat (lipolysis). Therefore, they are frontline therapies for hypertension, depression, shock, asthma, angina & etc. Adrenergic agonists
  • 3. 12 May 2018 3 Neurotransmission at adrenergic neurons synthesis, storage, release, binding, removal (reuptake) of the neurotransmitter 1. Synthesis of norepinephrine: • Tyrosine is transported by a carrier into the adrenergic neuron, • Tyrosine hydroxylated by tyrosine hydroxylase to dihydroxyphenylalanine (DOPA). This is the rate-limiting step in the formation of norepinephrine. • DOPA is then decarboxylated by the enzyme aromatic I-amino acid decarboxylase to form dopamine in the presynaptic neuron.
  • 4. • Synthesis and Storage of norepinephrine in vesicles: Dopamine is then transported into synaptic vesicles by an amine transporter system. This carrier system is blocked by reserpine. Dopamine is next hydroxylated to form norepinephrine by the enzyme dopamine β-hydroxylase. • Release of norepinephrine: An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. • The increase in calcium causes synaptic vesicles to fuse with the cell membrane and to undergo exocytosis to expel their contents into the synapse. Drugs such as guanethidine block this release. • Binding to receptors: Norepinephrine binds to postsynaptic receptors or to presynaptic receptors. Adrenergic receptors use both the cAMP second messenger system and the phosphatidylinositol cycle to transduce the signal into an effect. Neurotransmission at adrenergic neurons & drugs target:
  • 5. • Removal of norepinephrine: 1. diffuse out of the synaptic space and enter the systemic circulation; 2. be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space; or 3. undergo reuptake back into the neuron. Reuptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of its effects. The reuptake by the neuronal membrane involves a sodium-chloride (Na+/Cl-)-dependent norepinephrine transporter (NET) that can be inhibited by tricyclic antidepressants (TCAs), such as imipramine, by serotonin–norepinephrine reuptake inhibitors such as duloxetine, or by cocaine. Potential fates of recaptured norepinephrine: • it may be taken up into synaptic vesicles via the amine transporter system and be sequestered for release by another action potential, • or it may persist in a protected pool in the cytoplasm. • Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. Neurotransmission at adrenergic neurons & drugs target:
  • 6. 12 May 2018 6 • Tyrosine hydroxylase can be inhibited by methyl-p-tyrosine. • MAO: inhibitors of MAO (e.g., phenelzine, tranylcypromine) • The mobile pool; many indirect-acting sympathomimetics (e.g., amphetamine, ephedrine, tyramine) can displace NE from the mobile pool • Uptake: some indirect-acting sympathomimetics (cocaine, TCA). • Presynaptic α2-receptors: (e.g., clonidine, alpha methyldopa) cause inhibition of NE release. • Granular uptake of NE: blocker of granular uptake of NE (e.g., reserpine) . • NE release from granules: blockers (e.g., guanethidine). • Postsynaptic receptors: can be activated or blocked. Neurotransmission at adrenergic neurons & drugs target:
  • 7. Divided into subgroups on the basis of their Direct acting: I. α agonists: • Non selective, • α1-selective, • α2-selective II. β agonists: • Non selective, • β1-selective, • Β2-selective Indirect acting ↑ CAO in the synapse: • Releaser: Amphetamine, tyramine Potentiate by MAOI, COMT blocker. Why? • Reuptake inhibitor: Cocaine, TCA Spectrum of action: α, β, or dopamine receptor affinity Mode of action: Direct, Indirect or both (Mix) Mixed acting Ephedrine, metaraminol
  • 8. 12 May 2018 8 Adrenoceptors • Selective for NE & EP. • dopamine can also activate some adrenoceptors at very high ‘supraphysiologic’ concentrations. • Divided into two main classes: • α & β adrenoceptors • All are members of GPCR superfamily.
  • 9. 12 May 2018 9 α-receptors: EP≥NE>>Isoproterenol β-receptors: Isop>EP>NE
  • 10. 12 May 2018 10 • α-receptors are subdivided into two subgroups α1 & α2, e.g., α1 receptors have a higher affinity for phenylephrine than do α2 receptors. Conversely, clonidine selectively binds to α2 receptors and has less effect on α1 receptors. • α1 Are present on the postsynaptic membrane • α2 Located primarily on presynaptic nerve endings. The stimulation of α2 receptors causes feedback inhibition of the ongoing release of NE; • α2 Located on other cells such as the β-cell of the pancreas control insulin output. α-adrenoceptors (α1 & α2)
  • 11. 12 May 2018 11 β-receptors: • Subdivided to β1, β2 and β3-receptors • β1-receptors have ~equal affinities for both EP & NE., • β2-receptors have higher affinity for EP than for NE. thus tissue with a predominance of β2-receptors (vasculature of skeletal muscle) are particularly responsive to hormonal effects of circulating EP released by adrenal medulla. Mechanism of action: • binding of neurotransmitter at the β1 or β2-receptor→ result in activation of AC→↑cAMP concentrations within the cell.
  • 12. 12 May 2018 12 Mechanisms of action of adrenergic receptors :
  • 13. 12 May 2018 13 Mechanisms of action of adrenergic receptors :
  • 14. 12 May 2018 14 Desensitization of receptors: • Prolonged exposure to the CAO reduces the responsiveness of the receptors due to: 1. Sequestration of the receptors 2. Down-regulation (destruction, or decreased synthesis) 3. An inability to couple to G-protein
  • 15. Properties of Catecholamines& Noncatecholamines Catecholamines • High potency in activating α & β receptors • Rapid inactivation by: 1. COMT postsynaptically, gut wall, 2. MAO intraneuronally, liver or gut Thus, CAO have only a brief duration of action when given parenterally, and are ineffective when administered orally because of inactivation. • Poor penetration into the CNS (polar) Noncatecholamines • phenylephrine, ephedrine, amphetamine • Have longer t1/2 because they are not inactivated by COMT, and they are poor substrate for MAO • Increased lipid solubility permits the greater access to the CNS
  • 16. 12 May 2018 16 Major effects mediated by adrenoceptors Stimulation of 1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Stimulation of 1 receptors characteristically causes cardiac stimulation (increase in heart rate and contractility), whereas stimulation of 2 receptors produces vasodilation (in skeletal muscle vascular beds) and smooth muscle relaxation.
  • 17. 12 May 2018 17 SITE OF ACTION
  • 18. 12 May 2018 18 SITE OF ACTION