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Medicinal Chemistry > The Adrenergic System > Flashcards

The Adrenergic System Flashcards

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1
Q

Why are agonists and antagonists of the adrenergic receptors made? How are they made?

A

Given the diversity of receptors and tissue distribution, it would be desirable to make agonists and antagonists of adrenergic receptors that are receptor specific and therefore tissue specific
This is done primarily done by producing analogues of the endogenous ligand that increases potency at the desired receptor while decreasing potency at undesired receptors (if possible)

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2
Q

Describe the potency of beta 2 selective agonists

A

The beta2 selective agonist has very high potency for beta 2 and low potency at other adrenergic receptors. The result is only beta 2 receptor effects (like bronchodilation) are observed at low doses.
However, at very high doses, beta 1 receptor effects can be observed (like increased heart rate). At sufficiently high doses, effects from alpha receptors can also be observed

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3
Q

What G alpha proteins do alpha receptors act on?

A

Alpha 1: G alpha q

Alpha 2: G alpha i

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4
Q

What are the tissue locations fro alpha receptors?

A

Alpha 1: arterioles, pupils, liver, GI smooth muscle

Alpha 2: Presynaptic (autoreceptor), platelets

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5
Q

What are the functions of alpha receptors?

A

Alpha 1: vasoconstriction (increase BP), pupil dilation, glycogenolysis, relax GI smooth muscle
Alpha 2: presynaptic inhibition (i.e., inhibit neurotransmitter release), platelet aggregation

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6
Q

What are the cellular effects of alpha1 receptors?

A

Activate PLC gamma, which increases IP3 and DAG, increases intracellular calcium, decreases potassium outflow
Results: excitation

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7
Q

What are the cellular effects of alpha 2 receptors?

A

Inhibit adenylate cyclase, which decrease cAMP, intracellular calcium and increase potassium outflow
Results: inhibition

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8
Q

What are the ligands of alpha receptors?

A

Noradrenaline

Adrenaline

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9
Q

What G alpha proteins do beta receptors act on?

A

G alpha s

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10
Q

What are the tissue locations of beta receptors?

A

Beta1: heart and GI smooth muscle
Beta2: lungs, muscle blood vessels, liver, GI smooth muscle, skeletal muscle
Beta3: adipose tissue

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11
Q

What are the functions of beta receptors?

A

Beta1: Increase heart rate, increase force of contraction, relax smooth muscle
Beta2: bronchodilation, vasodilation, glycogenolysis, smooth muscle relaxation, muscle tremor
Beta3: lipolysis

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12
Q

What are the cellular effects of beta1 receptors?

A

Activation of adenylate cyclase, which increase cAMP, calcium store in ER
Results: excitation

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13
Q

What are the cellular effects of beta2 receptors?

A

Activation of adenylate cyclase, which increases cAMP

Results: excitation

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14
Q

What are the cellular effects of beta3 receptors?

A

Activation of adenylate cyclase, which increases cAMP

Results: excitation

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15
Q

What are the ligands of beta receptors?

A

Beta 1 and 3: noradrenaline and adrenaline

Beta 2: adrenaline

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16
Q

What are the 3 ways to eliminate signal from NA?

A 
Reuptake at synapse (this is the most important mechanism for the elimination of NA signal)
Catechol-O-methyl transferase (COMT; a major reason NA and A are not orally bioavailable. This is a phase II metabolism enzyme)
Monoamine oxidase (MOA; this is a phase I metabolism enzyme but NOT a CYP enzyme)
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17
Q

What are MOPEG and VMA?

A

MOPEG and VMA are the main metabolites of NA and A and they are conjugated before excretion

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18
Q

Describe MAO

A

Found in the mitochondria of presynaptic terminal

Removal of N eliminates activity

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19
Q

Describe COMT

A

Found in the synapse
Always adds the methyl group in the meta position
This reduces the activity

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20
Q

What is the relative potency of noradrenaline?

A

High potency for alpha 1, alpha 2 and beta 1 receptors

No potency for beta 2

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21
Q

What is the relative potency of adrenaline?

A

Moderate potency for alpha receptors

High potency for beta receptors

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22
Q

What is the relative potency of isproterenol?

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A

High potency for beta receptors

No potency for alpha receptors

23
Q

What is the relative potency of phenylephrine?

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A

Moderate potency for alpha 1

No potency for alpha 2 or beta receptors

24
Q

What is the relative potency of clonidine?

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A

High potency for alpha 2

No potency for alpha 1 or beta receptors

25
What is the relative potency of salbutamol?
High potency for beta 2 Low potency for beta 1 No potency for alpha receptors
26
What is the relative potency of terbutaline?
High potency for beta 2 | No potency for beta 1 or alpha receptors
27
What is the relative potency of dobutamine?
High potency for beta 1 Low potency for beta 2 No potency for alpha receptors
28
What do amphetamine like drugs do?
Amphetamines and amphetamine like drugs cause the release of NA, dopamine and serotonin from the presynaptic vesicles into the synaptic cleft This is not mediated by fusion of the vesicle with the presynaptic membrane or by an action potential
29
What is the mechanism of amphetamines?
Amphetamine binds to and inhibits MAO. This increases the non-vesicular MA. Vesicular monoamine transporter 2 (VMAT2) normally takes up MA into the vesicles. Amphetamines inhibit this. The concentration of non-vesicular NA, DA and 5HT are so high that the reuptake pump works in the opposite direction and they are pumped into the synaptic cleft Amphetamine is taken up by the same reuptake pump, so it acts a a competitive inhibitor
30
What is the mechanism of cocaine?
Cocaine inhibits reuptake of DA, NA and 5HT, which increases their concentration in the synaptic cleft
31
What do cocaine and amphetamine have in common?
Although cocaine and amphetamine work by different mechanisms, they both the same effect of increasing the concentration of MA in the synaptic cleft All the psychological effects of cocaine and amphetamine are because of their effects on DA (including euphoria, addiction and psychotic symptoms)
32
What is tyramine? Why is it important?
It is a naturally occuring metabolite that has amphetamine activity. Red wine, cheese, fermented foods are all high in tyramine These foods are contraindicated while taking irreversible inhibitors of MAO (Phenelzine, brand name: Nardil; Tranylcypormine, brand name: Parnate) Reversible MAO inhibitors are ok (Moclobemide, brand name: Manerix)
33
What are sympathomimetics?
Drugs that mimic the sympathetic nervous system
34
What are the three basic types of sympathomimetics?
Drugs that bind to the receptors of the SNS (i.e., alpha and/or beta receptors) - direct acting Drugs that have amphetamine like action - indirect acting Drugs that both bind to alpha and/or beta receptors and have amphetamine like actions - mixed acting
35
What are examples of sympathetic agonists (direct acting sympathomimetics)?
Noradrenaline | Phenylephrine
36
What are examples of mixed acting sympathomimetics?
Ephedrine Phenylpropanolamine Phenylethanolamine Metyramine
37
What are examples of indirect acting sympathomimetics?
Tyramine Phenethylamine Amphetamine Methamphetamine
38
What is dexamphetamine?
The pure (S) isomer of amphetamine It is the most potent It is used to treat ADHD and possibly narcolepsy
39
What isomer of NA and A is preferred? R or S?
R isomer (5 sites of interaction with the receptor vs only 4 sites)
40
What happens to the intrinsic activity of alpha adrenergic agonists as the size f the substituent increases?
The intrinsic activity decreases but the affinity can increase (creating antagonists)
41
What makes clonidine an alpha 2 agonist?
Two oath substitutions, which restricts orientation The plane of the phenyl ring is 90º to the plane of the guanidine It has not meta OH so it cannot be inactivated by COMT It crosses the BBB
42
What is methyldopa
Methyldopa is converted into alpha-methylnoradrenaline, which is the active form of the drug and it is a selective alpha 2 agonist
43
What is the clinical significance of alpha 2 agonists?
Alpha 2 agonists were originally marketed for hypertension In the CNS, alpha 2 agonists reduce sympathetic output because of auto-inhibition decreasing heart rate and causing peripheral vasodilation There are too many side effects Clonidine (brand name: Dixarit) is still used for the treatment of symptoms of menopause Methyldopa is occasionally used to treat hypertension during pregnancy (pregnancy risk category B)
44
What makes up an alpha 1 agonist?
Imidazoline
45
What are examples of alpha 1 agonists?
Xylometazoline Oxymetazoline Nephazoline Tetrahydrozoline
46
What are imidazoline alpha 1 agonists used as?
Topical decongestants Xylometazoline, brand name: Otrivin nasal spray Oxymetazoline, brand name: Drixoral nasal spray Tetrahydrozoline, brand name: Visine eye drops They cause vasoconstriction. In the eyes they reduce the appearance of red eyes. In the nose, it reduces swollen gin the nasal membranes
47
What are examples of oral decongestants?
Phenylephrine (brand name: Benylin Cold and Sinus Plus) | Pseudoephedrine (brand name: Sudafed)
48
Describe phenylephrine
Is a selective alpha 1 receptor agonist Has an N-methyl group (alpha agonist) Presence of meta OH (no amphetamine like activity) Beta OH (no amphetamine like activity)
49
Describe pseudoephedrine
Has activity and affinity for alpha 1 and alpha 2 receptors Lack of ring substitution (amphetamine like activity) Beta OH (not a pure amphetamine - mixed activity) The main mechanism of action for pseudoephedrine is mixed amphetamine like activities
50
What is the most potent alpha 2 agonist?
Erythro ephedrine
51
What is nasal congestion?
Inflammation or swelling of the nasal membranes, making it difficult to breath through the nose
52
What is sinusitis?
Inflammation or swelling of the tissues lining the sinuses. The inflammation can become so severe that the sinuses become filled with fluid and the exits from the sinuses become blocked off preventing drainage. This can cause a frontal headache
53
What are the pros to nasal spray decongestants? What are the cons?
Used for those who cannot tolerate oral decongestants (hypertensive patients) It can cause rebound congestion if used for more than 3 days in a row
54
What are the pros to oral decongestants? What are the cons?
Generally preferred by those who can tolerate it. No rebound congestion They can cause peripheral vasoconstriction and increases heart rate, resulting in hypertension, which is a problem for patients with hypertension

Medicinal Chemistry (13 decks)

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