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Flashcards in The Adrenergic System Deck (54):
1

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

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)

2

Describe the potency of beta 2 selective agonists

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

3

What G alpha proteins do alpha receptors act on?

Alpha 1: G alpha q
Alpha 2: G alpha i

4

What are the tissue locations fro alpha receptors?

Alpha 1: arterioles, pupils, liver, GI smooth muscle
Alpha 2: Presynaptic (autoreceptor), platelets

5

What are the functions of alpha receptors?

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

6

What are the cellular effects of alpha1 receptors?

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

7

What are the cellular effects of alpha 2 receptors?

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

8

What are the ligands of alpha receptors?

Noradrenaline
Adrenaline

9

What G alpha proteins do beta receptors act on?

G alpha s

10

What are the tissue locations of beta receptors?

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

11

What are the functions of beta receptors?

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

12

What are the cellular effects of beta1 receptors?

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

13

What are the cellular effects of beta2 receptors?

Activation of adenylate cyclase, which increases cAMP
Results: excitation

14

What are the cellular effects of beta3 receptors?

Activation of adenylate cyclase, which increases cAMP
Results: excitation

15

What are the ligands of beta receptors?

Beta 1 and 3: noradrenaline and adrenaline
Beta 2: adrenaline

16

What are the 3 ways to eliminate signal from NA?

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)

17

What are MOPEG and VMA?

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

18

Describe MAO

Found in the mitochondria of presynaptic terminal
Removal of N eliminates activity

19

Describe COMT

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

20

What is the relative potency of noradrenaline?

High potency for alpha 1, alpha 2 and beta 1 receptors
No potency for beta 2

21

What is the relative potency of adrenaline?

Moderate potency for alpha receptors
High potency for beta receptors

22

What is the relative potency of isproterenol?

High potency for beta receptors
No potency for alpha receptors

23

What is the relative potency of phenylephrine?

Moderate potency for alpha 1
No potency for alpha 2 or beta receptors

24

What is the relative potency of clonidine?

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