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3.23 > Lecture 23: Drug development - Beta blockers and Statins > Flashcards

Lecture 23: Drug development - Beta blockers and Statins Flashcards

1
Q

Where are alpha 1 receptors found?

A

Vascular smooth muscle

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2
Q

What is the mechanism of action of alpha 1 receptors?

A

Gq protein coupled activates phospholipase C, IP3 and DAG

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3
Q

What are the physiological effects of alpha 1 receptors?

A
  • Smooth muscle contractions
  • Gluconeogenesis
  • Vasocnstriction
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4
Q

What are the alpha 1 receptor agonists?

A
  • Norepinephrine
  • Phenylephrine
  • Methoxamine
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5
Q

What are the alpha 1 receptor antagonists?

A
  • Doxazosin
  • Phentolamine
  • Prazosin
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6
Q

Where are alpha 2 receptors found?

A
  • Pre synaptic terminals
  • Pancreas
  • Platelets
  • Ciliary epithelium
  • Salivary glands
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7
Q

What is the mechanism of action of alpha 2 receptors?

A

Gi protein coupled inhibits adenyl cyclase

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8
Q

What is the mechanism of action of alpha 2 receptors?

A

Gi protein coupled inhibits adenyl cyclase

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9
Q

What are the physiological effects of alpha 2 receptors?

A

Inhibits release of neurotransmitters

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10
Q

What are the alpha 2 receptor agonists?

A
  • Clonidine
  • Monoxidine
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11
Q

What are the alpha 2 receptor antagonists?

A
  • Yohombine
  • Idazoxan
  • Tolazoline
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12
Q

Where are beta 1 receptors found?

A
  • Heart
  • Kidney
  • Some presynamptic terminals
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13
Q

What is the mechanism of action of beta 1 receptors?

A

Gs protein coupled activates adenyl cyclase + PKA

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14
Q

What are the physiological effects of beta 1 receptors?

A

Increase heart rate and renin secretion

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15
Q

What are beta 1 receptor agonists?

A
  • Isoproternol
  • Norepinephrine
  • Dobutamine
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16
Q

What are beta 1 receptor antagonists?

A
  • Propanolol
  • Metoprolol
  • Atenolol
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17
Q

Where are beta 2 receptors found?

A
  • Visceral smooth muscles
  • Bronchioles
  • Liver
  • Skeletal muscles
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18
Q

What is the mechanism of action of beta 2 receptors?

A

Gs protein coupled activates adenyl cyclase and PKA, Ca channels

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19
Q

What are the physiological effects of beta 2 receptors?

A
  • Vasodilation
  • Bronchodilation
  • Inhibits insulin secretion
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20
Q

What are beta 2 receptor agonists?

A
  • Isoproterenol
  • Salbutamol
  • Salmeterol
  • Albuterol
  • Formoterol
  • Terbutaline
  • Levalbuterol
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21
Q

What are the beta 2 receptor antagonists?

A
  • Propanolol
  • ICI 118,551
  • Nadolol
  • Butoxamine
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22
Q

What are beta blockers used to treat?

A
  • Angina
  • Heart failure
  • Atrial fibrilation
  • Hypertension
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23
Q

What do beta blockers do?

A

Slow the SA node which initiates a heartbeat. The slow heart rate allows the left ventricle to fill completely and lowers the heart workload.

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24
Q

What do beta 1 receptors acting on the kidney do?

A

Renin relaese

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25
Q

What do beta 1 receptors acting on the adipose tissue do?

A

Lipolysis

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26
Q

What do beta 1 receptors acting on the heart affect?

A
  • Rate
  • Force
  • Automaticity
  • Cardiac output
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27
Q

What are the effects of beta blockers on the heart?

A
  • Decreased heart rate
  • Decreased contractility
  • Decreased conduction
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28
Q

What are the effects of beta blockers on the kidney?

A
  • Decreased renin release from renal juxtaglomerular cells
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29
Q

What are the cardiovascular beneficial effects of beta blockers?

A
  • Decreased blood pressure
  • Decreased myocardial oxygen demand
  • Decreased water and salt retention
  • Decreased oxidative and inflammatory stress
  • Attenuated cardiovascular remodeling
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30
Q

What are beta adrenoreceptors?

A

G protein coupled receptors which activate adenylyl cyclase to form cAMP from ATP when stimulated by noradrenaline

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31
Q

What causes calcium entry into a cell?

A

Increased cAMP activated a cAMP dependant protein kinase (PK-A) that phosphorylates L type calcium channels, which cause increased calcium entry into the cell

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32
Q

What does in increase of calcium entry lead to?

A

Leads to enhanced release of calcium by the sarcoplastic reticulum in the heart, these actions increase inotropy (contractility)

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33
Q

What are the actions of PK-A?

A
  • Phosphylate myosin light chain
  • Phosphorylate L type calcium channels
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34
Q

What does phosphorylation of L type calcium channels result in?

A

Increased calcium entry into the cell

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35
Q

What does phosphorylation of myosin light chain result in?

A

May contribute to the positive inotropic effect of beta adrenoreceptor stimulation

36
Q

What do beta blockers cause a decrease in?

A
  • Heart rate
  • Contractility
  • Conduction velocity
  • Relaxation rate
37
Q

When do beta blockers have an even greater effect?

A

When there is elevated sympathetic activity

38
Q

What causes activation of beta 2 adrenoreceptors on vascular smooth muscle?

A

Noradrenaline from sympathetic adrenergic nerves

39
Q

What does an increase in cAMP in vascular smooth muscle lead to?

A

Smooth muscle relaxation beacuse cAMP inhibits myosin light chain kinase that is responsible for phosphotylating smooth muscle myosin

40
Q

What is blockage of beta 2 adrenoreceptors associated with?

A

A small degree of vasonctrsiction in many vascular beds

41
Q

What does stimulation of beta 2 receptors cause?

A

Smooth muscle relaxtation

42
Q

What is the effect of beta 2 receptors on bronchial smooth muscle?

A

Bronchodilation

43
Q

What is the effect of beta 2 receptors on uterine muscle?

A

Uterine relaxation (tocolysis)

44
Q

What is contraindicated in patients who have astma?

A

Beta 1 adrenergic receptors

45
Q

What has clinical benifits, particularly in asthma?

A

Mimicking the action of noradrenaline and adrenaline at beta 2 receptors

46
Q

Why should beta 2 target engagement be avoided?

A

Causes smooth muscle contraction in asthmatics - bronchoconstriction

47
Q

How does beta 1 target engagement affect blood pressure?

A

Causes reduced heart rate/ blood vessel dilation, so reduced heart failure and reduced blood pressure

48
Q

How does beta 1 adrenergic receptor have its affect?

A
  • Agonist (adrenaline/ noradrenaline) binds to its GPCR and induced a conformational change that is transmitted through the 7TM helical domain from outside the membrane to inside
  • coupled G-protein complex bound to it on the internal face of the membrane exchanges GDP for GTP
  • Gα-protein decouples from the Gβγ subunit and interacts with target functional proteins to initiate cellular signalling
49
Q

What porportion of proteinn drug targets are GPCRs?

A

12%

50
Q

What GPCR does olanzapine react with?

A

5HT 2

51
Q

What GPCR does loratadine react with?

A

H1

52
Q

What GPCR does ranatidine react with?

A

H2

53
Q

What GPCR does sumatriptan react with?

A

5HT

54
Q

What GPCR does ropinirole react with?

A

D2

55
Q

What GPCR does fentanyl react with?

A

u-opiod

56
Q

What GPCR does loperamide react with?

A

u-opiod

57
Q

What GPCR does salbutamol react with?

A

B2

58
Q

What GPCR does losartan react with?

A

Angiotensin II

59
Q

What is olanzapine for?

A

Schrisophrenia

60
Q

What is loratadine for?

A

Rhinitis

61
Q

What is ranitadine for?

A

GORD

62
Q

What is sumatriptan for?

A

migrane

63
Q

What is ropinirole for?

A

Parkinsons disease

64
Q

What is fentanyl for?

A

Pain

65
Q

What is loperamide for?

A

Diarrhoae

66
Q

What is salbutamol for?

A

Asthma

67
Q

What is losartan for?

A

Hypertension

68
Q

What are they key interactions when noradrenaline binds to beta 1

A
  • Hydrogen bonds
  • Salt bridges
  • Ring stacking effects
69
Q

What was the first beta blocker developed

A

Propanalol

70
Q

What enantiomer of propanalol is more active?

A

S enantiomer

71
Q

What can propanolol not be used in patients with asthma?

A

It is a non selective beta blocker. It isnt selective for beta 1 over beta 2.

72
Q

What side effects does propanalol have?

A

CNS side effects - dizziness, nightmares and sedation

73
Q

How can beta blockers be improved?

A
  • Improve selectivity: find interactions with beta 1 receptors that are absent in beta 2
  • Reduce CNS side effects by reducing lipophilicity to lower penetration through the blood-brain barrier
73
Q

How can beta blockers be improved?

A
  • Improve selectivity: find interactions with beta 1 receptors that are absent in beta 2
  • Reduce CNS side effects by reducing lipophilicity to lower penetration through the blood-brain barrier
74
Q

How do you get from propanalol to practolol?

A

Removing the naphyl ring and replacement with a H-bonding amide group

75
Q

What did the change from propanalol to practolol lead to?

A
  • Reduced logP
  • Has an H-bonding interaction in the β1 receptor that was absent in β2
76
Q

Why was practolol withdrawn?

A

Because of serious off-target side effects in small numbers of patients eg peritonitis, liver damage

76
Q

Why was practolol withdrawn?

A

Because of serious off-target side effects in small numbers of patients eg peritonitis, liver damage

77
Q

How were atenolol and metoprolol developed?

A

Replacement of the acetamido group with other H-bonding groups by separating the amide from the aromatic ring

78
Q

What is the most β1-selective β–blockers clinically available

A

Bisoprolol

79
Q

Can patients with asthma have bisporolol

A

No

80
Q

What is the oral absorption of atenolol?

A

30%

81
Q

What is the oral absorption of propanolol?

A

100%

82
Q

What is the CNS penetration of atenolol?

A

Low penetration - fewer side effects

83
Q

What is the CNS penetration of propanlol?

A

High CNS penetration – CNS side effects

3.23 (26 decks)

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