Lecture 23: Drug development - Beta blockers and Statins Flashcards
1
Q
Where are alpha 1 receptors found?
A
Vascular smooth muscle
2
Q
What is the mechanism of action of alpha 1 receptors?
A
Gq protein coupled activates phospholipase C, IP3 and DAG
3
Q
What are the physiological effects of alpha 1 receptors?
A
- Smooth muscle contractions
- Gluconeogenesis
- Vasocnstriction
4
Q
What are the alpha 1 receptor agonists?
A
- Norepinephrine
- Phenylephrine
- Methoxamine
5
Q
What are the alpha 1 receptor antagonists?
A
- Doxazosin
- Phentolamine
- Prazosin
6
Q
Where are alpha 2 receptors found?
A
- Pre synaptic terminals
- Pancreas
- Platelets
- Ciliary epithelium
- Salivary glands
7
Q
What is the mechanism of action of alpha 2 receptors?
A
Gi protein coupled inhibits adenyl cyclase
8
Q
What is the mechanism of action of alpha 2 receptors?
A
Gi protein coupled inhibits adenyl cyclase
9
Q
What are the physiological effects of alpha 2 receptors?
A
Inhibits release of neurotransmitters
10
Q
What are the alpha 2 receptor agonists?
A
- Clonidine
- Monoxidine
11
Q
What are the alpha 2 receptor antagonists?
A
- Yohombine
- Idazoxan
- Tolazoline
12
Q
Where are beta 1 receptors found?
A
- Heart
- Kidney
- Some presynamptic terminals
13
Q
What is the mechanism of action of beta 1 receptors?
A
Gs protein coupled activates adenyl cyclase + PKA
14
Q
What are the physiological effects of beta 1 receptors?
A
Increase heart rate and renin secretion
15
Q
What are beta 1 receptor agonists?
A
- Isoproternol
- Norepinephrine
- Dobutamine
16
Q
What are beta 1 receptor antagonists?
A
- Propanolol
- Metoprolol
- Atenolol
17
Q
Where are beta 2 receptors found?
A
- Visceral smooth muscles
- Bronchioles
- Liver
- Skeletal muscles
18
Q
What is the mechanism of action of beta 2 receptors?
A
Gs protein coupled activates adenyl cyclase and PKA, Ca channels
19
Q
What are the physiological effects of beta 2 receptors?
A
- Vasodilation
- Bronchodilation
- Inhibits insulin secretion
20
Q
What are beta 2 receptor agonists?
A
- Isoproterenol
- Salbutamol
- Salmeterol
- Albuterol
- Formoterol
- Terbutaline
- Levalbuterol
21
Q
What are the beta 2 receptor antagonists?
A
- Propanolol
- ICI 118,551
- Nadolol
- Butoxamine
22
Q
What are beta blockers used to treat?
A
- Angina
- Heart failure
- Atrial fibrilation
- Hypertension
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.
24
Q
What do beta 1 receptors acting on the kidney do?
A
Renin relaese
25
What do beta 1 receptors acting on the adipose tissue do?
Lipolysis
26
What do beta 1 receptors acting on the heart affect?
- Rate
- Force
- Automaticity
- Cardiac output
27
What are the effects of beta blockers on the heart?
- Decreased heart rate
- Decreased contractility
- Decreased conduction
28
What are the effects of beta blockers on the kidney?
- Decreased renin release from renal juxtaglomerular cells
29
What are the cardiovascular beneficial effects of beta blockers?
- Decreased blood pressure
- Decreased myocardial oxygen demand
- Decreased water and salt retention
- Decreased oxidative and inflammatory stress
- Attenuated cardiovascular remodeling
30
What are beta adrenoreceptors?
G protein coupled receptors which activate adenylyl cyclase to form cAMP from ATP when stimulated by noradrenaline
31
What causes calcium entry into a cell?
Increased cAMP activated a cAMP dependant protein kinase (PK-A) that phosphorylates L type calcium channels, which cause increased calcium entry into the cell
32
What does in increase of calcium entry lead to?
Leads to enhanced release of calcium by the sarcoplastic reticulum in the heart, these actions increase inotropy (contractility)
33
What are the actions of PK-A?
- Phosphylate myosin light chain
- Phosphorylate L type calcium channels
34
What does phosphorylation of L type calcium channels result in?
Increased calcium entry into the cell
35
What does phosphorylation of myosin light chain result in?
May contribute to the positive inotropic effect of beta adrenoreceptor stimulation
36
What do beta blockers cause a decrease in?
- Heart rate
- Contractility
- Conduction velocity
- Relaxation rate
37
When do beta blockers have an even greater effect?
When there is elevated sympathetic activity
38
What causes activation of beta 2 adrenoreceptors on vascular smooth muscle?
Noradrenaline from sympathetic adrenergic nerves
39
What does an increase in cAMP in vascular smooth muscle lead to?
Smooth muscle relaxation beacuse cAMP inhibits myosin light chain kinase that is responsible for phosphotylating smooth muscle myosin
40
What is blockage of beta 2 adrenoreceptors associated with?
A small degree of vasonctrsiction in many vascular beds
41
What does stimulation of beta 2 receptors cause?
Smooth muscle relaxtation
42
What is the effect of beta 2 receptors on bronchial smooth muscle?
Bronchodilation
43
What is the effect of beta 2 receptors on uterine muscle?
Uterine relaxation (tocolysis)
44
What is contraindicated in patients who have astma?
Beta 1 adrenergic receptors
45
What has clinical benifits, particularly in asthma?
Mimicking the action of noradrenaline and adrenaline at beta 2 receptors
46
Why should beta 2 target engagement be avoided?
Causes smooth muscle contraction in asthmatics - bronchoconstriction
47
How does beta 1 target engagement affect blood pressure?
Causes reduced heart rate/ blood vessel dilation, so reduced heart failure and reduced blood pressure
48
How does beta 1 adrenergic receptor have its affect?
- 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
What porportion of proteinn drug targets are GPCRs?
12%
50
What GPCR does olanzapine react with?
5HT 2
51
What GPCR does loratadine react with?
H1
52
What GPCR does ranatidine react with?
H2
53
What GPCR does sumatriptan react with?
5HT
54
What GPCR does ropinirole react with?
D2
55
What GPCR does fentanyl react with?
u-opiod
56
What GPCR does loperamide react with?
u-opiod
57
What GPCR does salbutamol react with?
B2
58
What GPCR does losartan react with?
Angiotensin II
59
What is olanzapine for?
Schrisophrenia
60
What is loratadine for?
Rhinitis
61
What is ranitadine for?
GORD
62
What is sumatriptan for?
migrane
63
What is ropinirole for?
Parkinsons disease
64
What is fentanyl for?
Pain
65
What is loperamide for?
Diarrhoae
66
What is salbutamol for?
Asthma
67
What is losartan for?
Hypertension
68
What are they key interactions when noradrenaline binds to beta 1
- Hydrogen bonds
- Salt bridges
- Ring stacking effects
69
What was the first beta blocker developed
Propanalol
70
What enantiomer of propanalol is more active?
S enantiomer
71
What can propanolol not be used in patients with asthma?
It is a non selective beta blocker. It isnt selective for beta 1 over beta 2.
72
What side effects does propanalol have?
CNS side effects - dizziness, nightmares and sedation
73
How can beta blockers be improved?
- 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
How can beta blockers be improved?
- 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
How do you get from propanalol to practolol?
Removing the naphyl ring and replacement with a H-bonding amide group
75
What did the change from propanalol to practolol lead to?
- Reduced logP
- Has an H-bonding interaction in the β1 receptor that was absent in β2
76
Why was practolol withdrawn?
Because of serious off-target side effects in small numbers of patients eg peritonitis, liver damage
76
Why was practolol withdrawn?
Because of serious off-target side effects in small numbers of patients eg peritonitis, liver damage
77
How were atenolol and metoprolol developed?
Replacement of the acetamido group with other H-bonding groups by separating the amide from the aromatic ring
78
What is the most β1-selective β–blockers clinically available
Bisoprolol
79
Can patients with asthma have bisporolol
No
80
What is the oral absorption of atenolol?
30%
81
What is the oral absorption of propanolol?
100%
82
What is the CNS penetration of atenolol?
Low penetration - fewer side effects
83
What is the CNS penetration of propanlol?
High CNS penetration – CNS side effects
