Biochemical principles of pharmacology Flashcards
1
Q
what are ACE inhibitors an example of?
A
enzyme inhibitors
2
Q
what are the proteins targeted by drugs?
A
enzymes
ion channels
transport proteins
3
Q
what are the most common targets of drugs?
A
receptors because they can stimulate or stop an action
4
Q
what inhibitors are used in the hospitals for cardiovascular?
A
ACE inhibitors
statins
aspirin
5
Q
what inhibitors are used in the hospitals as blood thinners?
A
Warfarin
Rivaroxaban
Dabigatran
6
Q
what inhibitors are used in the hospitals as Analgesic/pain?
A
paracetamol
ibuprofen
7
Q
what inhibitors are used in the hospitals as antibiotics?
A
Amoxicillin
8
Q
what is ACE an example of?
A
protease which catalyses peptide bonds
9
Q
where are ACE taken from and inspired by?
A
taken from venom of snakes inspired by carboxypeptidase A
10
Q
what do ACE inhibitors do?
A
reduce the formation of Angiotensin ll causing decrease in blood pressure
decrease breakdown of Bradykinin causing coughing
11
Q
what is Angiotensin ll?
A
signalling hormone
12
Q
what is Angiotensin l?
A
precursor peptide
13
Q
what is angiotensinogen?
A
precursor protein
14
Q
what are At1 receptors for?
A
vasoconstriction and aldosterone release
15
Q
what are the two kinds of inhibtion?
A
reversible (non-covalent)
irreversible (covalent)
competitive
uncompetitive
mixed
16
Q
how can the mode of action of an enzyme inhibitor be determined?
A
enzyme kinetics
17
Q
what is the Michaelis-Menten constant Km?
A
βConcentration of substrate [S] at which the initial velocity V0 of catalysis is half maximal.β
18
Q
how do you determine Km?
A
carry experiments where:
enzyme concentration remains constant
substrate concentrations is varied
initial velocity is determined over time
19
Q
why is Lineweaver-Burk plot used?
A
βbecause hyperbola is difficult to fit so 1/[S] (x-axis) vs 1/V0 (y-axis) is usedβ
20
Q
what are the effects of calcium blocker?
A
stop uptake of Ca2+ ions by smooth muscle cells
causing smooth muscle relaxation: vasodilation
decreases muscle contractions which decreases heart rate
21
Q
what are the adverse effects of calcium blockers?
A
arteries dilate
veins are unaffected
swollen ankles because excess fluid remains
22
Q
what are examples of membrane transport proteins?
A
ion channels
ion pumps
solute transporters
ABC transporters
23
Q
what are pharmaceutically important types of proteins?
A
drug targets
drug uptake and secretion
24
Q
what are the two types of ion channels?
A
voltage gated
ligand gated
25
how do particles pass ion channels?
diffusion which is passive process
26
what is the structure of ion channels?
integral membrane proteins
multimetric proteins
27
what is a selectivity filter?
negatively charged amino acids only allow certain ions through
28
what is the selective filter for calcium ion channels?
four aspartates
29
what causes asymmetry in selectivity filter?
'binding of calcium-channel blocker amlodipine therefore Ca2+ is unable to pass through'
30
how is the potency of inhibitors determined?
comparing concentration at 50% of inhibition (IC50)
31
what is potency?
the amount of drug needed for an effect showing drug activity
32
what is selectivity?
comparing the action of two inhibitors to each other
33
what are other classes of proteins in membrane transport?
Solute transporters
Thiazide diuretics
34
what are Thiazide diuretics?
inhibit activity of a transporter
involves active transport
Na+, Cl- symporter on kidney
increased water and slat excretion
reduced blood volume and cardiac output
reduced blood pressure
35
what is vasoconstriction?
narrowing blood vessels increasing blood pressure
36
what does aldosterone do?
salt and water control
37
what is Km a measure of?
how well enzyme binds to substrate
38
what does a Michaelis-Menten plot and Lineweaver-Burk plot for competitive inhibitor look like?
slide 23
lecture 1 Biochem Pharmacology
39
what does a Michaelis-Menten plot and Lineweaver-Burk plot for uncompetitive inhibitor look like?
slide 24
lecture 1 Biochem Pharmacology
40
what does a Michaelis-Menten plot and Lineweaver-Burk plot for mixed inhibitor look like?
slide 25
lecture 1 Biochem Pharmacology
41
what is the sodium/potassium pump inhibited by?
cardiac glycosides
42
what does the sodium/potassium pump result in?
reduced heart rate while increases force of contraction of heart muscle so used for heart failure treatment
43
what does inhibition of Na+/K+-ATPase lead to?
increase in intracellular Na+
and then increase in intracellular Ca2+
44
what happens when a bioassay increases in complexity?
better representation of pateint
45
what happens when bioassay decreases in complexity?
better understanding of mechanism
46
what is the central nervous system?
brain and spinal chord
47
what is the peripheral nervous system?
somatic nervous system
autonomic nervous system
48
what does the somatic nervous system consist of?
voluntary response of skeletal muscles
motor control- efferent nerves
sensory control-afferent nerves
an axon connecting from CNS to effector
49
what does the autonomic NS?
sympathetic and parasympathetic NS
subconscious control
smooth muscle, glands
two neurones from CNS to ganglion and then to effector
50
what is sympathetic NS?
fight or flight
body prepared for activity
increases heart rate
vasoconstriction
51
what is parasympathetic NS?
rest and digest
encourages restorative functions
slows heart rate
movement and secretion by GI tract
52
what is ganglion?
cluster of peripheral autonomic neurones
53
what is the neurotransmitter used in parasympathetic NS?
acetylcholine
54
what are the receptors for noradrenaline and adrenaline?
adrenergic receptors
55
what are adrenergic receptors?
similar 3D shape
similar amino acid sequence
different genes
different expression pattern
56
what are the receptors for acetylcholine?
muscarinic receptors
57
what are muscarinic receptors?
similar 3D shape
similar amino acid sequence
different genes
different expression pattern
58
what does SNAP stand for?
sympathetic/noradrenaline
acetylcholine/parasympathetic
59
signals for sympathetic and parasympathetic?
antagonistic
cooperative
complimentary
60
adrenergic and muscarinic receptors?
'Members of the largest group of receptors: G protein-coupled receptors (GPCRs)
Characteristic: seven trans-membrane ο‘-helices (7-TM)'
61
what do beta blockers do?
compete for adrenergic receptors with noradrenaline and adrenaline
62
relationship between beta blockers and B1 receptors?
antagonistic pairs
63
what are beta blockers used to treat?
angina
heart failure
heart attack
atrial fibrillation
high blood pressure
64
what are the types of receptors?
ligand-gated ions channels-nicotinic acetylcholine receptors
G protein-coupled receptors-Adrenergic and cholinergic receptors
Kinase-linked receptors
Nuclear receptors
65
what do drugs do to receptors?
they can stimulate or oppose receptors
66
what kind of drug is an adrenaline and beta blocker?
adrenaline is an agonist
beta blocker is an antagonist
67
what is the role of a receptor?
protein that recognises a chemical signal then brings about a response
68
what is ligand?
chemical that forms complex with receptor
69
what are examples of receptors?
adrenergic receptors
cholinergic receptors
70
what is the process of G protein-coupled receptor signalling?
noradrenaline binds to B1 receptor
ligand-receptor complex causes GDP bound to GSa to change into GTP
then GTP bound-Gsa dissociates from GsBy protein then binding to adenylyl cyclase
converting ATP to cAMP
GTP hydrolysed by GSa
cAMP converted to PKA
71
what membrane proteins are linked to GPCR singalling?
integral membrane protein
lipid-modified membrane protein
accesory membrane protein
72
when is a G protein-coupled receptor active?
a-helix structure of the receptor
Gsa
GTP converted to GDP
acts as an agonsit
73
when is a G-protein-coupled receptor inactive?
loop structure
Gsa cannot bind
antagonist
74
what do receptors use when signalling?
receptors signalling use interchangeable parts
75
example of interchangeable parts used?
B1 and B2 both use Gs proteins and adenylyl cyclase.
76
what is principle 4 of signalling?
desensitisation
once receptor activated then feedback loop is triggered inactivating the receptor
77
what is the process of desensitisation of B1 receptor?
'decrease in noradrenaline, reducing binding and activation, Ga not activated further
GTP hydrolysed by Ga protein, Adenylyl cyclase isn't stimulated anymore
cAMP degraded to AMP
Internalisation of Ξ²1 receptor upon continued activation'
78
what is the 5 principle of singalling?
integration of singalling
79
what is integration signalling?
'activation of two receptors that leads to a response that integrates both signals'
80
how does a ligand binding assay work?
tissue is extracted
Incubated with [3H]-compound
separate bound from unbound ligands
Detect bound [3H]-compound
81
what is Bmax in Scatchard analysis?
total number of possible binding sites of receptor-ligand interactions
82
what is the two state receptor response?
there is a resting state R and an activated state R*
83
what is the binding and stabilising during R?
during resting state R there is a high affinity binding by antagonist and stabilising by antagonist
84
what is the binding and stabilising during R*?
during activated state R* there is a high affinity binding by agonist and stabilising by agonist
85
what is the tow state receptor model?
lecture 5
slide 3
86
in the presence of an antagonist what is the shift of equilibrium?
to resting state
87
in presence of an agonist what is the shift of equilibrium?
to activated state
88
what is potency?
'a measure of drug activity expressed in terms of the amount required to produce an effect'
89
what is E50?
effective concentration at 50% of maximal response
90
what is receptor occupancy?
the amount of drug bound by ligand
91
what is the graph of [Agonist] against response % show?
relationship between receptor occupancy and response
relationship between EC50 and Kd
92
what is the equation for a simple system?
π
=π
_πππ₯Γ ( [π·])/([π·]+πΈπΆ50) )
93
what is the definition of efficacy?
'the ability of a drug to produce and effect'
94
what is a partial agonist?
can't produce a full response even with full receptor occupancy
95
what is Kd?
affinity- the ability of ligand to bind to receptor
96
what is the efficacy of a ligand-receptor interaction?
intrinsic ability of ligand to induce an activated state of the receptor
97
what do different agonists differ in?
different agonists have different efficacy and affinity
98
what are the features of a reversible inhibtor?
non-covalent ligand
competitive, non-competitive, other
an example: binding of propranolol to ο’1 adrenergic receptor
99
what are the feature of a irreversible inhibtor?
covalent ligand
example:: phenoxybenzamine binding to a1 and a2 adrenergic receptors
100
what is pure antagonists effect?
no change in receptor activity
101
what is inverse agonist?
inhibits constitutive activity
102
features of Receptor antagonists β competitive binding?
in antagonist prescence the potency of agonisst is reduced
no change in efficacy
inverse agonist behave similarly to pure antagonist
antagonists have affinity no efficacy
102
how can partial agonists can act as antagonists β competitive binding?
in the presence of an agonist a partial agonist has antagonistic activity
102
what is constitutive activity?
receptors showing noticeable activity in the absence of an agonist
103
what is the potency and efficacy of agonist in the presence of partial agonist?
Potency and efficacy of agonist are reduced in presence of partial agonist
104
what is a treatment for bradycardia?
Adrenaline Ξ²1 receptor agonist and Atropine M2 receptor antagonist stimulate myocyte contraction
105
what is adrenaline an example of?
sympathomimetric drug
106
what is Atropine M2 receptor antagonist an example of?
parasympatholytic drug
107
what is the effect of adrenaline?
increases sympathetic signal
108
what is the effect of atropine?
decreases parasympathetic signals
109
what does noradrenaline do?
promotes smooth muscle relaxation
110
what does acetylcholine do?
promotes smooth muscle contraction
111
what receptor promotes muscle relaxation?
B2 receptor agonist
112
what drug promotes muscle relaxation?
anticholinergic drugs
113
what are the adverse effects of B2 receptor agonist?
Fine tremor, feeling shaky, anxiety
114
what are the adverse effects of antimuscarinics?
Dry mouth and/or throat irritation
115
why is it difficult to make a drug specific to a receptor?
B1 and B2 adrenergic receptors are similar
116
why are beta blockers no used for asthma patients?
ins't recommended because it can be harmful
117
what are the drugs in treatment of asthma?
Salmeterol and Salbutamol
118
what is therapeutic index?
ratio of the dose of drug that causes toxic effect vs the effective dose
πβππππππ’π‘ππ πππππ₯ ππΌ = TD50/ ED50
TD50 is toxic dose for 50% of population
ED50: effective dose for 50% of population
119
what is a narrow therapeutic index?
therapeutic index <10
120
what are teh main targets of drugs?
enzymes
ion channels
transport proteins
receptors
121
examples of drugs that target enzymes, ion channels, transport proteins?
Proton-pump inhibitors
ibuprofen, paracetamol
122
examples of drugs for receptors?
Histamine H1 antagonists
Histamine H2 antagonists
123
what are the features of Receptor antagonists β irreversible binding?
In the presence of an irreversible antagonist, the efficacy of an agonist is reduced
There is no change in potency
124
what are antagonists binding at different site than agonist?
unsurmountable antagonists
125
what are spare receptors?
the fraction of receptors that is not occupied at Rmax
