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MPharm Year 2 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Drug targets are usually?

A

Proteins

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2
Q

What do anti-acid drugs target?

A

Protons

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3
Q

Types of protein targets?

A

Receptors
Enzymes
Ion channels
Transporters

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4
Q

What is a ligand?

A

The endogenous molecule that binds to a receptors to illicit a response

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5
Q

Examples of ligands?

A

Neurotransmitters
Hormones
Growth factors
Cytokines
Metabolites

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6
Q

How do ligands cause a response?

A

Ligand binds receptor
Receptor activated
Signal transmitted from outside cell to inside cell
Signal relayed to effector proteins via signalling pathway
Effector mediates response

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7
Q

Signals can be relayed from a receptor via?

A

Protein kinases
GTP-binding proteins or G-proteins
Seconds messengers
Calcium ions

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8
Q

What do protein kinases do?

A

Add phosphate molecules to amino acids in proteins (protein phosphorylation)
Enzyme function can be regulated by addition or removal of a covalently bonded phosphate group

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9
Q

Two main types of protein kinases?

A

(a) serine/threonine kinases
(b) tyrosine kinases

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10
Q

How does protein phosphorylation change protein shape?

A

Each phosphate group carries a 2- charge
Binding to an amino acid causes surround positively charged amino acids to move closer causing a conformational change to the proteins shape

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11
Q

How can phosphorylation affect proteins?

A

1) change to activity- can affect binding of ligands to proteins, change in shape can effect intrinsic activity
2) mask binding sites- disrupting protein-protein interactions

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12
Q

Picture of the protein kinase cascade

A
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13
Q

What activity to G-proteins have?

A

GTPase activity

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14
Q

What is GTPase activity?

A

An enzymatic activity able to hydrolyse GTP to GDP

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15
Q

What can G-proteins bind?

A

GTP
GDP

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16
Q

How to tell if G-protein is active or inactive?

A

Active if bound to GTP
Inactive if bound to GDP

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17
Q

What are second messengers?

A

Small molecules and ions that relay signals received by cell-surface receptors to effector proteins

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18
Q

Examples of second messengers?

A

Cyclic AMP (synthesised from ATP by adenylyl cyclase)
Cyclic GMP (synthesised from the nucleotide GTP using guanylyl cyclase)
Nitric oxide
Calcium

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19
Q

Four major classes of receptors?

A

G Protein-couples receptors (GPCR)(metabotropic)
Ligand gated ion channels (ionotropic)
Enzyme-linked receptors
Nuclear receptors

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20
Q

What is a G protein-coupled receptor?

A

Ligand binding to receptor activates a G-protein which then activates or inhibits an enzyme or ion channel

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21
Q

What is a ligand gated ion channel?

A

Ligand binding to ion channel causes it to open or close. Conformation change takes place

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22
Q

What are enzyme-linked receptors?

A

Ligand binding to the receptor activates the intrinsic enzymes activity of the receptor or associated enzyme. Conformation change takes place

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23
Q

What are nuclear receptors?

A

Intracellular receptors. Ligand binding activates the receptor which then acts as a transcription factor to alter gene expression

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24
Q

What is steady state?

A

When the rate the drug enters the plasma is equal to its clearance from plasma

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25
Q

How to calculate constant infusion rate?

A

Maintenance dose rate/clearance from single IV dose

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26
Q

How many half-lives until steady state is reached?

A

~5

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27
Q

What can be done if steady state needs to be reached sooner?

A

Use a loading dose

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28
Q

How to calculate loading dose?

A

Steady state X volume of distribution

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29
Q

How to calculate steady state with an infusion?

A

Maintenance dose rate/clearance

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30
Q

How to calculate steady state with an oral drug?

A

Bioavailability X Maintenance dose rate/clearance

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31
Q

What else needs to be considered with steady state when using intermittent dosing?

A

Variability of drug concentration
Must be above minimum effective concentration and below minimum toxic concentration

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32
Q

General dosing regimens in relation to half-life?

A

<30 mins- difficult to maintain therapeutic concentrations
30mins- 8 hours- based upon range of therapeutic index and dosing interval convenience
8 hours -24 hours- most desirable half-life, usually given every half-life
>24 hours- usually once daily, sometimes every several days. Delays in reaching steady state

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33
Q

What is the structure of a GPCR?

A

Single polypeptide chain
Contain seven alfa-helical transmembrane domains
All are glycoproteins

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34
Q

Why is the 3rd intracellular loop and C-terminal tail of GCPRs important?

A

Highly variable in length and sequence
Responsible for G protein interaction
Contain sites of phosphorylation

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35
Q

Subunits of a G protein?

A

Alpha
Beta
Gamma

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36
Q

Which subunits of a G protein form a complex?

A

Beta and gamma
Form beta-gamma complex, a stable dimer

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37
Q

Which subunits of a G protein associate with the plasma membrane?

A

Alpha and gamma

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38
Q

What G protein subunit does GTP/GDP bind to?

A

Alpha
It has GTPase activity

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39
Q

How does GPCR signalling work?

A

1) hormone binds to receptor and causes conformation change in receptor
2) activated receptor binds to alpha subunit of G protein
3) binding causes conformational change in alpha subunit, GDP dissociates and is replaced by GTP
4) alpha subunit dissociates from beta-gamma complex
5) alpha subunit binds to effector protein activating or inhibiting it

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40
Q

What is the effector protein for Gs?

A

Adenylyl cyclase

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41
Q

What does Gs stand for?

A

Stimulatory

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42
Q

What is the second messenger for Gs?

A

Increased cAMP

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43
Q

What does Gi stand for?

A

Inhibitory

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44
Q

What is the effector protein for Gi?

A

Adenylyl cyclase

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45
Q

What is the second messenger for Gi?

A

Decreased cAMP

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46
Q

What is the effector protein for Gq?

A

Phospholipase C

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47
Q

What are the second messengers for Gq?

A

IP3 and DAG

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48
Q

Examples of GsPCRs and drugs that bind?

A

B-receptors- salbutamol, propranolol
H2- ranitidine
Glucagon
Some 5HT- amitriptyline

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49
Q

What does cAMP activate?

A

Protein kinase A

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50
Q

The Gs protein is activated by which toxin?

A

Cholera

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51
Q

What do phosphodiesterase do?

A

Turn cAMP to 5’AMP

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52
Q

Examples of GiPCRs and drugs that bind?

A

Alpha-2 clonidine
Opioid receptor codeine
Some 5HT sumatriptan

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53
Q

What toxin inactivates Gi?

A

Pertussis

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54
Q

What does the beta-gamma complex do in GiPCRs/GsPCRs?

A

Regulates ion channels

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55
Q

Which is faster? G-protein gated ion channels or ligand gated ion channels

A

Ligand gated

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56
Q

Examples of GqPCRs?

A

Some 5-HT
Adrenergic alpha-1
Vasopressin type 1
Angiotensin II type 1
H1
M1 M3 M5

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57
Q

Examples of drugs that target GsPCRs?

A

Propranolol
Salbutamol
Ranitidine
Amitriptyline

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58
Q

Examples of drugs that target GiPCRs?

A

Clonidine
Codeine
Sumatriptan

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59
Q

Examples of receptors and drugs that target GqPCRs?

A

H1 Loratadine
Alpha-1 doxazosin
Angiotensin II Losartan

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60
Q

IP3 promotes an increase in?

A

Intracellular calcium

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61
Q

What does DAG activate?

A

Protein kinase C

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62
Q

What does PIP2 do?

A

Gets cleaved to IP3 and DAG

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63
Q

What does PIP2 stand for?

A

Phosphatidyl inositol 4, 5 bisphosphate

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64
Q

What does IP3 stand for?

A

Inositol 1, 4, 5-trisphosphate

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65
Q

What does DAG stand for?

A

Diacylglycerol

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66
Q

What is receptor desensitization?

A

Where repeated exposure of the agonist leads to a decreased response

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67
Q

Most common ligand of ligand-gated ion channels?

A

Neurotransmitters

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68
Q

Examples of ligand-gated ion channel receptors?

A

GABA receptors
Some 5-HT
NMDA receptors

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69
Q

Examples of drugs that target ligand-gated ion channel receptors?

A

Benzodiazepines
Z drugs
Memantine
Ketamine
Mirtazapine

70
Q

The two domains of ligand-gated ion channels?

A

Transmembrane domain including the ion pore
Extracellular domain containing the ligand binding location

71
Q

Three families of ligand-gated ion channels?

A

Cys-loop
Ionotropic glutamate receptors
ATP-gated channels

72
Q

Ligand-gated ion channel structure?

A

Pentameric- made up of five subunits
Beta, delta, gamma and 2 x alpha

73
Q

What type of ligand-gated ion channels are stimulatory?

A

Cation selective

74
Q

What type of ligand-gated ion channels are inhibitory?

A

Anion selective

75
Q

Example of a cation selective ligand-gated ion channel?

A

Nicotinic acetylcholine receptor (nAchR)

76
Q

Example of a anion selective ligand-gated ion channel?

A

GABAa

77
Q

How many different classes of enzyme linked receptors are there?

A

Seven

78
Q

Two important classes of enzyme linked receptors?

A

Receptor tyrosine kinases (RTKs)
Cytokine receptors

79
Q

What kind of activity do receptor tyrosine kinases have?

A

Intrinsic tyrosine kinase- they phosphorylate their substrate proteins on the amino acid tyrosine

80
Q

What do receptor tyrosine kinases respond to?

A

Peptide/protein ligands

81
Q

Common structure of receptor tyrosine kinases?

A

N-terminal extracellular ligand-binding domain
Single transmembrane alpha helix
Cytosolic C-terminal domain with protein kinase activity
Usually a single polypeptide

82
Q

Example of a receptor tyrosine kinase that is not a single polypeptide?

A

Insulin- a dimer

83
Q

What are mitogens?

A

Ligands that stimulate cell division

84
Q

What are growth factors?

A

Ligands that stimulate cell growth

85
Q

Activation of receptor tyrosine kinases?

A

1) ligand binds and causes dimerisation of receptor
2) activation of tyrosine kinase domain by trans-autophosphorylation, creating binding sites for proteins
4) proteins bind and are activated
5) proteins relay signal downstream leading to response

86
Q

What does MAPK stand for?

A

Mitogen activated protein kinase pathway

87
Q

What is the Mitogen activated protein kinase pathway

A

Activated growth factor receptors can activate a G-protein calles Ras
Ras activates a protein kinase cascade
Promotes cell division

88
Q

Mutant Ras is associated with?

A

Cancer

89
Q

Types of tyrosine kinase inhibitors?

A

Small molecule TK inhibitors
Monoclonal antibodies

90
Q

Where do small molecule TK inhibitors target?

A

ATP-binding cleft

91
Q

Where do monoclonal antibodies target?

A

Extracellular ligand binding domain or the ligand

92
Q

Examples of small molecule TK inhibitors?

A

Imatinib
Sunitinib

93
Q

Example of monoclonal antibodies?

A

Trastuzumab
Cetuximab

94
Q

What are cytokine receptors stably associated with?

A

Janus kinases

95
Q

What does JAKs stand for?

A

Janus kinases

96
Q

JAKs activate transcription factors called?

A

Signal transducers and activators of transcription

97
Q

What does STATs stand for?

A

Signal transducers and activators of transcription

98
Q

Cytokine receptor activation?

A

1) ligand binds and leads to dimerisation of receptor
2) this activates JAK
3) JAK phosphorylates itself and the receptor and STATs
4) STATs translocate to nucleus, bind DNA and regulate gene expression

99
Q

Where can cytokine receptors be targeted?

A

The binding domain
The ligand

100
Q

Examples of cytokine based drugs?

A

Anakinra
Peginterferon alpha
Adalimumab
Basiliximab
Tocilizumab

101
Q

Where is noradrenaline release from?

A

Adrenergic neurones and adrenal gland

102
Q

Where is adrenaline release from?

A

Adrenal gland

103
Q

What type of receptors are adrenergic receptors?

A

GPCRs

104
Q

What are catecholamines?

A

Compounds containing a catechol moiety and an amine side chain

105
Q

What is a catechol moiety?

A

A benzene ring with two adjacent hydroxyl groups

106
Q

What amino acid are catecholamines synthesised from?

A

Tyrosine

107
Q

Catecholamine synthesis?

A
108
Q

What happens when smooth vascular muscle alpha receptors are activated?

A

Vasoconstriction

109
Q

What happens when heart muscle beta-1 receptors are activated?

A

Increase force of myocardial contraction
Increased heart rate

110
Q

What happens when airway smooth muscle b-2 receptors are activated?

A

Bronchodilation

111
Q

What happens when B-3 receptors are activated?

A

Lipolysis

112
Q

What happens when smooth muscle A-1 receptors are activated?

A

Increase intracellular calcium and contraction apart from smooth muscle where it relaxes

113
Q

What happens when a-2 receptors are activated at pre-synaptic neurones?

A

Decrease calcium and contraction

114
Q

Example of a B-receptor agonist?

A

Isoprenaline
Adrenaline
Noradrenaline

115
Q

Example of a B receptor antagonist?

A

Propranolol

116
Q

Example of a B-2 receptor agonist?

A

Salbutamol

117
Q

Example of an a-1 receptor antagonist?

A

Doxazosin
Alfuzosin

118
Q

Example of an a-2 antagonist?

A

Clonidine
Guanfacine

119
Q

How do a-1 receptor antagonist work?

A

Relax smooth muscle in arteries and veins thus decrease systemic arterial blood pressure

120
Q

How do a-2 receptor agonists work?

A

Reduce noradrenaline release to decrease both heart rate and blood pressure

121
Q

What type of G-protein do a-1 receptors have?

A

Gq

122
Q

What type of G-protein do a-2 receptors have?

A

Gi

123
Q

What type of G-protein do B receptors have?

A

Gs

124
Q

Where are most a-1 receptors found?

A

Smooth muscle

125
Q

Where are most a-2 receptors found?

A

Presynaptic nerves

126
Q

Where are most b-1 receptors found?

A

Heart

127
Q

Where are most b-2 receptors found?

A

Smooth muscle

128
Q

Where are most b-3 receptors found?

A

Fat tissue

129
Q

Examples of a-1 agonists?

A

Phenylephrine
Metaraminol

130
Q

How do a-2 agonists reduce noradrenaline release?

A

Cause hyperpolarisation by K+ efflux from a G-protein gated channel, therefore reducing neuronal activity

131
Q

How does theophylline work?

A

PDE 3 and 5 inhibitor

132
Q

What are sympathomimetic drugs?

A

Produce similar action to adrenaline and noradrenaline. Also called adrenergic drugs

133
Q

What are sympatholytic drugs?

A

Interfere with actions of sympathetic nervous system stimulation, also called anti-adrenergic drugs

134
Q

Example of a selective B-1 agonist?

A

Dobutamine

135
Q

What do cholinesterase do?

A

Break down acetylcholine

136
Q

What are the two forms of cholinesterase?

A

Acetylcholinesterases
Plasma cholinesterases

137
Q

Acetylcholine is hydrolysed to?

A

Choline and acetic acid

138
Q

What do anticholinesterases do?

A

Slow or prevent the degradation of acetylcholine released at synapses

139
Q

Three groups of anticholinesterases?

A

Short-acting
Medium acting
Irreversible

140
Q

How do short-acting anticholinesterases work?

A

They are mono-quaternary ammonium alcohols. They bind to the anionic site of cholinesterases and competitively replace acetylcholine from the site

141
Q

Example of a short-acting anticholinestrase?

A

Edrophonium (used as diagnostic aid for myasthenia gravis)

142
Q

How do medium-acting anticholinesterases work?

A

Interact with serine hydroxyl of the esteratic site to give a carbamylated produced which is hydroxylated slower

143
Q

Example of a medium-acting anticholinestrase?

A

Pyridostigmine
Neostigmine

144
Q

How do irreversible anticholinesterases work?

A

Phosphorylates the serine hydroxyl group of esteratic site. Takes days to regenerate the enzymes.

145
Q

Example of an irreversible anticholinestrase?

A

Organophosphates (chemical weapons and insecticides)

146
Q

Antidote for irreversible anticholinesterases?

A

Pralidoxime

147
Q

Uses of anticholinesterases?

A

Reversal of NMBAs
Myasthenia gravis
Alzheimer’s (donepezil)

148
Q

What causes myasthenia gravis?

A

Circulating antibodies that block acetylcholine from binding to nicotinic reception at the neuromuscular junction

149
Q

What type of receptors do cholinergic transmitter act on?

A

Nicotinic
Muscarinic

150
Q

Where are nicotinic receptors found?

A

Neuromuscular junctions in skeletal muscle
Autonomic ganglia
Postsynaptic at both sites

151
Q

Examples of nicotinic agonists that act at the neuromuscular junction?

A

Suxamethonium

152
Q

Examples of nicotinic agonists that act at the autonomic ganglia?

A

Nicotine
Varenicline

153
Q

Examples of nicotinic antagonists that act at the neuromuscular junction?

A

Rocuronium
Pancuronium
Atracurium

154
Q

Examples of nicotinic antagonists that act at the autonomic ganglia?

A

Timethaphan
Hexamethonium

155
Q

Examples of nicotinic antagonists that act at the autonomic ganglia?

A

Trimethaphan (hypertensive emergencies)

156
Q

Why are neuromuscular blocking agents given intravenously?

A

Most are quaternary ammonium compounds which penetrate cell membranes poorly

157
Q

Effects of muscarinic receptor agonists?

A

1) smooth muscle contraction
2) pupillary constriction, ciliary muscle contraction
3) decrease rate and force of heart
4) increases glandular secretion
5) increases gastric acid secretion
6) vasodilation through release of nitrous oxide
7) inhibition of neurotransmitter release

158
Q

Effects of muscarinic receptor antagonists?

A

1) inhibition of secretion
2) increase heart rate
3) papillary dilation
4) relaxation of smooth muscle
5) inhibition of gastric secretion
6) antiparkinson action
7) anti-emetic action

159
Q

Example of muscarinic receptor agonist?

A

Pilocarpine

160
Q

Example of muscarinic receptor antagonist?

A

Atropine
Hyoscine
Ipratropium
Tiotropium
Oxybutynin
Tropicamide

161
Q

Effects of B-2 stimulation in the airways?

A

Bronchodilation
Inhibition of cytokine and leukotriene release
Inhibit plasma exudation
Inhibit cholinergic transmission
Increase mucus clearance

162
Q

Order of affinity of neurotransmitters to alpha receptors?

A

Adrenaline=noradrenaline>isoprenaline

163
Q

Order of affinity of neurotransmitters to beta receptors?

A

Isoprenaline>adrenaline>noradrenaline

164
Q

How do depolarising NMDAs work?

A

Activate the nicotinic receptor and produces initial contraction of muscle fibre. The maintained depolarisation event leads to the inactivation of sodium channels. Preventing further action potentials

165
Q

How do non-depolarising NMBAs work?

A

Act as competitive antagonists at nicotinic receptor sites. Competes with acetylcholine to block transmission

166
Q

What type of receptors are nicotinic receptors?

A

Inonotropic

167
Q

What kind of receptors are muscarinic receptors?

A

GPCRs

168
Q

What receptor does clonidine bind to?

A

Alpha 2

169
Q

Activation of Gq receptors?

A

Ligand binds receptor
Phospholipase C becomes active
Alpha unit dissociations
PIP-2 cleaved to IP3 and DAG
IP3 binds SER to release Ca2+
DAG binds protein kinase C
Protein kinase C phosphorylates target proteins

170
Q

Activation of Gs receptors?

A

Ligand binds receptor
Adenylyl cyclase activated and alpha subunit dissociates
Increase cAMP
cAMP binds protein kinase A
Target proteins phosphorylated

171
Q

Activation of Gi receptors?

A

Ligand binds receptor
Adenylyl cyclase becomes active and alpha subunit dissociates
Reduction in cAMP so cannot bind protein kinase A

MPharm Year 2 (6 decks)

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