Drug Action 2 Flashcards
1
Q
What are the two most common NSAIDs?
A
Aspirin and paracetamol
2
Q
What are the benefits of aspirin over paracetamol?
A
Anti-platelet action, reduced risk of colonic and rectal cancer, reduced risk of Alzheimer’s, it’s a weak acid - rapid and efficient absorption in the ileum
3
Q
What are the disadvantages of aspirin over paracetamol?
A
Aspirin is an irreversible suicide inhibitor
4
Q
What are the benefits of paracetamol over aspirin?
A
Weak anti-inflammatory, COX-2 selective, well absorbed and metabolised in the liver, fewer side effects long term
5
Q
What are the disadvantages of paracetamol over aspirin?
A
Kidney damage in large acute doses, n-acetyl-p-benzoquinoneimine is hepatoxic, it’s a competitive inhibitor
6
Q
What are the new NSAIDs?
A
Celecoxib and rofecoxib
7
Q
Which type of COX is involved with inflammatory response?
A
COX-2
8
Q
Which NSAID forms a metabolite that damages the liver?
A
Paracetamol
9
Q
What is rheumatoid arthritis?
A
Incurable common chronic inflammatory and destructive arthropathy that typically affect synovial joints
10
Q
What is the average onset and incidence of rheumatoid arthritis?
A
70 years, can be much younger, 1% of UK population
11
Q
How much does RA cost the UK per year?
A
3.4-8.75 billion
12
Q
What does RA stand for?
A
Rheumatoid arthritis
13
Q
What is the prognosis for RA patients?
A
Poor - 80% disabled after 20 years, life expectancy reduced by 3-18 years
14
Q
What disease presents with three or more warm, swollen joints, with stiffness in the morning?
A
RA
15
Q
What nine symptoms can lead to a positive diagnosis of RA?
A
Three or more warm, swollen joints; stiffness in the mornings; arthritis of hand joints; symmetrical arthritis; presence of rheumatoid nodules; fatigue; fever; tiredness; presence of rheumatoid factor
16
Q
What are rheumatoid nodules?
A
Firm tissue bumps under the skin on the arms
17
Q
What occurs in synovial joints during early RA?
A
Synovial membrane becomes hyperplastic and synoviocytes become hypertrophic; an immune response is launched and neutrophils, T cells and B cells descend
18
Q
What would hyperplastic synovial membranes and hypertrophic synoviocytes lead to?
A
RA
19
Q
What do chondrocytes produce?
A
Cartilage
20
Q
What do fibroblasts produce?
A
ECM components
21
Q
What do osteoclasts produce?
A
Involved in bone absorption during growth
22
Q
What two cytokines are involved in RA?
A
IL-1 and TNF-alpha
23
Q
What condition are IL-1 and TNF-alpha involved in?
A
RA
24
Q
Where is IL-1 produced?
A
Monocytes, macrophages and other cells
25
What three kinds of IL-1 exist?
Alpha, beta and ra
26
What response does IL-1 evoke?
Proinflamamtory
27
What does IL-1 stimulate the release of?
Matrix metalloproteinases from fibroblasts and chondrocytes
28
What stimulates the release of metalloproteinases?
IL-1
29
Where is TNF-alpha produced?
Macrophages, monocytes and mast cells
30
What response does TNF-alpha evoke?
Proinflammatory
31
Why does blocking TNF-alpha have more profound effects than blocking other cytokines?
It induces other pro-inflammatory cytokines so blocking TNF-alpha can simultaneously block many other cytokines
32
What does TNF-alpha stimulate the release of?
Metalloproteinases from chondrocytes
33
What are DMARDs?
Disease-modifying antirheumatic drugs
34
What are DMARDs used for?
May be useful in limiting the progression of disease
35
What is methotrexate?
DMARD - folic acid antagonist
36
What does methotrexate do?
Reduces antigen activated T-cell proliferation
37
What secondary function is methotrexate known to perform?
Promote adenosine release and adenosine-mediated suppression of inflammation
38
What is the primary difference between methotrexate and other DMARDs?
Superior in terms of efficacy, unwanted effects and rapid onset
39
Why must methotrexate treatment be closely monitored?
High incidence of blood and liver toxicity
40
What is sulfasalazine used to treat?
RA
41
What effect does sulfasalazine have on active RA?
Remission
42
What is sulfasalazine a complex of?
Sulphonamide and salicylate
43
What does a complex of sulphonamide and salicylate form?
Sulfasalazine
44
What does MOA stand for?
Method of action
45
What is the MOA of sulfasalazine?
Scavenges toxic oxygen metabolites produced by neutrophils
46
What are the three main classes of immunosuppressant drugs for RA?
IL-2 production/action inhibitors, cytokine gene expression inhibitiors, purine/pyrimidine synthesis inhibitors
47
Describe ciclosporin's structure.
Naturally occuring 11 a/a cyclic peptide found in fungus
48
What does ciclosporin do?
Decrease clonal proliferation of T cells by inhibitting IL-2 synthesis and decreasing expression of IL-2 receptors
49
Where is ciclosporin metabolised and excreted?
Liver and mainly excreted in bile
50
What are the side effects of ciclosporin?
Nephrotoxicity, hepatoxicity and hypertension
51
Name a drug that inhibits IL-2 production and action.
Ciclosporin
52
What is the primary function of glucocorticoids?
Anti-inflammatory and immune suppression
53
How do glucocorticoids work?
Transciptional inhibition of cytokines including - IL-1,2,6 and TNF
54
What other activities do glucocorticoids perform?
Inhibition of adhesion molecule expression, arachidonic acid metabolism, metalloproteinase production
55
Name a family of drugs that inhibits cytokine gene expression.
Glucocorticoids
56
What two drugs inhibit purine and pyrimidine synthesis in RA treatments?
Azathioprine, mycophenolate mofetil
57
What does azathioprine do?
Inhibits DNA synthesis through its active metabolite mercaptopurine
58
What is the active ingredient in azathioprine?
Mercaptopurine
59
What side effects are associated with azathioprine and mycophenolate mofetil?
GI side effects
60
What extra side effect does azathioprine have over mycophenolate mofetil?
Mild hepatotoxicity
61
What does mycophenolate mofetil do?
Inhibits DNA synthesis through inhibition of de novo urine synthesis
62
What are anticytokine drugs?
Engineered recombinant antibodies and other proteins that target specific aspects of RA and other inflammatory diseases
63
What are some anticytokine drugs co-administered with?
Methotrexate
64
What are the three mechanisms of anticytokine drugs?
Neutralisation of cytokines, receptor blockade and activation of antiinflammatory pathways
65
How do anticytokine drugs neutralise cytokines?
Cytokine is prevented from binding to cell-surface receptor by soluble receptor or monoclonal anti-body attachment to the cytokine
66
How do anticytokine drugs peform receptor blockade?
Antagonistic occupation of receptor or monoclonal antibody attachment to the receptor, blocking binding site
67
Name five anticytokine therapies.
Etanercept, infliximab, anakinra, abatacept, efalizumab
68
At what indication are anticytokine therapies prescribed to RA sufferers?
Moderate-severe
69
What type of anticytokine therapy is etanercept?
Fusion protein
70
What type of anticytokine therapy is infliximab?
Chimeric antibody
71
What type of anticytokine therapy is anakinra?
Recombinant protein
72
What type of anticytokine therapy is abatacept?
Fusion protein
73
What type of anticytokine therapy is efalizumab?
Humanised monoclonal antibody
74
What is the target cytokine for etanercept?
TNF - by decoy receptor
75
What is the target cytokine for infliximab?
TNF - by neutralisation
76
What is the target cytokine for anakinra?
IL-1 - by receptor agonism
77
What is the target cytokine for abatacept?
B7 - by antigen presentation in cells
78
What is the target cytokine for efalizumab?
CD11a - neutralises leukocytes
79
What drug therapies can nausea and vomiting be side-effects of?
Cytotoxic chemotherapy, opioids, general anaesthetics and digoxin
80
What endogenous stimuli can cause nausea and vomiting?
Motion sickness, morning sickness, numerous disease states, migraine, ingestion of toxins, fear, pain and olfactory stimuli
81
What antagonists can block emetic effects?
5-HT-3 anatagonists
82
What can 5-HT-3 antagonists do?
Block the emetic effects of cytotoxic drugs used during cancer chemotherapy
83
What two main pathways supply visceral sensation?
Vagal and spinal
84
Which of the two pathways of visceral sensation supplies mainly physiological stimuli?
Vagal
85
Which of the two pathways of visceral sensation supplies mainly noxious stimuli?
Spinal
86
Where do vagal cell bodies of the visceral sensation pathway reside?
Nodose ganglia
87
Which visceral sensatory cell bodies lie in the nodose ganglia?
Vagal
88
Where do spinal cell bodies of the visceral sensation pathway reside?
Dorsal root ganglia
89
Which visceral sensatory cell bodies lie in the dorsal root ganglia?
Spinal
90
What two systems does the spinal visceral sensatory pathway split into?
Splanchnic and pelvic
91
Describe the vagal 5HT-3 receptor.
Pentameric ligand gated ion channel - subunits 5HT-3A to 5HT-3E
92
Can 5HT-3 form a homomeric complex? If so, of which subunit?
Yes - 5HT-3A
93
What are the most studied 5HT-3 receptors?
Heteromeric 5HT-3A/B
94
What is the ionic activity about a 5HT-3 receptor?
K out, Na and Ca in
95
What are EC cells?
Enterochromaffin cells
96
What cells are responsible for sensory transduction in the gut?
Enterochromaffin cells
97
What proportion of the body's serotonin is found in the gut?
95%
98
Where is 95% of the body's serotonin found?
The gut
99
In what cells is serotonin found in the gut?
EC cells, enteric neurons and mast cells
100
What are the setron family of drugs?
Antiemetics - 5HT-3 receptor antagonists
101
Name three first generation setron family drugs.
Granisetron, ondansetron and tropisetron
102
What kind of drug is gransetron?
Anti-emetic - setron family - 1st generation 5HT-3 receptor antagonists
103
What kind of drug is ondansetron?
Anti-emetic - setron family - 1st generation 5HT-3 receptor antagonists
104
What kind of drug is tropisetron?
Anti-emetic - setron family - 1st generation 5HT-3 receptor antagonists
105
How do 1st generation setron family drugs function?
Competitive antagonists at both peripheral and central 5HT-3 receptors
106
What are 1st generation setron family drugs usually used to treat?
Acute chemotherapy-induced emesis; not very good at treating delayed emesis
107
Name one second generation setron family drug.
Palonosetron
108
What is different about second generation setron family drugs?
Effective in preventing both acute and delayed emesis; believed to act through allosteric mechanisms causing receptor internalisation
109
What are NK-1 receptors, and what are they activated by?
Neurokinin receptors - tachykinin peptides
110
What is the order of potency of tachykinin peptides?
Substance P > NK A > NK B
111
What is a strong alternative to the setron family anti-emetics?
NK-1 receptor antagonism
112
Name one NK-1 receptor antagonist.
Aprepitant
113
What family of drugs does aprepitant belong to?
NK-1 receptor antagonists - anti-emetics
114
What is hyoscine also known as?
Scopolamine
115
What type of drug in hyoscine?
Anti-emetic
116
What receptors does hyoscine act upon?
mAChR
117
What is the indication for hyoscine?
Motion sickness
118
What are the side effects of hyoscine?
Drowsiness, dry mouth, blurred vision
119
What type of drug is chlopromazine?
Anti-emetic
120
What type of drug is perphenazine?
Anti-emetic
121
What type of drug is prochlorpenazine?
Anti-emetic
122
What type of drug is trifluoperzine?
Anti-emetic
123
What receptor does chlopromazine act upon?
Dopamine antagonists (D2)
124
What receptor does perphernazine act upon?
Dopamine antagonists (D2)
125
What receptor does prochlorpenazine act upon?
Dopamine antagonists (D2)
126
What receptor does trifluoperzine act upon?
Dopamine antagonists (D2)
127
What is the indication for chlopromazine?
Severe cases of chemo/radio therapy or pharmacologicaly induced emesis
128
What is the indication for perphenazine?
Severe cases of chemo/radio therapy or pharmacologicaly induced emesis
129
What is the indication for prochlorpenazine?
Severe cases of chemo/radio therapy or pharmacologicaly induced emesis
130
What is the indication for trifluoperzine?
Severe cases of chemo/radio therapy or pharmacologicaly induced emesis
131
What are the side effects of chlopromazine?
Sedation, hypotension, dystonias, tardive dyskinesia
132
What are the side effects of perphenazine?
Sedation, hypotension, dystonias, tardive dyskinesia
133
What are the side effects of prochlorpenazine?
Sedation, hypotension, dystonias, tardive dyskinesia
134
What are the side effects of trifluoperzine?
Sedation, hypotension, dystonias, tardive dyskinesia
135
What type of drug is metaclopromide?
Anti-emetic
136
What receptor does metaclopromide act upon?
Dopamine antagonists (D2)
137
What is the indication for metaclopromide?
Increases gut motility and acts on CTZ
138
What does CTZ stand for?
Chemoreceptor trigger zone
139
What type of drug is domperidone?
Anti-emetic
140
What type of drug is cinnarizine?
Anti-emetic
141
What type of drug is cyclizine?
Anti-emetic
142
What type of drug is promethazine?
Anti-emetic
143
What receptor does domperidone act on?
Dopamine antagonists (D2)
144
What receptor does cinnarizine act on?
Histmamine antagonists (H1)
145
What receptor does promethazine act on?
Histmamine antagonists (H1)
146
What receptor does cyclizine act on?
Histmamine antagonists (H1)
147
What is the indication for domperidone?
Cytotoxic therapies
148
What is the indication for cinnarizine?
Motion sickness
149
What is the indication for cyclizine?
Motion sickness
150
What is the indication for promethazine?
Motion sickness
151
What are the side effects of cinnarizine?
Drowsiness, fatigue
152
What are the side effects of cyclizine?
Drowsiness, fatigue
153
What are the side effects of promethazine?
Drowsiness, fatigue
154
Name six D2 antagonistic anti-emetics.
Chlopromazine, perphenazine, prochlorpenazine, trifluoperzine, metaclopromide, domperidone
155
Name three H1 antagonistic anti-emetics.
Cinnarizine, cyclizine, promethazine
156
What family of drugs is gathering evidence as anti-emetic?
Cannabinoids
157
What family does the CB1 receptor belong to?
Endocannabinoid family
158
What does CB1 agonism prevent?
Emesis
159
What is emesis?
Vomiting
160
What does CB1 inverse agonism cause?
Emesis
161
Name two excitatory a/a NTs.
Glutamate, aspartate
162
Name two inhibitory a/a NTs.
GABA, glycine
163
What does GABA stand for?
Gamma-aminobutyric acid
164
What seven characteristics define glutamate receptors?
Subunit, composition, pharmacology, time course, Ca permeability, distribution and neuronal function
165
Characterise AMPA receptor Ca permability, and why they have evolved.
Low Ca permability, evolved for rapid depolarisation of cells
166
Characterise GABA-A receptors.
Post-synaptic, choride selective ionotropic receptors
167
What do GABA-A receptors do?
Mediate fast inhibitory transmission
168
How many units comprise GABA-A receptors?
5
169
What is the orthosteric GABA-A agonist?
Muscimol
170
What are the orthosteric GABA-A antagonists?
Bicuculline, picrotoxin
171
What is the allosteric GABA-A agonist?
Diazepam
172
What is the allosteric GABA-A antagonist?
Flumazenil
173
What does the allosteric GABA-A site do?
Increases or decreases strength of response
174
Which GABA-A site does muscimol bind to? Agonist or antagonist?
Orthosteric agonist
175
Which GABA-A site does bicuculline bind to? Agonist or antagonist?
Orthosteric antagonist
176
Which GABA-A site does picrotoxin bind to? Agonist or antagonist?
Orthosteric antagonist
177
Which GABA-A site does diazepam bind to? Agonist or antagonist?
Allosteric agonist
178
Which GABA-A site does flumazenil bind to? Agonist or antagonist?
Allosteric antagonist
179
Characterise GABA-B receptors.
Pre and post-synaptic G-i/o protein coupled receptor
180
What do GABA-B receptors do?
Mediate slow transmission
181
Inhibiton of which channels causes pre-synaptic inhibition?
Ca-v channels
182
Activation of which channels causes post-synaptic inhibition?
K channels (GIRK)
183
Name a GABA-B agonist.
Beclofen
184
Name a GABA-B antagonist.
Phaclofen
185
What is baclofen?
GABA-B agonist
186
What is phaclofen?
GABA-B antagonist
187
What does GIRK stand for?
G-protein-coupled inwardly-rectifying K channel
188
What six drug types target GABA-A receptors?
Sedatives, anxiolytics, hypnotics, anti-convulsants, neurosteroids and some general anaesthetics
189
What is the general structure of GABA-A receptors?
2 alpha, 2 beta and 1 'other' subunit (usually gamma)
190
Which superfamily does the GABA-A receptor belong to?
Nicotinic
191
What are the five physiological effects of benzodizepine agonists?
Sedation, hypnosis, anterograde amnesia, anti-convulsant, reduction of muscle tone
192
What determines the use of benzodiazepine agonists?
Pharmacokinetics
193
Which benzodiazepines are used mainly as sleeping tablets?
Short acting
194
What can intravenous diazepam be used to treat?
Status epilepticus
195
Why have some benzodiazepines have such long half lives?
Metabolized in the liver to produce active intermediates
196
What five key adverse effects can benzodiazepine agonists cause?
Sleepiness, impaired psychomotor function, amnesia, additive effects, tolerance, misuse, dependence
197
What 'additive effects' can occur with benzodiazepine agonists?
Combinative effects with other CNS depressants - can be fatal
198
Define drug tolerance.
Decreased responsiveness to a drug following continuous exposure
199
What must physical dependence be characterised by?
Withdrawal - increased anxiety, insomnia, CNS excitability, convulsions
200
How would you alleviate physical withdrawal?
Use a slower acting drug
