Pharmacological Aspects of Immunology 1 Flashcards
1
Q
Discovery of aspirin
- Rev Edmund Stone (1763)
- White willow (Salix alba)
- Used bark to treat fever and joint pain (mostly post-rheumatic fever)
- Felix Hoffman* (Bayer) (1899)
- … acid ‘Aspirin’
A
- Rev Edmund Stone (1763)
- White willow (Salix alba)
- Used bark to treat fever and joint pain (mostly post-rheumatic fever)
- Felix Hoffman* (Bayer) (1899)
- Acetylsalicylic acid ‘Aspirin’
2
Q
NSAIDS
- Large, chemically diverse family of drugs
- Aspirin
- Propionic acid derivatives - e.g. ibuprofen, naproxen
- Arylalkanoic acids – e. g indometacin, diclofenac
- Oxicams - e.g. piroxicam
- Fenamic acids - e.g. mefanamic acid
- Butazones - e.g. phenylbutazon
A
- Large, chemically diverse family of drugs
- Aspirin
- Propionic acid derivatives - e.g. ibuprofen, naproxen
- Arylalkanoic acids – e. g indometacin, diclofenac
- Oxicams - e.g. piroxicam
- Fenamic acids - e.g. mefanamic acid
- Butazones - e.g. phenylbutazon
3
Q
NSAIDS
- Large, chemically diverse family of drugs
- Aspirin
- Propionic acid derivatives - e.g. …, naproxen
- Arylalkanoic acids – e. g indometacin, diclofenac
- Oxicams - e.g. piroxicam
- Fenamic acids - e.g. … acid
- Butazones - e.g. phenylbutazon
A
- Large, chemically diverse family of drugs
- Aspirin
- Propionic acid derivatives - e.g. ibuprofen, naproxen
- Arylalkanoic acids – e. g indometacin, diclofenac
- Oxicams - e.g. piroxicam
- Fenamic acids - e.g. mefanamic acid
- Butazones - e.g. phenylbutazon
4
Q
Eicosanoid pathways
- Where do NSAIDs act? (antagonise which part?)
A
- NSAIDs are non specifc inhibitors of cyclo-oxygenase
5
Q
NSAIDs are non-selective … inhibitors
A
NSAIDs are non-selective COX inhibitors
6
Q
NSAIDs are …-… COX inhibitors
A
NSAIDs are non-selective COX inhibitors
7
Q
NSAID mechanism of action
- All inhibit …
- Three isoforms
- COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also side effects
- COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
- COX-3 – CNS only?
- May be relevant to paracetamol
- COX-1 - Constitutive expression – all tissues
A
- All inhibit cyclo-oxygenase
- Three isoforms
- COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also side effects
- COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
- COX-3 – CNS only?
- May be relevant to paracetamol
- COX-1 - Constitutive expression – all tissues
8
Q
NSAID mechanism of action
- All inhibit cyclo-oxygenase
- Three isoforms
- COX-1 - Constitutive expression – … tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-… activity, also side effects
- COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → … and anti-inflammatory actions
- COX-3 – CNS only?
- May be relevant to …
- COX-1 - Constitutive expression – … tissues
A
- All inhibit cyclo-oxygenase
- Three isoforms
- COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also side effects
- COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
- COX-3 – CNS only?
- May be relevant to paracetamol
- COX-1 - Constitutive expression – all tissues
9
Q
NSAID mechanism of action
- All inhibit cyclo-…
- Three isoforms
- COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also … effects
- COX-2 – Induced in … (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
- COX-3 – … only?
- May be relevant to paracetamol
- COX-1 - Constitutive expression – all tissues
A
- All inhibit cyclo-oxygenase
- Three isoforms
- COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also side effects
- COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
- COX-3 – CNS only?
- May be relevant to paracetamol
- COX-1 - Constitutive expression – all tissues
10
Q
COX-1 is expressed where?
A
Constituitvely expressed in all tissues (Stomach, Kidney, Platelets, Vascular endothelium)
11
Q
Inhibition of COX-1 produces …-… activity and also … …
A
Inhibition of COX-1 produces anti-platelet activity and also side effects
12
Q
Inhibition of COX-… produces anti-platelet activity and also side effects
A
Inhibition of COX-1 produces anti-platelet activity and also side effects
13
Q
Inhibition of COX-… - predominant mechanism for analgesia and anti-inflammatory actions
A
Inhibition of COX-2 - predominant mechanism for analgesia and anti-inflammatory actions
14
Q
Inhibition of COX-2 - predominant mechanism for … and anti-… actions
A
Inhibition of COX-2 - predominant mechanism for analgesia and anti-inflammatory actions
15
Q
COX-2 is induced in …
A
inflammation
16
Q
COX-3 is only expressed in the the … (probably)
A
COX-3 is only expressed in the the CNS (probably)
17
Q
COX-3 may be relevant to which drug?
A
paracetamol
18
Q
Indications for NSAID therapy
- …-term management of pain (and fever)
- As … analgesics (orally and topically)
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
- As … analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic
A
- Short-term management of pain (and fever)
- As mild analgesics (orally and topically)
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
- As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic
19
Q
Indications for NSAID therapy
- Short-term management of pain (and …)
- As mild … (orally and topically)
- … pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
- As potent … (orally, parenterally, rectally)
- peri-operative pain
- ureteric …
A
- Short-term management of pain (and fever)
- As mild analgesics (orally and topically)
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
- As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic
20
Q
Indications for NSAID therapy
- mainly painkiller, but - As anti-inflammatories (?)
- in g..
- Inflammatory … eg ankylosing spondylitis, rheumatoid arthritis
- mainly painkiller, but - As anti-inflammatories (?)
A
- mainly painkiller, but - As anti-inflammatories (?)
- gout
- Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis
- mainly painkiller, but - As anti-inflammatories (?)
21
Q
Indications for NSAID therapy
- mainly …, but - As anti-… (?)
- gout
- Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis
- mainly …, but - As anti-… (?)
A
- mainly painkiller, but - As anti-inflammatories (?)
- gout
- Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis
- mainly painkiller, but - As anti-inflammatories (?)
22
Q
What % of people use non-prescription NSAIDS?
A
20-30%
23
Q
What % experience serious side-effects from NSAIDS?
A
1-2%
24
Q
How many million’scriptios/year in UK of NSAIDS?
A
25 million
25
Q
How many hospital admissions and deaths from NSAIDs? (yearly)
A
12,000 admissions, 2600 deaths
26
Q
Aspirin
- Use for pain and inflammation limited by
- … toxicity
- … – mechanism obscure, usually reversible
- … syndrome (fulminant hepatic failure in children)
- Anti-platelet effect
- Primary and secondary prevention eg stroke and MI
- Treatment of acute MI and stroke
A
- Use for pain and inflammation limited by
- GI toxicity
- Tinnitus – mechanism obscure, usually reversible
- Reye’s syndrome (fulminant hepatic failure in children)
- Anti-platelet effect
- Primary and secondary prevention eg stroke and MI
- Treatment of acute MI and stroke
27
Q
Aspirin
- Use for pain and inflammation limited by
- GI toxicity
- Tinnitus – mechanism obscure, usually …
- Reye’s syndrome (fulminant hepatic failure in children)
- Anti-… effect
- Primary and secondary prevention eg … and MI
- Treatment of acute MI and …
A
- Use for pain and inflammation limited by
- GI toxicity
- Tinnitus – mechanism obscure, usually reversible
- Reye’s syndrome (fulminant hepatic failure in children)
- Anti-platelet effect
- Primary and secondary prevention eg stroke and MI
- Treatment of acute MI and stroke
28
Q
What is Reye’s syndrome?
A
fulminant hepatic failure in children
29
Q
What is aspirin mainly used for?
A
primary and secondary prevention e.g. stroke and MI, also treatment of acute MI and stroke (anti-platelet effect)
30
Q
What can aspirin cause? (3 things)
A
- GI toxicity
- Tinnitus - mechanism obscure, usually reversible
- Reye’s syndrome (fulminant hepatic failure in children)
*
31
Q
NSAID GI toxicity
- In the GI tract … E2 and I2
- … acid production
- … mucus production
- … blood supply
- NSAID inhibition in stomach and duodenum
- Irritation
- … (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
A
- In the GI tract prostaglandins E2 and I2
- Decrease acid production
- Increase mucus production
- Increase blood supply
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
32
Q
NSAID GI toxicity
- In the GI tract prostaglandins … and I2
- Decrease … production
- Increase … production
- Increase … supply
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
A
- In the GI tract prostaglandins E2 and I2
- Decrease acid production
- Increase mucus production
- Increase blood supply
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
33
Q
NSAID GI toxicity
- In the GI tract prostaglandins E2 and …
- Decrease acid production
- Increase mucus production
- Increase blood supply
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- …
- Similar effect in the colon
- … – esp with local preps e.g. rectal diclofenac
A
- In the GI tract prostaglandins E2 and I2
- Decrease acid production
- Increase mucus production
- Increase blood supply
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
34
Q
NSAIDS have what affect on prostaglandins? (GI tract prostaglandins E2 and I2)
A
They inhibit them in stomach and duodenum leading to irritation, ulcers (gastric 15-30%, duodenal 10%) and bleeding
35
Q
NSAIDS inhibit GI tract prostaglandins E2 and I2 in stomach and duodenum leading to … (3 things)
A
NSAIDS inhibit GI tract prostaglandins E2 and I2 in stomach and duodenum leading to irritation, ulcers (gastric 15-30%, duodenal 10%) and bleeding
36
Q
NSAID GI toxicity
- … GI …
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Also
- Age
- … disease (e.g.rheumatoid disease)
- Steroids
A
-
Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Also
- Age
- Chronic disease (e.g.rheumatoid disease)
- Steroids
37
Q
NSAID GI toxicity
- Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = …
- Also
- …
- Chronic disease (e.g.rheumatoid disease)
- …
A
- Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Also
- Age
- Chronic disease (e.g.rheumatoid disease)
- Steroids
38
Q
What is the relative risk for upper GI bleeding for NSAID users?
A
Relative Risk 4.7 all users
39
Q
NSAID GI toxicity
- Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Also
- Age
- Chronic disease (e.g.rheumatoid disease)
- Steroids
A
- Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Also
- Age
- Chronic disease (e.g.rheumatoid disease)
- Steroids
40
Q
What is the biggest risk factor for GI bleed?
A
previous GI bleed
41
Q
What contributes to risk of NSAID GI toxicity? (3)
A
42
Q
NSAID nephrotoxicity
- Primarily related to changes in glomerular blood flow
- Decreased … … …
- … retention
- Hyperkalaemia
- Papillary …
- Acute renal failure 0.5-1%
- Avoid or dose adjust in renal …
- Avoid in patients likely to develop renal …
A
- Primarily related to changes in glomerular blood flow
- Decreased glomerular filtration rate
- Sodium retention
- Hyperkalaemia
- Papillary necrosis
- Acute renal failure 0.5-1%
- Avoid or dose adjust in renal failure
- Avoid in patients likely to develop renal failure
43
Q
NSAID nephrotoxicity
- Primarily related to changes in glomerular blood flow
- … glomerular filtration rate
- Sodium retention
- Hyper…
- Papillary necrosis
- Acute renal failure …-…%
- Avoid or dose adjust in renal failure
- Avoid in patients likely to develop renal failure
A
- Primarily related to changes in glomerular blood flow
- Decreased glomerular filtration rate
- Sodium retention
- Hyperkalaemia
- Papillary necrosis
- Acute renal failure 0.5-1%
- Avoid or dose adjust in renal failure
- Avoid in patients likely to develop renal failure
44
Q
Acute renal failure in …-…% of people using NSAID
A
Acute renal failure in 0.5-1% of people using NSAID
45
Q
In those with renal failure/likely to develop it, can you use NSAIDS?
A
Avoid or dose adjust in renal failure and avoid in patients likely to develop it
46
Q
Asthma and asprin
- About …% of asthmatics experience bronchospasm following NSAID – perhaps because of … acid is shunted down the 5LPO pathway when COX is inhibited
A
- About 10% of asthmatics experience bronchospasm following NSAID – perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited
47
Q
Asthma and asprin
- About 10% of asthmatics experience … following NSAID – perhaps because of arachidonic acid is shunted down the 5LPO pathway when … is inhibited
A
- About 10% of asthmatics experience bronchospasm following NSAID – perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited
48
Q
What % of astmatics experience bronchospasm following NSAID?
A
10%
49
Q
Preventing NSAID toxicity
- Is an NSAID the answer (paracetamol, opioids, COX2 inhibitor, non-pharmacological?)
- Consider risk factors eg age, renal impairment, previous peptic ulcer disease
- Avoid or dose adjust in … …
- Consider co-administration of … with proton pump inhibitor
A
- Is an NSAID the answer (paracetamol, opioids, COX2 inhibitor, non-pharmacological?)
- Consider risk factors eg age, renal impairment, previous peptic ulcer disease
- Avoid or dose adjust in renal impairment
- Consider co-administration of gastroprotection with proton pump inhibitor
50
Q
Preventing NSAID toxicity
- Is an NSAID the answer (…, opioids, COX2 inhibitor, non-pharmacological?)
- Consider … …
- Avoid or dose adjust in renal impairment
- Consider co-administration of gastroprotection with … … inhibitor
A
- Is an NSAID the answer (paracetamol, opioids, COX2 inhibitor, non-pharmacological?)
- Consider risk factors eg age, renal impairment, previous peptic ulcer disease
- Avoid or dose adjust in renal impairment
- Consider co-administration of gastroprotection with proton pump inhibitor
51
Q
Which NSAID? – non-selective NSAIDS
A
- Proably the four NSAIDS I’d recommend you know are these
- Ibuprofen available over the counter is demonstrably the least associated with side-effects
- Naproxen is similar but probably slightly more prone to side-effects
- The most widely prescribed NSAID for more severe short term analgesis is probably diclofenac – often referred to by its trade name
- Indomethacin may be slightly more potent again and is generally reserved for specialist use in diseases like gout where marked inflammation ispresent
60
Q
Paracetamol metabolism
A
61
Q
Paracetamol metabolism
- In overdose, can go from managing paracetamol that is taken to having saturation pathway with production of NAPQI - problem with this is that it is hepatotoxic and causes delayed hepatic … - classic overdose story = present when?
- Overdose is much … common now
A
- In overdose, can go from managing paracetamol that is taken to having saturation pathway with production of NAPQI - problem with this is that it is hepatotoxic and causes delayed hepatic necrosis - classic overdose story = present late (maybe days later) and too late to do anything, potential liver transplant
- Overdose is much less common now - harder to get lots of packs in one go
62
Q
Production of NAPQI leads to what? (paracetamol metabolism)
A
hepatic necrosis - typically present a few days later when it is too late
63
Q
Paracetamol metabolism
- What is used in paracetamol poisoning?
A
- N-acetylcysteine (glutathione precursor)
70
Q
Coxibs – GI side-effects
- Which had the highest rate of GI side effects?
A
- Population based retrospective study
- 1.3 million people aged 66 years or older in Ontario
- 365,000 (28%) had a prescription for an NSAID
- NSAIDs had highest rate
75
Q
Corticosteroids
- Steroids … immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system.
- Their onset of action is … and they must be taken regularly
A
- Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system.
- Their onset of action is delayed and they must be taken regularly
76
Q
Corticosteroids
- Steroids reduce … activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the … … system. Their onset of action is delayed and they must be taken …
A
- Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system. Their onset of action is delayed and they must be taken regularly
84
Q
Corticosteroids as drugs
- Five you should know about… (list)
A
85
Q
Corticosteroids as drugs
- Fill in the table
A
86
Q
Corticosteroids as drugs
- Fill in the table
A
87
Q
Corticosteroids as drugs
- Fill in the table
A
88
Q
Corticosteroids as drugs
- Fill in the table
A
