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CPTP 3 > CPTP 3.14 Drugs used in Inflammation Allergy and Pain 2 > Flashcards

CPTP 3.14 Drugs used in Inflammation Allergy and Pain 2 Flashcards

1
Q

Name the analgesic drugs (non-opioid)

A 
NSAIDs (mnemonic = NCAIDs)
  •  Naproxen
  •  Celecoxib
  •  Aspirin
  •  Ibuprofen
  •  Diclofenac

Paracetamol

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2
Q

What are compound analgesics?

A

Analgesics made from a combination of two drugs, usually:
• Paracetamol
• Aspirin
• Codeine

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3
Q

Recall the eicosanoids. Which of these are prostanoids?

A 
Prostanoids:
  •  Prostaglandins 
  •  Prostacyclin
  •  Thromboxanes
Others:
  •  Leukotrienes
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4
Q

What are the main prostaglandins?

A
  • PGE2
    • PGD2
    • PGF2a
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5
Q

What is prostacyclin also called?

A

PGI2

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6
Q

What is the main thromboxane?

A

TXA2

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7
Q

What are the main leukotrienes?

A
  • LTB4
    • LTC4
    • LTD4
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8
Q

When are local hormones such as the eicosanoids made?

A

They’re not pre-formed but generated in response to stimuli in all tissues

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9
Q

What are eicosanoids made from? Through which two pathways?

A

(IMG 8)

Arachidonic acid
• Cyclooxygenase (1 or 2) pathway
• Lipoxygenase pathway

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10
Q

How is arachidonic acid made?

A

From phospholipids in the plasma membrane by Phospholipase A2

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11
Q

What do the cyclooxygenase and lipoxygenase enzymes produce from arachidonic acid?

A

(IMG 8)
Cyclooxygenase:
• PGH2 (prostaglandin H2 is an INTERMEDIATE)

Lipoxygenase
• Leukotrienes

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12
Q

What happens to PGH2?

A

(IMG 8)
It is immediately acted on by various enzymes

  • Prostaglandins
  • Prostacyclin (from prostacyclin synthase)
  • Thromboxane (from thromboxane synthase)
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13
Q

What effects does prostacyclin have?

A
  • Potent vasodilator
    • Inhibits platelet aggregation
    • Hyperalgesic
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14
Q

What effects does thromboxane have?

A
  • Vasoconstrictor

* PROMOTES platelet aggregation

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15
Q

How do thromboxane and prostacyclin usually operate?

A

They are antagonists, and are in a homeostatic balance, controlling local blood tone and platelet aggregation

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16
Q

Which enzymes produce the prostaglandins? Which tissues are these produced in?

A

PGE2 (E=everywhere)
• PGE2 isomerase
• All tissues

PGD2 (D=decisions)
• PGD2 synthase
• Mast cells
• Neurones

PGF2a (F=flow and fucking)
• PGF2a reductase
• Vascular smooth muscle
• Uterine smooth muscle

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17
Q

Which product of phospholipids are the targets of analgesic drugs?

A

PGE2 because it potentiates responses to pain.

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18
Q

Recall the local hormone substances which stimulate pain

A
  • Serotonin
    • Bradykinin (and other kinins)
    • Prostaglandin E2
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19
Q

What do sensitising local hormones do to pain sensation?

A

They sensitise the pain response to stimuli, but do not alone cause it:
allodynia and hyperalgesia

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20
Q

What are the prostanoid functions on:

1) Vasodilation?
2) Vascular permeability?
3) Pain?

A

1) Vasodilators, have synergy with:
• Histamine
• Bradykinin

2) Potentiate the following substances: (no effect on their own)
• Histamine
• Bradykinin

3) Potentiate the sensitising effects of bradykinin on C-fibres (except PGE2 which directly sensitises it)

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21
Q

How do prostanoids potentiate the effects of histamines and bradykinin in increasing vascular permeability?

A

The vasodilation caused by prostaglandins facilitates these mediators to increase the permeability

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22
Q

What is the mechanism of action of NSAIDs?

A

They inhibit the cyclooxygenase enzymes thus preventing the production of prostanoids (IMG 8)

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23
Q

Compare COX-1 and COX-2:
• Expression
• Role

A

COX-1:
• Ubiquitously expressed (all tissues) and constitutive (always present and with some basal activity)
• Protection and maintenance

COX-2
• Inducible, not normally present, seen in inflamed and activated tissues
• Pro-inflammatory functions and sensitisation

24
Q

What induces COX-2?

A 
Cytokines:
  •  LPS
  •  TNFa
  •  IL-1 and IL-2
  •  IFNy
25
Q

Which drugs act on COX-1 and COX-2?

A

COX-1
• Classic NSAIDS

COX-2
• Classic NSAIDS
• COX-2 inhibitors

26
Q

What three main effects do COX-inhibitors such as NSAIDs have?

A

Anti-inflammatory
• The decrease in PGE2 decreases vasodilation and permeability

Analgesic
• There is less PGE2 to sensitise neurones

Antipyretic
• Prevents prostaglandins increasing the set point for temperature control

27
Q

What are the shortcomings of NSAIDs when used to treat chronic inflammatory diseases such as rheumatoid arthritis? Which drugs would be needed for this?

A

They have no effect on processes that contribute to the tissue damage in chronic inflammatory diseases as they cannot prevent the recruitment of inflammatory cells (they’re still used for pain relief though)

Corticosteroids would be needed for this

28
Q

What are NSAIDs best used for?

A 
Acute inflammation to reduce the sensitising effects, in those conditions associated with increased prostanoid synthesis:
  •  Toothache
  •  Postpartum pain
  •  Dysmenorrhoea
  •  Muscular or vascular pain
29
Q

What can NSAIDs be used with?

A

Opioids or paracetamol

30
Q

What is the purpose of using opioids with NSAIDs together

A

The process of ‘opioid sparing’. Opioids are very potent pain-relievers, however they have many adverse side effects, especially at higher doses:
• Constipation
• Drowsiness
• Withdrawal/addiction

Therefore, to reduce the likelihood of these in post-OP or severe pain, a combination can be given, which strikes a balance between pain relief and loss of side-effects

31
Q

How do the pain-alleviating mechanisms of NSAIDs differ when used for headaches?

A

Instead of reducing sensitisation from prostaglandins, the main pain-alleviating effects actually come from decreased PG-mediated vasodilation

32
Q

What are the common side effects of NSAIDs? What type of ADR is each?

A

GI disturbances: TYPE A
• COX-1 inhibition removes the protective mechanism of prostaglandins (causes vasodilation, decreased acid secretion and increase mucous secretion)

Skin reactions: TYPE B
• Toxic epidermal necrosis

Renal effects: TYPE A
• Prostaglandins are involved in maintenance of normal kidney functions

33
Q

As a rule of thumb, what type of ADR are allergies and hypersensitivities?

A

TYPE B

34
Q

Outline the NSAIDs in order of selectivity for COX-1

A 
Most selective for COX-1
  •  Aspirin
  •  Ibuprofen
  •  Naproxen
  •  Diclofenac
  •  Celecoxib 
Least selective for COX-1, most selective for COX-2

(typically COX-2 is the better pharmacological target, as these are the ones induced in inflammation)

35
Q

Describe the pharmacodynamics of aspirin

A
  • Irreversible antagonist of COX-1 (weakly COX-2)
    • Also inhibits NFKB (k=kappa) an inflammatory cytokine
    • Anti-platelet activity
36
Q

Describe the pharmacokinetics of aspirin

A

ABSORPTION:
• It’s a weak acid, and so is mostly neutral in the acidic stomach, facilitating its passage across the mucosa
• Regardless, most is still absorbed in the ileum due to its extensive surface area

ACTIVATION:
• Aspirin is rapidly HYDROLYSED, yielding salicylate

METABOLISM AND EXCRETION:
• 25% oxidised
• Some is conjugated
• 25% excreted unchanged

37
Q

Which subclass of NSAIDs are inhibitors of COX 1 and 2 (but mostly 1)?

What type of inhibitor are these?

Which of these inhibits leukocytes?

A

Propionic acid derivatives:
• Ibuprofen
• Naproxen

These are competitive inhibitors

Naproxen

38
Q

Describe the pharmacokinetics of propionic acid derivatives with respect to:
• Route of admission
• State in plasma
• Excretion

A
  • Well absorbed orally
    • Extensively plasma protein bound (>99%)
    • Metabolised in liver, excreted by kidneys
39
Q

Why should conditions which alter plasma protein concentration be considered when using drugs such as propionic acid

A

It increases the amount of free drug in the blood, due to the lack of availability of plasma proteins (e.g. albumin)

As a result, there is an increased chance of a toxic side effect (as free drug is the pharmacologically active proportion)

40
Q

Which NSAID is best for arthritic joint pain alleviation and why?

A

Propionic acid derivatives, because they can penetrate arthritic joints

41
Q

Which formulary drug is COX-2 selective and does not bind to COX-1?

A

Celecoxib

42
Q

What are the adverse drug effects for celecoxib?

A

causes CVD

43
Q

State the half life of:

1) Ibuprofen
2) Naproxen
3) Celecoxib

A

1) 2 hours (short acting)
2) 11 hours (long acting)
3) 11 hours

44
Q

Describe the pharmacokinetics of celecoxib

A
  • Absorbed orally
    • 90% plasma protein bound
    • Lipophilic –> accumulates in fat
    • Metabolised by CYP450s
    • Excreted in faeces and urine
45
Q

What other mechanism of action does celecoxib have?

A

Central analgesic effect, as it is lipophilic and can cross the BBB

46
Q

What are the benefits of celecoxib?

A

They have no GI side-effects (although be careful due to CVD effects)

47
Q

What main tissues is serotonin produced in?

A
  • Intestine wall
    • Blood platelets
    • CNS
48
Q

What is serotonin broken down by, and what into?

A

Monoamine oxidase

Broken down into 5-HIAA

49
Q

What are the effects of serotonin on blood vessels?

A

They have different effects depending on the receptor:

5-HT1:
• Constriction
5-HT2:
• Dilation

50
Q

What causes MIGRAINES?

A

(IMG 9)
• Vasodilation occurs due to serotonin release stimulating 5-HT2 and subsequent NO release
• NO stimulates sensory nerves, causing nociception and also central pain sensitisation
• Then there is positive feedback, as the sensory nerves release neuropeptides, which cause neuroinflammation then further NO release, sensitisation and stimulation

51
Q

Describe how serotonin causes vasodilation when acting on 5-HT2 receptors. What does this cause when occurring in the brain?

A
  • Acts on endothelial cells causing NO release
    • Acts on neurones to inhibit noradrenaline release from nerve terminals

This causes headache

52
Q

How can migraines be prevented?

A

5-HT2 antagonists

53
Q

How can migraines be acutely treated?

A

5-HT1 agonists:
• These cause constriction
• They also directly inhibit the sensory nerves and prevents the neuropeptide release

54
Q

Name the formulary migraine drug, which mechanism it uses, and its route.

A

Sumatriptan
• 5-HT1 agonist
• SC, intranasal
• Can be given orally but poor absorption

55
Q

What effect do prostanoids have in:

1) Bronchioles?
2) Uterus?
3) Blood vessel diameter?
4) Algesia?

A

1) Bronchoconstriction
2) Uterine contraction
3) Vasodilation
4) Potentiation of sensitising effect on pain

CPTP 3 (21 decks)

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