steroids and non steroidal antiinflammatory drugs Flashcards Preview

Yr 2 - Pharmacology > steroids and non steroidal antiinflammatory drugs > Flashcards

Flashcards in steroids and non steroidal antiinflammatory drugs Deck (96):
1

What are Eicosanoids?

A precursor generated from phospholipids in the CNS

2

What are the 3 key groups of Eicosanoids?

- prostaglandins (PGs)

- thromboxanes (TXA)

- Leukotrienes

3

Which enzyme produces Eicosanoids from the phospholipids in the plasma membrane?

Phospholipase A2

4

What activates phospholipase A2 to produce Eicosanoids (5)?

- bradykinin

- antigen-antibody binding on mast cells

- thrombin

- complement C5a

- cell damage

5

What is the precursor of Eicosanoids?

Arachidonic acid

6

What other chemical mediator is produced from plasma membrane?

Platelet activating factor

7

Which two Eicosanoids can also be called prostanoids?

Prostaglandins

Thromboxanes

8

What is the nomenclature of prostaglandins?

PG = prostaglandin

Letter = basic structure it comes from

Number = the no of C=C

9

Most often (arachidonic acid is the precursor)

- how many C=C does PG have?

2

10

Which cells release prostaglandins?

ANY injured cell

11

Which process is Prostaglandin a key mediator in?

Inflammation

12

What are the effects of prostaglandin in blood vessels?

Vasodilation (PGE1&2, PGI1)

13

What are the effects of prostaglandin in healing?

Inhibit platelet aggregation (PGI2 & PGE)

n.b. TXA2 = increased platelet aggregation

14

What are the effects of prostaglandin in the respiratory system?

N.b. varies with prostaglandin

Bronchodilation = PGI2 & PGE2

Bronchoconstriction = PGF2 & TXA2

15

How do prostaglandins affect pain?

Sensitise nociceptive neurones to the action of mediators (bradykinin & serotonin) = activate pain fibres

16

How do prostaglandins affect fever?

Act on the hypothalamus = increase body temperatureInflammation = macrophages release IL-1 = AA-> PGE2 = acts on neurones in pre optic area (sets our internal core temp) = increase thermostatic set point = heat generation (shivering, skin vasoconstriction = destroy infection)

When PG production stops (immediately broken down) = decrease set point = heat dissipating (sweating and vasodilation)

17

Which enzyme converts arachidonic acid (AA) to PG H2 = prostanoid precursor?

Cyclo-oxygenases (COX)

18

How many active sites does COX have?

2

19

What are the actions of the two COX active sites?

- Cycloxegynase site = AA -> PGG2

- Heme with peroxidase activity = reduces PGG2 to PGH2

20

How many COX isoenzymes exist?

3

COX-1

COX-2

COX-3 (not really understood = splice variant of COX-1)

n.b. different tissues express varying levels of COX-1 & 2= SELECTIVE INHIBITION POSSIBLE

21

Where is COX-1 found?

Consitutive (always there) in most cells

22

What does COX-1 do?

Maintains tissue homeostasis

Housekeeping: gastric protection, blood clotting, renal blood regulation

n.b. inflammation is NOT the main role

23

What is the key difference between COX-1 & COX-2?

COX-1 binding pocket is NARROW

COX-2 binding picket is WIDE

24

What induces COX-2?

Inflammation (abundant in activated macrophages)

25

When is COX-2 unregulated?

In various carcinomas

26

What does COX-2 produce?

Prostanoids = mediate inflammation

27

What are the two main types of anti-inflammatory agents?

- non steroidal anti-inflammatory drugs (NSAIDs)

- Glucocorticoids

28

Which 3 other drugs act as anti- inflammatory agents?

- H1 receptor antagonists

- chondroprotective drugs

- immunosupressants

29

What does NSAIDs stand for?

Non steroidal anti-inflammatory drugs

30

How do NSAIDS target inflammation?

inhibit cyclo-oxygenase (COX) = reduced prostaglandin & thromboxane synthesis

31

When are NSAIDs most commonly used in treatment?

- non-infectious/non-allergenic inflammation (e.g. headache, sprained ankle)

- control inflammation and pain (e.g. trauma, post-surgery & osteoarthritis)

32

Which action of cyclo-oxygenase do most NSAIDs inhibit?

Endoperoxidase synthase (no PGG2 produced)

n.b. PGG2 & PGH2 = unstable = produced on demand & broken down very quickly

33

What are the 3 different effects that NSAIDs have?

- Anti-inflammatory (reduce vasodilation, oedema, pain & fever)

- Analgesic (reduce PG synthesis -> pain from inflammation & tissue damage)

- Anti-pyretic = anti-fever

34

NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) is COX-1 preferring?

Salicylates (aspirin)

35

NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) has an equal effect on both isoenzymes?

Ibuprofen

36

NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) is COX-2 preferring?

Celecoxib (withdrawn)

Rofecoxib(withdrawn)

37

List these 4 drugs in order of strength of their anti-inflammatory effects?

 

Paracetamol

Aspirin & ibuprofen

Indomethacin

Strongest = Indomethacin

Moderate = Aspirin & Ibuprofen

Essentially none = Paracetamol

38

What are the 2 additional effects of salicylates (aspirin)?

- reduce platelet aggregation (prophylaxis of strokes & thromboembolism)

- analgesic- antipyretic (partial)

39

What are the pharmacokinetics of salicylates (aspirin)?

Weak acid = absorbed in stomach

Hydrolysed to salicylic acid in plasma & at low therapeutic doses most is bound to serum albumin

40

What % of salicylates (aspirin) is excreted unchanged?

25%

41

What % of salicylates (aspirin) is oxidised?

25%

42

The effects of aspirin are DOSE DEPENDANT!! What are the effects of aspirin at the following doses?

0.5-1 mg/kg

5-10 mg/kg

>30 mg/kg

0.5-1 mg/kg = anti-platelet

5-10 mg/kg = analgesic/antipyretic

>30 mg/kg = anti-inflammatory

43

What is the main side effects of salicylates?

- Gastric bleeding(loss of mucosal protection by PGs & inhibition of platelet aggregation)

44

What is salicylism?

Overdose

45

What can cause salicylism?

- viral infection (liver/CNS disturbances)

- repeated ingestion of high doses = chronic toxicity (20-40% fatal)

- altered acid/base balance (uncouples oxidative phosphorylation

46

What are the effects of overdose?

Respiratory & metabolic acidosis (tinnitus, dizziness, hearing loss & nausea;

skin rashes;

reye's syndrome = serious liver & brain damage)

47

What is the name drug that Aspirin interacts with?

Displaces warfarin from plasma proteins = increases the effects of warfarin

48

What are the 3 effects of paracetamol?

Weak antipyretic

Mild analgesic

Weak/no anti-inflammatory activity

49

What is the mechanism of action of paracetamol?

Uncertain

- often appears to be COX-2 selective

- now thought to inhibit COX-1 & 2 by peroxidase function = inhibits PG synthesis of PGs when low levels of arachidonic acid & peroxides are available but little activity at substantial levels of these!

= doesn't suppress inflammation of rheumatoid arthritis & gout but does inhibit the lesser inflammation from tooth extraction

50

What is the toxic dose of paracetamol?

2-3 X normal dose

51

What happens when the toxic dose of paracetamol is taken?

= potentially liver toxicity due to saturation of normal liver enzymes

52

How is paracetamol normally metabolised in the liver?

Glucuronidation

Sulfation

53

When the toxic dose of paracetamol is take how is it metabolised in the liver?

Glucuronidation & sulfination is saturated= mixed function oxidases instead (CYP450) = producs NAPQ (toxic metabolite) -> if not inactivated by conjugation with glutathionine it reacts with cell proteins = cell death

54

Where are ibuprofens derived from?

propanoic acids

55

Which COX enzyme does ibuprofen inhibit?

All of them! = non selective (COX1 & COX2)

56

What are the 5 effects of ibuprofen?

Anti-inflammatory

Anti-pyretic

Analgesic

Mild anti platelet effect

Vasodilation

57

What property of ibuprofen means it can be administered as a topical gel?

It is stable in solution (used for sports injuries - absorbed through skin = less risk of digestive problems)

58

What are the common side effects of Ibuprofen (11)?

Nausea

Dyspepsia (indigestion)

GI ulceration/bleeding

Raised liver enzymes

Diarrhoea/constipation

Epistaxis (nose bleeds)

Headache

Dizziness

Rash

Salt & fluid retention

Hypertension

59

What are the infrequent adverse effects of ibuprofen?

Oesophageal ulceration/bleeding

Heart failure

Hyperkalaemia

Renal impairment

Confusion

Bronchospasm

60

Which condition can be exacerbated by ibuprofen?

Asthma -> sometimes fatally!

61

How does COX-1 inhibition cause gastric ulceration?

inhibition of PGE2 & PGI2 synthesis

62

Which drugs can cause direct damage to the gastric mucosa?

aspirin can precipitate in cells lining the stomach

63

Which two drugs irreversibly inhibit platelet COX-1?

Aspirin

Phenylbutazone

64

What other things (4) can increase GI damage?

- concurrent glucocorticoid administration

- dehydration

- hypovolemic shock

- disruption to gastric blood flow

65

Why are selective COX-2 inhibitors beneficial in theory?

Target inflammation and reduces the risk of peptic ulceration

66

Why are selective COX-2 inhibitors not used?

In clinical trials they caused a significant increase in heart attacks and strokes

67

Which (4) cells produce leukotrienes?

Leukocytes

Lung cells

Mast cells

Platelets

68

What are the two different leukotriene receptor classes?

BLT (LTB) -> LTB4

= important mediator in all inflammation (activate & targeting of leukocytes & cytokine production)

 

CysLT (LTC3, LTD4, LTE4)

= mediate bronchoconstriction, vasodilation in most vessels (coronary vasoconstriction), plasma extravasation, role in hayfever & astha treatment

69

Name two CysLT receptor antagonists:

Zafirlukast

Montelukast

70

Where are corticosteroids secreted from?

Adrenal gland

71

Which area of the adrenal gland secretes mineralocorticoids (e.g. aldosterone)?

Outer layer of cortex = zona glomerulosa

72

What action do mineralocorticoids have?

regulate water and electrolyte balance

73

Which area of the adrenal gland secretes glucocorticoids (e.g. hydrocortisone & corticosterone)?

Middle layer of cortex = zone fascilculata

74

What action do glucocorticoids have?

Affect carbohydrate and protein metabolism

75

Which is the most important human glucocorticoid?

Cortisol (hydrocortisone)

76

In which fashion are glucocorticoids released?

Pulsitile circadian rythmn (highest in morning = declines in evening/night)

77

What are glucocorticoids produced from?

Cholestrol

78

Which hormone regulates the initial step of glucocorticoid production?

Adrenocorticotrophic hormone

79

What happens in a loss of corticosteroids (4)?

muscle weakness

hypotension

hypoglycaemia

weight loss

80

Which disease causes destruction of the adrenal gland?

Addison's disease (autoimmune or due to chronic inflammation)

81

How do glucocorticoids have an anti-inflammatory action?

They are part of the immune systems feedback system:

= stimulate Annexin1 (lipocortin) production = blocks phospholipase A2 = blocks parts of inflammatory responseBind to glucocorticoid receptor= up regulates expression of nuclear anti-inflammatory proteins= represses expression of systolic pro-inflammatory proteins (less complement in plasma, less induce NO production, less histamine release from basophils & reduced IgG production)

82

What are the clinical uses of glucocorticoids (8)?

- Asthma

- Eczema, Rhinitis & allergic conjunctivitis

- hypersensitivity states (severe allergic reactions)

- miscellaneous diseases with autoimmune & inflammatory components (e.g. IBD & rheumatoid arthritis)

- replacement therapy for glucocorticoid deficiency- stop graft rejection

- cancer treatment

- acute spinal injury

83

Through which routes can glucocorticoids be administered (4)?

Oral

Topical

IV

IM

84

What are the pharmacokinetics of glucocorticoids (3)?

- bound to corticosteroid binding globulin in blood

- diffuses into cells

- metabolised by liver

85

What are the unwanted side effects of glucocorticoid use?

- Suppress response to infection

- suppress endogenous glucocorticoid synthesis

- metabolic actions

- osteoporosis

- cushings syndrome (m. wasting)

86

Which glucocorticoid drug is used to treat asmtha?

Flutricansone proprionate

87

Which glucocorticoid drug is used to treat eczema?

Hydrocoritsone

Prednisolone

Dexamethasone

88

Which glucocorticoid drug is used to treat rhinitis & allergy?

Beclometasone dipropionate

89

Which glucocorticoid drug is used to treat Rheumatoid arthritis?

Prednisone

90

Which glucocorticoid drug is used to treat IBS & crohns disease?

Budesonide Dexamethasone

91

What is Flutricansone proprionate used to treat?

asmtha

92

What is Hydrocoritsone, Prednisolone and Dexamethasone used to treat?

eczema

93

What is Beclometasone dipropionate used to treat?

rhinitis & allergy

94

What is Prednisone used to treat?

Rheumatoid arthritis

95

What is Budesonide and Dexamethasone used to treat?

IBS & crohns disease

96

When should use of anti-inflammatory drugs be avoided?

- patients with congestive heart failure or renal insufficiency

-patients taking ACE inhibitors, methotrexate, blood thinners (warfarin) & some oral hypoglycaemic agents= increased risk of bleeding = possible complications during dental surgery