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IHO Week 6 > Anti-Inflammatory Drugs > Flashcards

Anti-Inflammatory Drugs Flashcards

1
Q

What changes occur to blood flow during acute inflammation?

A

arteriolar dilation
increased blood flow
slowing of flow, even to stasis

also increased vascular permeability as post capillary venules leak large molecules

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2
Q

What aspects of inflammation can be mediated by histamine?

A

redness, heat, swelling, hypotension, and airway constriction
NOT chemotaxis

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3
Q

What aspects of inflammation can be mediatec by PGE2 and PGI2?

A

vasodilation
increased vascular permeability
pain

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4
Q

What aspect o inflammation can be mediated by PGD2 and thromboxane?

A

bronchoconstriction

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5
Q

What aspects of inflammation can be caused by TXA2?

A

platelet aggregation and vasoconstriction

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6
Q

What aspect of inflammation can be OPPOSED by PGI2?

A

platelet aggregation

causes vasodilation

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7
Q

What aspects of inflammation can be mediateed by the leukotriene LTB4?

A

it’s a chemotatic factor for PMNs and it will reduce pain threshold

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8
Q

What are the two kinins we know?

A

bradykinin and kallidin

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9
Q

What aspects of inflammation cna be mediated by the kinins?

A

everything pretty much - just not a chemtatic factor

super strong vasodilator which will result in hypotension

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10
Q

What are the two pools of histamine in the body?

A

mast cell histamine

non-mast cell histamine

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11
Q

Where is histamine found in mast cells and basophils?

A

it’s preformed in granules - bound by ionic bonds to a heparin protein complex

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12
Q

Where is non-mast cell histamine located?

A

in cells of the CNS (nerve endings)
cells of epidermis
in tissues undergoing rapid growth or repair (bone marrow, wounds, etc.)
enterochromaffin-like cells in the stomach - used to activate the parietal cells

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13
Q

What enzyme will convert histidine to histamine in mast cells and other cells that synthesize histamine?

A

L=histidine decarboxylase

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14
Q

What happens with ORAL administration of histamine? why?

A

nothing - because as it’s absorbed it’s inactivated by enzymes in the intestinal wall or liver

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15
Q

WHat happens with INTRACUTANEOUS administration of histamine?

A

itching, pain and hives

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16
Q

What happens with INTRANASLA administration of histamine?

A

intense itching, sneezing, hypersecretion and nasal blockage (vasodilation and edema)

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17
Q

What happens with INTRAVENOUS administration of histamine?

A
  1. blood pressure decrease
  2. tachycardia (response to drop in BP)
  3. braonchoconstriction
  4. flushing of face
  5. headache
  6. urticaria/hives
  7. mucus secretion
  8. gastric acid secretion
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18
Q

What’s the clinical use of histamine?

A

pretty limited - we can inhale it to assess bronchial reactivity and use it intradermally to assess th eintegrity of sensory neurons - that’s about it

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19
Q

What type of agonist are the antihistamines?

A

inverse agonists - which means they reduce receptor activity below basal levels observe in the absence of any ligand (some classify them as antagonists, but they really go beyond that)

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20
Q

What dtermines how a cell will respond to histamine?

A

the histamine receptors it has: H1, H2, H3 or H4

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21
Q

What do the H1 receptors mediate?

A
  1. bronchoconstriciton
  2. contraction of GI smooth muscle
  3. increased capillary permeability (wheal)
  4. pruritis
  5. pain
  6. release of catecholamines from adrenal medulla
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22
Q

What do the H2 receptors mediate?

A

gastric acid secretion!!
inhibition of IgE-mediated basophil histamine release
inhibition of T lymphocyte-mediated cytotoxicity
suppression of Th2 cells and cytokines

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23
Q

What do the H3 and H4 receptors mediate?

A

they’re located on the histaminergic nerve terminals and many immune cells, so they regulate the activity of these cells - not of clinical use yet

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24
Q

What are the cardiac effects of the mixed H1 and H2 receptor mediated responses?

A

increased heart rate
icnreased force of contraction
increased arrhythmias
slowed AV conduction

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25
Q

Both H1 and H2 will trigger vasodilation, but how do they differ in this?

A

H1 - rapid dilator response that’s short lived

H2 - developes more slowly and is sustained

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26
Q

What receptors were blocked by the first generation antihistamines?

A

H1 receptors, but also muscarinic, alpha adrenerfic and serotonin receptors

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27
Q

True or false: first generation antihistamines couldn’t reach the CNS.

A

false - they could because they aren’t recognized by the P-glyc efflux pump

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28
Q

How were the first gen antihistamines metaoblized?

A

transformed to inactive metabolites in the liver and excreted in the urine

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29
Q

What were the side effects of the first gen antihistamines?

A

sedation! (and associated symptoms…like dizziness, etc.)
drying of secretions
GI disturbances

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30
Q

What would acute first gen antihistamine poisoning look like?

A

like atropine poisoning: fixed and dilated pupils, flushed face, fever, dry mouth, excitation, hallucinations

terminally - coma and cardiorespiratory collapse

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31
Q

What are the two first generation antihistamines we need to know?

A

diphenhydramine

chlorpheniramine

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32
Q

Of the two first gen antihistamines, which is better for daytime use and why?

A

chlorpheniramine - it causes less sedation than diphenhydramines

33
Q

What are the three second gen antihistamines we need to know?

A

cetirizine
fexofenadine
loratadine

34
Q

How do the second gens differ from the first gens in terms of side effect profile?

A

they have minimal anticholinergic properties, so they don’t cause the sedation and drying of secretions

35
Q

Why don’t the second gens cause sedation?

A

they have affinity for the P-glyc efflus pumps so they get pumped out of the CNS

36
Q

What are the therapeutic uses of the H1 antihistamines?

A
  1. allergies (like rhinitis, urticaria and atopic dermatitis - NOT asthma)
  2. motion sickness (the first gens - anticholinergic)
  3. sleep aid

not colds

37
Q

How are the prostanoids (thromboxanes and prostaglandins) synthesized?

A

PLA2 releases arachidonic acid from the phospholipid cell membrane

arachidonic acid is converted to the prostanoids by cyclooxygenase

38
Q

There are two COX - which one is constitutive and which is induced?

A

COX 1 is constitutive in most cells

COX2 is constitutive in the brain and kidney, but is induced in other cells

39
Q

Which COX is more important for the production of prostaglandins and thromboxanes in inflammation?

A

COX2

40
Q

Which COX is in platelets?

A

only COX1

41
Q

In general, the COX products have short half lives - how are they broken down?

A

spontaneous chemical hydrolysis or uptake into cells by transport protein with subsequent enzymatic degradation

42
Q

What are the 5 COX products receptors and what are they sensitive to?

A 
DP - prostaglandin D
FP - prostaglandin F
IP - Prostaglandin I2
TP - thromboxane A2
EP - prostaglanding E
43
Q

Which prostaglandin is the most potent fever inducer?

A

PGE

44
Q

What are the three things a drug has to be able to do to be considered an NSAID?

A

analgesic
antipyretic
anti-inflammatory

45
Q

Why do NSAIDs work for pain?

A

because they block the production of prostaglandins, which reduce the pain threshold

46
Q

Which NSAID is an irreversible inhibitor of COX?

A

aspirin

47
Q

What does ibuprofen do better than aspirin?

A

It has fewer GI side effects

48
Q

What’s the most potent NSAID, used for severe frontal headache and blood disorders?

A

indomethacin

49
Q

What NSAID is administered once a day and can cause dose-related serious GI bleeding?

A

piroxicam

50
Q

What are the four other NAIDS we didn’t just mention?

A

naproxen, ketorolac, ketoprofen and suldinac

51
Q

What’s the only selective COX2 inhibitor still on the market?

A

celecoxib (celebrex)

52
Q

Why isn’t acetaminophen (tylenol) considered an NSAID?

A

It is analgesic and antipyretic, but NOT anti-inflammatory

53
Q

Where does acetaminiophen effectively inhibit COX if not at the site of inflammation?

A

in the brain

54
Q

Acetaminophen OD can cause serious damage to what organ?

A

liver

55
Q

What are the adverse effects of drugs that inhibit COX?

A

gastric/intestinal ulceration
prolongation of gestation
renal function issues
decreased hepatic function

56
Q

What COX inhibitor is the most common culprit in hypersensitivity reactions?

A

aspirin - usually in atopic individuals

57
Q

What are the symptoms of an aspirin hypersensitivity?

A

rhinitis, urticaria, asthma and laryngeal edema

58
Q

What side effects of the nonselective COX inhibitors aren’t an issue for celecoxib?

A

gastric SEs are less common

doesn’t inhibit platelet function, soyou don’t need to worry about bleeding

59
Q

Why does long-term treatment with COX2 inhibitors result in higher risk of thrombotic cardiovascular events?

A

1 . platelets don’t have COX2, so they’ll continue to make thromboxane - a platelet aggregatory
2. COX2 will inhibit the production of prostacyclin (an aggregation inhibitor) by endothelial cells

60
Q

Why don’t we give aspirin to kids with viral infections?

A

Reye syndrome - encephalopathy and fatty liver

61
Q

What are the products of lipoxygenase?

A

the leukotrienes

62
Q

Leukoctrienes are predominantly generated in what cells?

A

leukocytes - especially PMNs, eosinophils, basophils, monocytes, macrophages and mast cells

63
Q

Some cells that lack 5-lipoxygenase (like endothelial and platelets) can still generate leukotrienes. How?

A

Through transcellular megabolism

LTA4 is synthesized elswehre and can travel to cell types where it can be converted to LTC4 or LTB4

64
Q

`What can LTB4 cause by binding its receptor?

A

CHEMOTAXIS of white blood cells
leukocyte adhesion
ROS production
hyperalgesia = reduced pain threshold

65
Q

What will LTC4, LTD4 and LTE4 cuase by binding to the cys LTR1 receptor?

A

BRONCHOCONSTRICTION
also eosinophil chemotaxis, increased vascular permeability, increased mucous production, dendritic cell maturation, smooth muscle proliferation

66
Q

What will LTC4, LTD4 and LTE4 cause by binding to the cyx LTR2 receptor?

A

endothelial cell and macrophage activation

fibrosis

67
Q

What will HETEs trigger?

A

chemokinetic and chemotactic - movement of WBCs

68
Q

What is the clinical relevance of LTC4 and LTD4?

LTB4?

A

C and D = asthma

B = rheumatoid arthritis and gout

69
Q

What type of asthma are the leukotriene inhibitors best for?

A

chronic asthma - not recommended for acute asthma attacks

70
Q

What are the 3 leukotriene inhibitors we know?

A

zileuton
zafirlukast
montelukast

71
Q

How does zileuton work?

A

It inhibits 5-lipoxygenase and thus prevents the synthesis of LTB4 and others

72
Q

How is zileuton metabolized and why doe sit require monitoring?

A

cytochrom p450 (so watch for drug interactions)

monitor for hepatic toxicity

73
Q

How do zafirlukast and montelukast work?

A

They are leukotriene receptor antagonists - specifically cys LTR1

74
Q

Which one is prescribed more? why?

A

montelukast - because it’s only administered once daily and zafirlukast inhibits cytochrome p450, so you have to worry about it more

75
Q

Where are the kinins synthesized in the body?

A

extracellularly! - in blood or interstitial fluid, not in cells

76
Q

What two moleculs degrade kinins?

A
  1. kininase 1 (carboxypeptidase N or anaphylatoxin inactivator)
  2. kininase 2 (Angiotensin converting enzyme or dipeptide hydrolase)
77
Q

Kininase 1 removes an arginine from bradykinin and kallidin. DOes this make them more or less active? On what receptors?

A

B1: without the arg are more active
B2: with the arg are more active

78
Q

What do the kinins due via the B2 receptor?

A

potent vasodilators, so hypotension
increased capillary permeability and edema
algesic agents - stimualtes nerve endings
contract gut smoth muscle slowly
contract airway smooth muscle
release catecholamines from adrenal medulla
release prostaglandins

79
Q

What do the kinins due via the B1 receptor?

A

have chronic inflammatory efffects
they’re INDUCED after trauma
hypotension
pain

IHO Week 6 (8 decks)

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