B6.005 Pharmacotherapy of RA and Joint Pain

Question 1

typical clinical presentation of gout

Answer 1

pain, erythema, and swelling in joint (often toe)
acute pain
middle aged male
overweight

Question 2

what is gout

Answer 2

metabolic disease characterized by recurrent episodes of acute arthritis due to depositions of monosodium urate in joint and cartilage

Question 3

therapeutic goals of gout treatment

Answer 3

terminating attacks
providing control of pain and inflammation
preventing future attacks
preventing complications such as renal stones, tophi, and destructive arthropathy

Question 4

drug classes used for acute gout treatment

Answer 4

NSAIDs
corticosteroids
intra-articular steroid injection
APAP
colchicine

Question 5

NSAIDs in acute gout treatment

Answer 5

most commonly used treatment
inhibit urate crystal phagocytosis
replaced colchicine as drug of choice

Question 6

corticosteroids in acute gout treatment

Answer 6

used in patients who cannot tolerate NSAID or failed NSAID/colchicine therapy

Question 7

intra-articular steroid injection in acute gout treatment

Answer 7

beneficial in patients with just one or two large joint affected
good option for elderly patients with other illnesses

Question 8

types of NSAIDs

Answer 8

nonselective:
-aspirin
-ibuprofen
-indomethacin
COX2 selective:
-celecoxib
-meloxicam

Question 9

features of COX1

Answer 9

enzymes in GI tract
constitutive
protective

Question 10

features of COX2

Answer 10

inducible

inflammatory

Question 11

anti inflammatory mechanism of aspirin

Answer 11

nonselective COX inhibitor

irreversibly inhibits COX and platelet aggregation

Question 12

analgesic effects of aspirin

Answer 12

most effective in reducing pain through reducing inflammation

Question 13

antipyretic effects of aspirin

Answer 13

mediated by COX inhibition in CNS and inhibition of IL-1

Question 14

aspirin adverse effects

Answer 14

gastric upset
gastric and duodenal ulcers
less frequently: hepatotoxicity, asthma, rashes, renal toxicity

Question 15

features of ibuprofen

Answer 15

nonselective COX inhibitor
prescribed in lower doses than aspirin
analgesic but not anti-inflammatory efficacy

Question 16

features of indomethacin

Answer 16

popular for gout and ankylosing spondylitis

Question 17

mechanism of COX2 selective inhibitors

Answer 17

inhibit PGE synthesis by COX2 induced at sites of inflammation without affecting actions of constitutively active housekeeping COX1 found in GI tract, kidneys, and platelets
binds active site of COX2 more effectively than COX1

Question 18

effects of COX2 selective inhibitors

Answer 18

analgesic, antipyretic, and anti inflamm effects similar to nonselective NSAIDs but with less GI adverse effects
no impact on platelet aggregation (mediated by COX1) thus, can have increased incidence of cardiovascular thrombotic events

Question 19

features of APAP

Answer 19

weak inhibitor of COX enzymes
central, direct analgesic effects (not well understood)
NOT an anti-inflammatory
antipyretic

Question 20

side effects of APAP

Answer 20

fewer GI sides effects than NSAIDs, generally well tolerated

danger of liver damage at doses > 4g/day

Question 21

mechanism of colchicine

Answer 21

inhibits microtubule aggregation which disrupts leukocyte chemotaxis and phagocytosis
inhibits crystal induced production of chemotactic factors

Question 22

side effects of colchicine

Answer 22

diarrhea and other GI effects

Question 23

2 classes of gout prophylaxis

Answer 23

urate concentration-lowering drugs

uricosuric drugs

Question 24

what are the urate concentration lowering drugs

Answer 24

xanthine oxidase inhibitors- allopurinol and febuxostat

Question 25

mechanism of allopurinol

Answer 25

blocks conversion of xanthine to uric acid

Question 26

mechanism of febuxostat

Answer 26

xanthine oxidase inhibitor more selective than allopurinol little dependence on renal excretion

Question 27

what are the uricosuric drugs?

Answer 27

probenecid sulfinpyrazone lesinurad (zurampic)

Question 28

mechanism of probenecid/sulfinpyrazone

Answer 28

increases renal clearance of uric acid by inhibiting tubular absorption GI and kidney stone side effects may limit use

Question 29

mechanism of lesinurad

Answer 29

inhibits urate transporter URAT1 | responsible for the majority of the renal reabsorption of uric acid

Question 30

what does DMARD stand for

Answer 30

disease modifying anti rheumatic drugs

Question 31

what is the difference between using DMARDs and NSAIDs in RA

Answer 31

NSAIDs offer mainly symptomatic relief but have little effect on disease progression DMARDs can be more expensive, but can improve prognosis DMARDs are slower acting than NSAIDs

Question 32

examples of DMARDs

Answer 32

``` methotrexate* chlorambucil cyclophosphamide* cyclosporine* azathioprine* mycophenolate mofetil chloroquine/ hydroxychloroquine gold compounds sulfalazine* ```

Question 33

methotrexate mechanism

Answer 33

inhibition of AICAR transformylase and thymidylate synthetase (by inhibiting dihydrofolate reductase) secondary effects of polymorphonuclear chemotaxis

Question 34

cyclophosphamide mechanism

Answer 34

cross links DNA to prevent cell replication

Question 35

cyclosporine mechanism

Answer 35

inhibits IL-1 and IL-2 receptor production

Question 36

azathioprine mechanism

Answer 36

suppresses B cell and T cell function, immunoglobulin production, and IL-2 secretion

Question 37

mycophenolate mofetil mechanism

Answer 37

inhibits cytosine monophosphate dehydrogenase and T cell lymphocyte proliferation

Question 38

chloroquine/ hydroxychloroquine mechanism

Answer 38

unclear

Question 39

gold compounds mechanism

Answer 39

alter morphology and functional capabilities of human macrophages

Question 40

sulfasalazine mechanism

Answer 40

IgA and IgM rheumatoid factor production are decreased

Question 41

what are biologic therapies

Answer 41

organic compounds made by living cells that modify biologic responses: - Ab-Ag interactions - cytokine-receptor interactions - cell signaling protein, inhibitors, or ligands

Question 42

classes of biologic therapies

Answer 42

``` anti-TNF agents B cell depleting agents T cell costimulation inhibitors cell growth arrestors IL-1 inhibitors IL-17A inhibitors ```

Question 43

etanercept

Answer 43

anti-TNF agent | cytokine receptor fusion protein

Question 44

infliximab

Answer 44

anti-TNF agent | chimeric monoclonal antibody

Question 45

adalimumab

Answer 45

anti-TNF monoclonal antibody

Question 46

rituximab

Answer 46

B cell depleting monoclonal antibody

Question 47

abatacept

Answer 47

T-cell co-stimulation inhibitor | receptor-ligand

Question 48

leflunomide

Answer 48

cell growth arrestor (G1 phase)

Question 49

anakinra

Answer 49

IL-1 inhibitor | cytokine receptor decoy

Question 50

secukinumab

Answer 50

anti-IL-17A monoclonal antibody

Question 51

ixekizumab

Answer 51

IL-17A receptor antagonist | used in moderate to severe plaque psoriasis

Question 52

mechanisms of steroidal anti-inflammatory therapy

Answer 52

molecular mechanism inhibits transcription of genes that encode inflammatory proteins (cytokines, chemokines, adhesion molecules, inflamm enzymes) - inhibition of NFkB and AP-1 transcription factors - recruitment of histone deacetylase 2, reversing histone acetylation

Question 53

net result of steroids

Answer 53

decreased lymphocytes (T and B), monocytes, eosinophils, and basophils

Question 54

short to medium duration corticosteroids

Answer 54

``` hydrocortisone (cortisol)* cortisone* prednisone* prednisolone methylprednisolone meprednisone ```

Question 55

intermediate duration corticosteroids

Answer 55

triamcinolone* paramethasone fluprednisolon

Question 56

long acting corticosteroids

Answer 56

bethamethasone | dexamethasone*

Question 57

use of corticosteroids in RA

Answer 57

widely used effects are prompt and dramatic slows the appearance of new bone erosions applicable in other rheumatic diseases (SLE, sarcoid, gout) pronounced side effects w long term use

Question 58

side effects of steroid treatment

Answer 58

``` weight gain (puffy face, truncal obesity) acne hypokalemia hypertension, diabetes peptic ulcer osteoporosis glaucoma muscle wasting acute psychosis ```

Question 59

why can progressive RA lead to neuropathic pain?

Answer 59

erosion of bone and cartilage in vertebral column can lead to flattened discs and compressed spinal nerves

Question 60

what types of drugs are useful for neuropathic pain?

Answer 60

non-opioid analgesics

Question 61

classes of non-opioid analgesics

Answer 61

drugs that modify 5-HT (serotonin) or NE uptake alpha-2 adrenergic agonists anticonvulsants NMDA receptor antagonists

Question 62

drugs that modify 5-HT (serotonin) or NE uptake

Answer 62

amitriptyline* duloxetine* desipramine

Question 63

alpha-2 adrenergic agonists

Answer 63

tizanidine | clonidine

Question 64

anticonvulsants

Answer 64

gabapentin* carbamazepine* pregabalin clonazepam

Question 65

NMDA receptor antagonists

Answer 65

dextromethorphan ketamine amantadine

Question 66

example opioid analgesics

Answer 66

fentanyl hydromorphone oxycodone morphine