Gout Flashcards
1
Q
Hyperuricemia levels
A
> 6.8 mg/dL
2
Q
Gout results from increased levels of __________ in blood
A
uric acid
3
Q
Gout is known as the deposition of ______________ in synovial fluid or tissue
A
monosodium urate crystals
4
Q
Serum Urate Concentrations will increase with what factors?
A
- age
- body weight
- gender (male)
- alcohol
- blood pressure
5
Q
Humans (and apes) are at higher risk of gout because they do not make the ___________
A
uricase protein (pseudogene)
6
Q
Uricase prevents ________ being made from ________
A
fat; sugar
7
Q
Hypoxanthine gets made to xanthine by what enzyme?
A
xanthine oxidase
8
Q
Xanthine gets made into Uric acid by what enzyme?
A
xanthine oxidase
9
Q
Uric acid is (more or less) soluble than hypoxanthine and xanthine
A
less soluble!
10
Q
Monosodium urate crystals can form when (low or high) plasma urate concentrations are present
A
high
11
Q
Uric acid is made into Allantoin by the __________ enzyme
A
uricase
12
Q
Uricase makes uric acid into ________
A
allantoin
13
Q
Uric acid is excreted _________
A
renally
14
Q
What 3 things will inhibit De Novo Synthesis of Purines
A
AMP, IMP, GMP
15
Q
(Increase or Decrease) PRPP synthetase activity (Increase or Decrease) De Novo Synthesis of Purines
A
Increase; increases
16
Q
Adenine and Guanine are broken down to ____________
A
hypoxanthine
17
Q
What is the recycle pathway in purine metabolism?
A
Hypoxantine is made into GTP
18
Q
When HGPRTase activity is DECREASED - what 2 effects are seen
A
1) increases hypoxanthine oxidation to uric acid
2) stimulates De Novo Synthesis through accumulated PRPP
19
Q
De Novo Synthesis of Purines:
PRPP —–10 steps—-> ___________
A
IMP (inosine monophosphate)
20
Q
Urate crystals are taken up by ________cytes and ________cytes
A
monocytes; synoviocytes
21
Q
Once synoviocytes have taken in urate crystals, they release what?
A
prostaglandins, lysosomal enzymes, and interleukin (aka cause inflammation)
22
Q
Synoviocytes take in urate crystals, release contents, and then attract _________ to increase inflammation
A
neutrophils
23
Q
Uricase converts uric acid to _________ which is (more or less) solbule
A
allantoin; more
24
Q
Urate crystals aka monosodium urate will deposit in the _________, _________, and may cause ________ in the kidneys
A
joints, cartilage, caliculi
25
Features of Acute Gout
- acute arthritis
- 1st metarsophalangeal joint
- excruciating pain
26
Medication options for Acute Gout (Hazbun Lecture)
1 - NSAIDs
2 - Colchicine
3 - Glucocorticoids
27
Medication options for Chronic Gout (Hazbun Lecture)
allopurinol/Febuxostat;
| Probenecid; Pegloticase
28
What are features of chronic gout?
Hyperuricemia; development of tophi; recurrent attacks of acute gout
29
Primary Gout vs Secondary Gout
Primary - happens because of overproduction or decreased secretion of uric acid
Secondary - uric acid increases due to cell death/lysis because nucleic acid is released
30
Reasons Primary Gout can occur
Ethanol, foods high in purines, Obesity
31
Why Does Ethanol increase uric acid levels
- increases purine catabolism in liver
- increases lactic acid which inhibits urate secretion
(ethanol competes with uric acid ---> uric acid get secreted)
32
what are some foods high in purines
red meat, seafood
33
Reasons Secondary Gout can occur
- chemotherapy
- Myelo- and lymphoproliferative disorders
- Polycythemia vera and anemia
- Psoriasis
34
2/3 of Uric acid is excreted in the _______
kidneys
35
90% of uric acid is __________ in the ________ tubule
reabsorbed; proximal
36
How to tell if a patient with Hyperuricemia is a overproducer or underexcretor?
- put on purine free diet
- measure amount of uric acid in urine for 24 hours
- if excreting < 600 mg = underexcretor
- if excreting > 1000 mg = overproducer
37
Drugs that can induce Hyperuricemia
- Diuretics (thiazides and loops)
- Nicotinic acid
- Salicylates
- Ethanol
- Cyclosporine
- Pyrazinamide
- Levodopa
- Ethambutol
- Cytotoxic Drugs
- Urate lowering therapies
38
Patients will be (asymptomatic or symptomatic) between flare ups
asymptomatic
39
Clinical Presentation of Gout:
Fever, intense pain, erythema, warmth, swelling, and inflammation
40
Definition of Podagra
gout involving first metatarsophlalangeal joint "the great toe"
41
Definition of Tophi
deposits of monosodium urate in cartilage, tendons, synovial membranes
42
Gout is more common in (lower or higher) joints
lower
43
why is gout more common in lower joints?
- lower temp
| - are more of the "weight bearing joints" during the day
44
most flare ups happen during what time of the day?
nighttime/when you are sleeping!
45
Uric acid nephrolithiasis:
| if urine is (acidic or basic) the uric acid is (less or more) soluble which leads to a risk of increased stone formation
acidic; less
46
Uric acid nephrolithiasis is more common when urine pH is < _____
6
47
What are the 3 long term conditions of Gout
- uric acid nephrolithiasis
- tophaceous gout
- gouty nephropathy
48
what is tophaceous gout?
late complication of gout; seen at base of great toe, helix of ear, bursae, achillies, knees, wrists, ankles
Joint destruction, pain and nerve compression syndrome
49
Gouty Neprhopathy can be acute or chronic:
| Facts about Acute Gout Nephropathy?
- urine flow is blocked bc of uric acid precipitation collecting ducts/ureters
- acute renal failure can occur
- seen in ALL/CLL/CML pts
50
Gouty Neprhopathy can be acute or chronic:
| Facts about Chronic Gout Nephropathy?
- LONG TERM deposition of urate crystals in renal system
- proteinuria can occur
- assoc. w/ HTN, DM, atherosclerosis
51
What are some Non-Pharmacotherapy options to help with asymptomatic or symptomatic hyperuricemia
- reduce purines rich foods
- reduce fructose containing products
- increase fluid intake (to decrease risk of nephrolithiasis)
- increase consumption of low-fat or nonfat dairy products
- encourage weight loss
- rest joint 1 - 2 days/ice it/AVOID HEAT
52
Two main agents used to treat ACUTE GOUT
- colchicine
| - NSAIDs
53
Colchicine - (does or does not) alter the metabolism of excretion of urates
DOES NOT (it just relieves pain and inflammation)
54
Colchicine inhibits inflammation by slowing down what?
slowing (their movement) down macrophages
55
MOA of Colchicine = ?
Colchicine binds to Tubulin --> no polymerization of tubulin occurs --> migration of leukocytes is inhibited --> decreased tyrsonie phosphorylation inhibits synthesis of LTB4
56
Drug interactions for Colchicine
- Cyclosporine/Tacrolimus (only) will cause colchicine to get excreted in the urine
- Cyclosporine/Tacrolimus/Verapamil will cause colchicine to get excreted in the bile
57
NSAIDs or Colchicine? which is preferred and why?
NSAIDs because they are less toxic than colchicine
58
NSAIDs: __________ can also increase ureate excretion in the urine
oxaprozin
59
2 main classes of drugs used to PREVENT Gout
Uricosuric Agents; Xanthine oxidase inhibitors
60
Which drugs are uricosuric agents
probenecid
| sulfinipyrazone is but not used in practice anymore
61
Which drugs are Xanthine oxidase inhibitors?
Allopurinol, Febuxostat
62
Why do Uricosuric Agents work to prevent gout? (aka what is its MOA)
Uricosuric drugs compete with uric acid @ site of reabsorption in renal tubule - therefore uric acid is not reabsorbed as much/uric acid IS renally excreted
63
Drug interactions for Uricosuric Agents:
| ________ decreases effectiveness of uricosuric agents by competing @ kidney
aspirin
64
Drug interactions for Uricosuric Agents:
| Aspirin
it decreases effectiveness of uricosuric agents by competing @ kidney's reabsorption
65
Probenecid blocks _________ of other drugs or metabolites (sulfamides, penicillins, cephalosporins)
urinary secretion
66
Drugs that interfere with the excretion of uric acid and therefore increase serum uric acid - are ...?
diuretics, salicylates, nicotinic acid
67
Allopurinol is a ________ of hypoxanthine
isomer
68
Allopurinol is a isomer of _________
hypoxanthine
69
MOA of Allopurinol
Allopurinol is substrate of xanthine oxidase; allopurinol is made into oxypurinol; oxypurinol will tightly bind to xanthine oxidase and inhibits the enzyme
70
Difference b/w Allopurinol and Febuxostat (Uloric)
Febuxostat is a NON-PURINE inhibitor of xanthine oxidase
71
Uloric is metbolized by the ________ and excreted by the ________
liver; kidney
72
Uloric is (not very or very) strong at binding
very strong!! it can inhibit both the reduced and oxidized enzyme
73
Uloric may be advantageous in what kind of patients? (3 groups)
- pts w/ allopurinol hypersensitivity
- pts w/ reduced kidney function
- pts not responding o high doses of allopurinol
74
Krystexxa is brand for ?
Pegloticase
75
How does Krystexxa work to treat gout?
it is URICASE bound to mPEG; Uricase will oxidize uric acid to allantoin (a soluble product that can be excreted easily)
76
Krystexxa is CONTRAINDICATED for what pts?
pts that are G6P dehydrogenase deficient
77
which drug causes decreased immunogenicity
Krystexxa
78
Elitek is brand for?
Rasburicase
79
Elitek works how?
it is recombinant urate oxidase enzyme from aspergillus flavus - will catalyze the oxidation of uric acid to allantoin!
80
how are Kyrystexxa and Elitek administered?
by IV
81
Zurampic is brand for ?
Lesinurad
82
Zurampic works how?
it is a selective uric acid reabsorption INHIBITOR aka will block URAT1 transporter
83
Therapy goal for target serum uric acid < ___ mg/dL
6
84
3 main options for an acute gout attach
- NSAIDs
- colchicine
- corticosteroid
85
FDA approved NSAIDs for gout?
Indomethacin, naproxen, sulindac
86
Dose for Indomethacin for Gout
50 mg TID
87
Dose for Naproxen for Gout
750 mg followed by 250 mg PO q8H
88
Dose for Sulindac for gout
200 mg BID
89
NSAIDs for acute gout - how to take them
at SCHEDULED doses - not when feeling pain....
90
NSAIDs are contraindicated in what situations?
- pt has hypersensitivity to aspirin/NSAIDs
- decompensated HF
- Active peptic ulcer disease or GI bleed
- Severe or Acute Renal impairment
91
NSAIDs should be used with caution in what situations?
- if pt is using anticoagulants or antiplatelet drugs
- Hx of HF
- Hx of peptic ulcer disease or GI bleed
- Renal Impairment (CrCl < 50 mL/min)
- Uncontrolled HTN
92
Adverse effects of NSAIDs
| GI effects and what to do to help prevent them?
can have Gastritis, bleeding, perforation
| Consider PPI
93
NSAIDs will effect the Kidney and this can be seen by a (decreased or increased) _______
increased SCr
94
Colchicine should be started within ________ of attack onset
36 hours
95
when should colchicine be used?
when pts do not tolerate NSAIDs or pt has a contraindication to NSAIDs
96
Colchicine Dosing
LOADING and CONTINUING DOSE
Loading: 1.2 mg once then 0.6 mg one hour later
Continue: 0.6 mg PO QD or BID 12 hours after loading dose (depending on pt tolerability)
97
what 4 things would indicate dose adjustments to colchicine
- CrCl < 30 mL/min
- Dialysis
- Use of CYP3A4 inhibitors
- Use of P-glycoprotein inhibitors
98
How to dose Colchicine if pt has CrCl < 30 mL/min
- DO NOT repeat dose w/in 14 days
| - Prophylaxis: 0.3 mg PO QD (instead of 0.6)
99
How to dose Colchicine if pt is on dialysis
Tx: 0.6 mg PO x 1 (DO NOT repeat dose w/in 14 days)
| - Prophylaxis: 0.3 mg 2x a week
100
Adverse Effects of Colchicine
GI - Diarrhea; Nausea Vomiting
Bone Marrow Suppression - Aplastic Anemia; Thrombocytopenia
Neuromuscular - Myopathy, Rhabdomyolysis
101
Examples of Corticosteroids used for Gout
- Prednisone
- Methylprednisolone
- Triamcinolone
102
Corticosteroids are used for gout when.....
- NSAID/Colchicine intolerance
- Polyarticular involvement
- Resistant Cases
103
Dosing of Prednisone for Gout:
____ mg/kg per day for___ - _____ days followed by discontinuation
OR
____ mg/kg for ____ - ____ days followed by tapering for ____ - _____ days before discontinuation
0. 5;5;10
| 0. 5; 2;5;7;10
104
Dosing of Triamcinolone Acetonide
____ IM once then oral prednisone as above
OR
____ - ____ intra-articular injection x1
60 mg; 2.5 mg; 40 mg
105
Adverse Effects of Corticosteroids
COMMON ones
______ in blood glucose
______ in appetite or weight gain
Dose Dependent ______ : ___/___/___
Fluid retention can lead to ________ or ____ concerns
CNS: HA, insomnia, mood swings, nervousness
increase; increase; GI upset; N;V;D; increase BP; HF
106
What are the less common adverse effects of corticosteroids
- neutropenia
- hepatotoxicity
- myleosuppresion
107
caution with glucocorticoids with situations?
- Diabetes
- HTN
- Peptic ulcer disease/GI bleed
- CHF
- Immunosuppression
- Psychiatric disorder
108
Possible Combination Therapy Options for ACUTE Gout ATTACKS
- Colchicine + NSAIDs
- Oral Corticosteroids + Colchicine
- Intra-Articular Steroids + all other modalities
(just not Oral steroid AND NSAIDs)
109
What are some disease states that are risk factors for Chronic Gout
- HTN
- Type 2 Diabetes
- Obesity
- Metabolic Syndrome
- CKD
110
```
When to start Urate Lowering Therapy:
- Pt has Diagnosis of Gout
AND
one of the four other traits...
what are the 4 other traits
```
- 2+ acute attacks per year
- Presence of Tophi
- CKD stage 2 or more
- Presence of Renal Stones
111
Urate lowering therapy is typically delayed for about ________ after acute attack resolution
2 weeks
112
Goals of Therapy in Urate Lowering Therapy
- Achieve a serum urate level < 6 mg/dL
| - Prevent acute attacks
113
Monitoring in Urate lowering therapy
During initiation monitor urate every ________
Once urate levels are under 6 mg/dL - monitor every _______
2 - 5 weeks; 6 months
114
Agents that are used to Lower Urate Levels
1st line -
2nd line -
3rd line -
1st: Xanthine Oxidase inhibitors
2nd: Uricosurics
3rd: Uricase Agents
115
Why is Allopurinol first line Xanthine Oxidase Inhibitors
efficacy, availability, low cost
116
Starting Dose for Allopurinol
100 mg QD
117
Starting dose of Allopurinol for patients with CKD stage 4
50 mg QD
118
Max dose for Allopurinol
800 mg/day
119
Slow titration of Allopurinol is recommended every _______
2 - 4 weeks
120
Common Adverse Effects of Allopurinol
- Skin rash
- Itching
- Leukopenia
- Thrombocytopenia
- GI intolerance
121
Less Common Adverse Effects of Allopurinol
- Hypersensitivity
- Stevens-Johnson Syndrom o Toxic Epidermal necrolysis
- Eosinophilia
- Vasculitis
122
Allopurinol Drug Interactions:
- Warfarin (increase INR)
- Antacids
- Mercaptopurine and Azathioprine (because these also use Xanthine Oxidase)
123
Allopurinol Monitoring - _________ screening in at-risk populations
HLA-B*580 (if have this, most likely people of asian decent, can put at high risk for life threatening hypersensitivity)
124
Starting Dose for Uloric
40 mg QD
125
Max dose for Uloric
80 mg QD
126
which drug should NOT be initiated or discontinued during an acute attack
Uloric
127
Dose Adjustments for Uloric if renal or hepatic impairment
No dose adjustment - data is limited; use with Caution
128
Adverse Effects of Uloric
- rash
- nausea
- Abnormal LFTs
- Precaution for CV thromboembolic events (CV deaths, non fatal MI, non-fatal stroke)
129
Largest Limitation of Uloric is?
Cost
130
Things to Monitor when Pt is on Uloric
Check LFTs at baseline, 2 mos, 4 mos
131
Contraindications for Uloric
concomitant use with azathioprine, mercaptopurine, or theophylline
132
MOA for Uricosuric Agents
increases clearance of uric acid by inhibiting secretory reabsorption in the proximal tubule
133
When is Probenecid used?
- pts cant tolerate allopurinol
- pts cannot reach target urate levels with just a XOI
- pts have documented underexcretion of urate
134
What is brand for probenecid
Benemid
135
Can Probenecid be added to Allopurinol?
yes
136
Max dose of Probenecid
2 gm QD
137
Encourage _______ when on Probenecid
adequate hydration - to prevent renal stone formation
138
Dosing of Probenecid
TITRATE UP
250 BID x 7 then 500 BID x 14
139
Why start at a low dose with Probenecid
to prevent uricosuria and renal stone formation
140
Adverse Effects for Probenecid
- flushing
- HA
- pruritis
- GI upset
- STONE FORMATION
- Aplast Anemia/Leukopenia
141
Contraindications for Probenecid
- Hypersensitivity
- Salicylates
- Blood Dyscrasias
- Uric Acid Kidney Stones
- CrCl < 50 mL/min
- Acute Attack
142
Example of Uricase Agents
Pegloticase
143
MOA of Uricase Agents
converts Uric acid to allantoin (which is more SOLUBLE IN WATER)
144
Brand for Pegloticase
Krystexxa
145
Pegloticase is a ________ line agent
LAST
146
How is Pegloticase administered?
by IV
147
Dose for Pegloticase
8 mg IV infusion q 2 weeks
| Administered over 120 minutes
148
for Pegloticase - Patients should be PRE-TREATED with what?
antihistamines and corticosteroids (bc of infusion related rxns)
149
When is Pegloticase indicated
for REFRACTORY GOUT
- pt with significant disease burden
or
pt has intolerance to conventional urate lowering therapy
150
Adverse Effects for Pegloticase
- infusion related rxns
- Anaphylaxis
- Nephrolithiasis
- Arthralgias
- HF exacerbation
- Nausea
151
Contraindications/Cautions for Pegloticase
- G6PD deficiency (bc puts them at risk for hemolysis and methemeoglobinemia - perform G6PD test)
- Caution: HF pts
152
Lesinurad is generic for ?
Zurampic
153
MOA for Lesinurad
URAT1 inhibitor - aka will enhance uric acid excretion
154
Lesinurad has been approved to be used in combination with what med?
XOI (xanthine oxidase inhibitor)
155
Dose of Lesinurad
200 mg QD PO
156
Adverse Effects for Lesinurad
BLACK BOX WARNING: for Acute Renal Failure
- HA
- GERD
157
Fenofibrate can be used for gout - how/what is the MOA
increases the clearance of both hypoxanthine and xanthine (decreases levels ~ 20 - 30%)
158
Losartan can be used for gout - how/what is the MOA
inhibits tubular reabsorption of uric acid
| unique to losartan - no other ARB will do this
159
Fenofibrate or Losartan can be used to help with gout - can they be used with another gout med?
yes - XOI and one of those can be used for refractory cases
160
What are two off label drugs that can be used for gout
fenofibrate, Losartan
161
Options for Prophylaxis
- Colchicine (preferred)
- Low Dose NSAIDs
- Low dose Prednisone/Prednisolone (< 10 mg /day tho)
162
Prophylaxis regimen should be initiated along with _________
ULT (urate lowering therapy)
163
Colchicine dosing - Prophylaxis
0.6 mg PO QD or BID
| colchicine is preferred over NSAIDs but both are first line options
164
Low Dose NSAIDs dosing - Prophylaxis
Naproxen 250 mg PO BID
165
Low dose Prednisone/Prednisolone dosing - Prophylaxis
ONLY if other options are contraindicated or not tolerated
