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MSK/Rheum > Pharm-Gout > Flashcards

Pharm-Gout Flashcards

1
Q

Drugs used in the Rx of Gout? (6)

A
  1. Colchicine
  2. Indomethacin
  3. Allopurinol
  4. Probenecid
  5. Febuxostat
  6. Pegloticase
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2
Q

Definition of Hyperuricemia?

A

plasma UA>7mg/dL

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3
Q

Causes of Hyperuricemia? (2)

A

A. Metabolic (10%)→Overproduction of UA

B. Renal (90%)→Underexcretion

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4
Q

What are the two types of Metabolic causes of hyperuricemia? Examples?

A
  1. Primary→Associated with 1 of 2 specific enzyme abnormalities in the Purine Metabolism
  2. Secondary→a. Blood disorders (myelo-/lymphoproliferative disorders) b. Tumor Lysis (chemotherapy or radiation therapy)
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5
Q

What are the two types of Renal causes of hyperuricemia?

A
  1. Primary: Kidney Ds/Failure→a) either Low GFR (less UA is filtered and therefore excreted) or b) Normal UA Excretion levels but they require increased plasma UA levels above normal to excrete normal amounts
  2. Secondary (MCC): a) Long Term Diuretics (MCC→induce volume depletion→enhanced reabs of UA in PCT; reduced bl. volume→increased concentration) or b) Toxemia of pregnancy (swelling of glomerular tuft, which reduces UA excretion)
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6
Q

What are the two specific enzyme abnormalities that cause Primary Metabolic Hyperuricemia?

A
  1. ↑’d PRPP Synthetase activity
  2. ↓’d Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRT) activity
    These are both important enzymes involved in Purine Metabolism (UA is byproduct of Purines)
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7
Q

How does ↑’d PRPP Synthetase activity cause hyperuricemia?

A

PRPPS catalayzes the RATE LIMITING STEP of UA biosynthesis:
↑’d conversion of Ribose-5-P+ATP→5-PRPP+Glutamine
This leads to increased UA in plasma

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8
Q

How does ↓’d HGPRT activity cause hyperuricemia?

A

HGPRT is the SALVAGE pathway enzyme which removes Inosinic Acid and Hypoxanthine from production of UA and into the production of Nucleic Acids. If salvage pathway is reduced, fewer of these will be removed from the UA synth pathway and these will contribute to production of more plasma UA.

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9
Q

Before beginning drug therapy for Rx of gout, what should the physician do?

A

Try Behavioral modifications→alter diet→reduced red meat/chicken

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10
Q

The 5 therapeutic aims in the Rx of Gout?

A
  1. Terminate an acute attack
  2. Prevent recurrence (flare up) of acute gouty arthritis
  3. Reverse or prevent complications of deposited ureate (UA) crystals
  4. Prevent other factors associated with the disease (obesity, HTN, hypertriglyceridemia)
  5. Prevent formation of urate kidney stones, which can cause renal failure
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11
Q

What agents are used to terminate an acute attack of gout?

A

Colchicine, Indomethacin

+corticosteroids

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12
Q

MoA/Effects of Coclchicine?

A

It causes DEPOLYMERIZATION OF MICROTUBULES, which has 2 consequences:
a. Prevents mvmt of PMNs/inflammatory cells from blood to site of inflammation
b. Prevents phagocytosis of UA crystals by PMNs, and therefore the subsequent release of inflammatory enzymes
Net: Colchicine blocks inflammatory response and reudces pain/symtpoms: decreased # and phagocytic activity of PMNs at site→reduced lysosomal enz/infamml mediatory release

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13
Q

Specific uses of Colchicine? (3)

A
  1. Terminate acute attacks of gout
  2. Prophylaxis to prevent recurrence of acute gouty arthritis attacks
  3. Familial Mediterranean Fever
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14
Q

T/F: Colchicine is only effective against gouty arthritis and reduces [UA] in blood.

A

False, It is only effective against gouty arthritis (doesnt treat any other types of arthritis bc not antipyretic or anti-inflammatory), but it does NOT reduce plasma UA levels.

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15
Q

ADEs of Colchicine? (2)

A
  1. GI disturbances (acute)→used as sign to know you’ve given pt too much
  2. Blood dyscrasias (w/ chronic use)→alter cellular composition of blood
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16
Q

Which drug is preferred to terminate and acute attack: Colchicine or Indomethacine?

A

Indomethacine b/c colchicine can be difficult to use

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17
Q

MoA/Properties of Indomethacine? (3)

A
  1. NSAID→COX inhibition
  2. Analgesic/Anti-inflammatory/Antipyretic (colchicine is none of these)
  3. Inhibits leukocyte (PMN) motility
    Net: Blocks the ability of immune system to attack UA crystals→alleviating the pain of gouty arthritis (GA)
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18
Q

How does the therapeutic use of Indomethacine compare with Colchicine? Why? How is this overcome?

A

a. Both are used to terminate and acute attack of GA, but unlike Colchicine, Indomethacin is NOT used for prophylaxis or familial Mediterranean fever.
b. Due to the fact that Indomethacine can only be used for a short period of time b/c of its many ADEs.
c. So, after 3-5 days, switch pt to Ibuporfen (or another safer NSAID) to blunt pain.

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19
Q

What is unique about the way indomethacine is prescribed?

A

It is always taken with an effective ANTACID (to prevent dev’t of peptic ulcers)

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20
Q

ADEs of Indomethacin?(3)

Drug-drug interactions? (2)

A 
ADEs:
1. GI: ulcers, N/V
2. CNS: severe frontal headache
3. Hematopoietic Disorders
D-D Interxns: it antagonizes the diuretic action of Furosemide and HCTZ
21
Q

Which two drugs inhibit Ureate (UA) synthesis? How?

A

Allopurinol, Febuxostat

Both inhibit Xanthine Oxidase (XO) (but they do it a little differently)

22
Q

What are the effects of inhibition of UA synthesis by allopurinol/febuxostat? (4)

A
  1. Reduces plasma levels and ,therefore,urinary excretion of UA (less is filtered)
  2. Increases plasma levels and urinary excretion of oxypurine precursors (xanthine and hypoxanthine), which are more soluble and less likely to form crystals/stones
  3. Dissolution of UA Crystals in joints and kidneys (b/c UA levels are decreased to soluble levels)
  4. Prevents formation of UA kidney stones (Aims 2 and 5)
23
Q

MoA of Allopurinol?

A
  • *SUICIDE INHIBITOR**
    a. Allopurinol itself is competitive reversible inhibitor of XO, binding at active site
    b. Allopurinol is also substrate of XO→XO metabolizes it to OXYPURINOL→NONCOMPETITIVE, IRREVERSIBLE inhibitor of XO (binds XO and kills it)
24
Q

What lab values will be high in a pt taking Allopurinol?

A

Elevated plasma and urine Oxypurine precursors (xanthine and hypoxanthine), which is not a problem b/c these are much more soluble and less likely to form crystals/stones)

25
Q

What is a consequence of dissolution of crystals by allopurinol? How is this managed?

A

Dissolution can cause flare ups of acute gout; to prevent this pt’s taking allopurinol also take mild NSAID (ibuprofen) to prevent acute symptoms

26
Q

Therapeutic uses of Allopurinol? (2)

A

Both are UA overproducers (think about MoA)
A. ***Children w/ Familial Juvenile Hyperuricemic Nephropathy (Renal ds due to primary metabolic hyperuricemia due to enzyme abnormalities →HGPRT deficiency or ↑’s PRPPS)
B. Prophylactic prevention of secondary hyperuricemia due to chemo (tumor lysis) or heme disorder (multiple myeloma)

27
Q

ADEs of Allopurinol? (5)

A

“DAM LFT Flares”

  1. D(ermatitis): Hypersensitivity rxns→ dermatitis/exfoliative dermatitis (give low test dose; substitute w/ oxypurinol)
  2. A: AMPICILLIN*** + related Abx are CI’d (↑ risk of exfoliative dermatitis)
  3. M: d-d interxn w/ 6MP (used to Rx blood cancers; metabolized to active by XO; allopurinol inhibits its activation)
  4. Elevated LFTs
  5. F(lare): ↑ incidence of acute gout flare ups (due to crystal dissolution); prevented w/ mild NSAID like ibuprofen
28
Q

MoA of Febuxostat?

A

Potent, strong, and stable inhibition of BOTH oxidized and reduced forms of XO
(Allopurinol only weakly inhibits oxidized form)

29
Q

How do Febuxostat and Allopurinol compare structurally?

A

They are structurally UNRELATED

Allopurinol is related to UA/purines so it binds XO active site, while Febuxostat is allosteric inhibitor???

30
Q

How do effects of Febuxostat and Allopurinol compare?

A

Febuxostat is more potent in lowering UA levels and displays less ADEs.

31
Q

Clinical uses of Febuxostat? (2)

A

Same indications as Allopurinol, but much more expensive b/c not generic, so mainly only used when allopurinol cannot be used.

  • It’s main indication is to LOWER UREATE (UA) LEVELS in:
    a. Pt’s who display ADVERSE SYMPTOMS TO ALLOPURINOL, such as HS RXNS
    b. Pt’s w/ mild or moderate RENAL INSUFFICIENCY (this is another limitation of allopurinol)
32
Q

ADEs of Febuxostat? (1)

A

SIDE EFFECTS ARE MILD, only small % have problems:

1. Elevated LFTs (transaminase)

33
Q

Renal handling of Uric Acid? What ultimately determines amount of UA in urine?

A

A. Freely filtered at the glomerulus (small molecule)
B. 3 steps in PCT:
1. Pre-Secretory Reabsorption→ALL filtered UA is reabsorbed in early PCT
2. Secretion of of UA from blood into PCT by Uric Acid Transporter (UAT)
3. Post-Secretory Reabsorption→PARTIAL reabsorption of secreted amount of UA by Brush Border Transporter (BBT)
Amt of UA in urine=Step 2 amt-Step 3 amt of UA
(UA is not handled anywhere else in kidney other than PCT)

34
Q

What is a Uricosuric agent? What Uricosuric agent is used in Rx of gout?

A

Uricosuric Agents→agents that increase urinary excretion of UA.

35
Q

General MoA of Probenecid?

A

It increases urinary excretion of UA by interfering w/ post-secretory reabsorption of UA.

36
Q

Specific MoA of Probenecid?

A

a. Probenecid is secreted into PCT by Organic Acid Transporter (different that UAT that secretes UA→so it does NOT interfere w/ UA secretion)
b. Probenecid then competes w/ UA for reabsorption by brush border transporter (BBT) in PCT, limiting BBT’s ability to reabsorb UA→more UA remain in tubular fluid and is excreted in urine.

37
Q

T/F: Probenecid and UA share affinity for secretor? Reabsorber?

A

a. False, NOT same secretory transporter:
UA→UAT; Probenecid→OAT; Therefore, probenecid DOES NOT AFFECT UA SECRETION
b. True, compete for same reabsorber→BBT

38
Q

Clinical effects/indications/uses of Probenecid? (2)

A

a. Increased UA urinary excretion leading to b

b. Dissolve of UA crystals in joints (b/c plasma UA levels drop below precipitory concentrations)

39
Q

What pt’s are given Probenecid?

A

Only given to dissolute crystals in:

a. Pt’s who EXCRETE LESS THAN 1g of UA/day (below normal UA excretion)
b. w/ PROPER RENAL FUNCTION and adequate hydration

40
Q

What is a potential complication of probenecid? How is this prevented?

A

Kidney stones due to increased amounts of UA passing thru renal tubules for excretion; prevent this w/ ADEQUATE HYDRATION of pt (and ensuring they have good renal function)

41
Q

ADE of Probenecid? (1) How is this overcome?

A

Only one and it’s a D-D Interxn:
SALICYLATES (NSAIDs) inhibit probenecid’s uricosuric action by blocking its secretion into tubular fluid by OAT.
TYLENOL does NOT have this effect, so use it instead if pt needs probenecid.

42
Q

What id Pegloticase?

A

BIO-URICOLYTIC AGENT:
Recombinant, PEG-ylated form of URATE OXIDASE (Uricase) from pig
(uric acid is present in most animals, but not humans)

43
Q

MoA of Pegloticase?

A

It breaks down Uric Acid (urate) into ALLANTOIN, a benign, more water-soluble product which is more easily excreted in urine: UA→Pegloticase→Allantoin=water-soluble→excreted easily in urine

44
Q

Administration/route of Pegloticase?

A

IV infusion b/c it’s an ENZYME!

45
Q

What pt’s are given Pegloticase?

A

Pt’s w/ obvious, unseemly TOPHI in joints and in whom ALL other drugs have failed/CI’d)
(aka Severe Gout to reverse severe cases of UA crystal deposition in joints)

46
Q

Pharmacologic effects of Pegloticase? (2)

A
  1. RAPIDLY lowers serum levels and urinary excretion of UA. (decreased serum levels→crystal dissolution but risk of repeat gout flares as with allopurinol)
  2. Increases serum levels and urinary excretion of allantoin which is 5x more soluble than UA→decreased risk of stones
47
Q

Clinical use of Pegloticase? (2)

A

a. ** Control hyperuricemia in pt’s w/ severe gout in whom conventional therapy is contraindicated or has been ineffective.
b. Many of these pt’s have unseemly TOPHI. Dissolution of these tophi is RAPID AND EFFECTIVE IN ALL Pt’s REFRACTORY TO THE OTHER AGENTS.

48
Q

What is the main reason Pegloticase is limited?

A

EXPENSIVE→$30K/year

49
Q

ADEs of Pegloticase?

A
  1. Rapid Dissolution→GOUT FLARES (pretty much for sure in all pt’s); prevented by prophylactic NSAIDs, colchicine, or glucocorticoids
  2. Dev’t of Ab’s against PEG moiety (PEG increases t1/2 but is antigenic; Uricase itself is NOT antigenic). Clinical manifestations seen w/ high IgG titers; reduce dose to prevent this.

MSK/Rheum (7 decks)

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