Sweatman - Treatment of Arthritis Flashcards
1
Q
What are the 3 classes of treatment approaches to arthritis?
A
- NSAID’s: treat pain, and provide anti-inflammatory action
- Disease-modifying anti-rheumatic drugs (DMARD’s): admin either locally by injection into arthritic joints, or systemically to provide immune suppression of the inflammatory process
- Biologicals: also DMARD’s, but target specific molecular epitopes, rather than broad spectrum effects classical DMARD’s
- NOTE: both classical and biological DMARD’s can slow progression of disease process (NSAID’s can NOT)
2
Q
NSAID’s overview
A
- Pts should take lowest effective dose for shortest duration needed to control symptoms
-
Analgesic, antipyretic, anti-inflammatory actions
1. Reversible (except ASA) INH of COX (COX-1 is constitutive, COX-2 is inducible)
2. Unintended INH of COX is reason for many of the chronic NSAID side effects - NO oral NSAID is consistently more effective than any other; different pts may respond to/tolerate different NSAID’s differently (pay attention to pt’s individual CV/GI risk, and max dose)
- ASA in high doses is as effective as any o/NSAID, but may have more GI toxicity -> non-acetylated salicylates have less GI toxicity than ASA
- All undergo extensive hepatic metabolism, and are eliminated mainly via urine
3
Q
What are PG’s? Which one plays a role in inflammation?
A
- PGD2: bronchoconstriction, sleep, Alzheimer’s
- PGE2: pain, vasodilation, bronchoconstriction, cytoprotective, INFLAMMATORY CELL ACTIVATION, fever, mucus production, possible erectile dysfunc
- PGF2alpha: vascular tone, repro physiology, bronchoconstriction
4
Q
How do NSAID’s relieve pain (molecularly)?
A
- After tissue damage, mast and macros activated and some polys may be recruited -> TNF-alpha, IL-1B, IL-6, NO, bradykinin nerve growth factor (NGF) released and activate nociceptive receptor that transduces sensation of tissue damage to CNS
1. Exert their algesic effects by acting directly on nociceptors or indiretly via release of other mediators, i.e., PROSTANOIDS
5
Q
Compare the effects of the traditional NSAID’s vs. those of the COX-2-specific drugs.
A
- Major marketing point for the COX-2-specific drugs was a lack of effect on platelet aggregation, and significantly reduced incidence of GI toxicity
1. However, unanticipated adverse effects on CV system
6
Q
How do NSAID’s vary according to structural class, COX specificity, and half-life? Provide some examples.
A
- Structural class: belong to several different structural classes
- COX specificity: vary from COX-1 specific drugs like Ketorolac to COX-neutral drugs like Ibuprofen and COX-2 selective drugs like Celecoxib and Etodolac
-
1/2 life: vary from Diclofenac/Ketoprofen with short duration to Piroxicam with long duration
1. Dosing rate for the drugs varies by agent, so some require multiple doses, and other only once-daily dosing
7
Q
How do chronic NSAID’s produce damage?
A
- Direct chemical irritation -> damage to the gastric mucosa with ulceration and gastric bleeds possible
- INH of the cyto-protective effects of PGI2 on the gastric mucosa (i.e., mucus secretion, bicarbonate release, and initiation of repair process in the underlying tissue)
8
Q
What are the risk factors for GI AE’s with the NSAID’s?
A
- Varies by individual patient based on the parameters in the attached table
- Risk also varies by drug: recent meta-analysis showed that RR risk for upper GI events was lowest for COX-2 INH and Diclofenac, and highest for Ibuprofen and Naproxen
9
Q
What are some ways to reduce NSAID GI toxicity w/o adding drugs?
A
- Use COX-2 agent or traditional one w/gastro-protection
- Enteric coating (aspirin): reduces, but doesn’t eliminate toxicity
- FDA recommends taking NSAID’s w/food or milk to avoid stomach upset, but there is NO data to support this -> may be more better to advocate taking them on empty stomach to achieve rapid onset and avoid “extra dose” bc pt expectations for relief not met (according to Dr. S)
- Pts w/gastric ulcers may remain asymptomatic, but occult blood will be evident in stool -> blood loss can be sufficient to produce iron deficiency anemia
10
Q
What are some ways to reduce NSAID GI toxicity by adding add’l drugs?
A
- Misoprostol: prostaglandin analogue
- H2 receptor antagonist
-
Proton pump inhibito__r: superior efficacy due to more complete acid suppression (NSAID + PPI as effective as COX-2 alone; COX-2 + PPI reduces risk of endoscopic gastric ulcers)
1. Caveat: can alter efficacy of concurrent drugs that rely on stomach acidity for absorption
2. Reports on CV AE’s in pts w/Clopidogrel and PPI’s
3. Adverse toxicity/INC risk for comorbid conditions still possible w/adjunctive PPI’s
11
Q
How are the effects of Celecoxib different than those shown here? Why do they INC CV risk?
A
- Traditional NSAID: no net change in balance b/t TXA2 and PGI2
- COX-2 INH (e.g., Celecoxib): production of prostacyclin significantly INH, but production of TXA2 is NOT -> shift toward more pro-thrombotic state
- However, the real situation is much more complex than this bc both Diclofenac (activity similar to Celecoxib) and Ibuprofen (COX-neutral) at high doses INC risk of vascular events in recent study
12
Q
Which high-dose NSAID is NOT associated with vascular events?
A
Naproxen
13
Q
How can NSAID’s potentially modulate the CV-protective effect of ASA?
A
- Potential for concurrent admin of NSAIDs to INH ability of low-dose ASA (MI prophylaxis) to reach its binding site on platelet and provide irreversible enzyme INH (remember: anuclear platelets cannot regenerate) -> competitive inhibtion
- Because traditional NSAID action is reversible, there is potential for antiplatelet activity to be lost, and INC CV risk to occur
14
Q
How do the NSAIDs affect the liver?
A
- Significany contribution (10%) to overall incidence of liver toxicity, reflecting their widespread use
- Overall incidence is low, however, except with the use of Sulindac
15
Q
How can the NSAIDs produce renal toxicity?
A
- PGE2 and PGI2 play an important role in the micro-regulation of perfusion in renal tissue, especially in abnormal “stress” situations, where they help to maintain GFR (and renal bloodflow via vasodilation)
- Can lead to diminished renal function, renal tissue damage (i.e., nephrotic syndrome), or even acute renal failure (higher risk when initiating therapy)
1. Reduce renal clearance of concurrent drugs (e.g., lithium and MTX)
2. Antagonize effects of uricosuric agents
16
Q
What routine pt monitoring should be done for folks on chronic NSAIDs?
A
- LFT’s, serum creatinine/BUN, stool guaiac, CBC
- NSAIDs very rarely (<1%) produce blood dyscrasias, incl hemolytic or aplastic anemia, pancytopenia, or thrombocytopenia
- Chronic ASA therapy may also warrant monitoring of serum salicylate (esp. in situations of intentional drug overdose)
17
Q
What is salicylate poisoning?
A
- Metabolic product of ASA (acetyl-salicylic acid) is capable of crossing BBB where it stimulates the medullary respiratory center -> RESPIRATORY ALKALOSIS
1. Hyperventilation leads to dehydration and compensatory metabolic acidosis - Also disrupts intermediary metabolism -> uncoupling of oxphos + interruption of glucose and FA metabolism lead to METABOLIC ACIDOSIS
- Cerebral and pulm edema (INC cap permeability) lead to CV collapse/death if pt not decontaminated
- Altered platelet function prolongs prothrombin time
18
Q
What are the Beers criteria for the NSAIDs?
A
- Avoid chronic use unless other alternatives are not effective and patient can take gastro-protective agent (PPI or misoprostol)
19
Q
How is Acetaminophen used to treat arthritis?
A
- NOT NSAID bc NO ANTI-INFLAMMATORY activity
- Exact mechanism unclear, but thought to produce analgesia and antipyretic actions via INH of COX-1 and 2 in the CNS
- Usually taken orally, but IV form just approved
-
Toxicity: NO GI AE’s w/oral therapy, but N/V, constipation, and diarrhea w/IV admin
1. Renal toxicity also a rare event
2. Most associated w/hepatic failure due to metabolic production of highly reactive adduct (risk for (un)intentional overdose)
20
Q
What is the current treatment practice for RA?
A
- Progressive approach
- Initially: DMARD like MTX + NSAID + CCS
- Milder cases: HYDROXYCHLOROQUINE preferred due to lower toxicity
-
Post-tx failure: Etanercept, Infliximab, Adalimumab, Golimumab, or Certolizumab alone or + MTX
1. Poor response to these may elicit switch to a different one, or trying out: Anakinra, Rituximab, or Toclizumab - Aggressive tx w/MTX and/or biologic agent results in longer disease-free remission, less joint destruction, and a better QOL
21
Q
How is MTX used to treat RA?
A
-
MOA: DHFR inhibitor, denying the cell essential methionine + INH cellular actions of adenosine via effects on adenosine deaminase and AMP deaminase enzymes
1. INH lympho proliferation and suppresses secretion of IL-1, IFN-gamma, and TNF
2. INC secretion of IL-4, impairs histamine release from basophils, DEC poly chemotaxis - Polyglutamated, helping to retain it in the cell
- Bone marrow suppression (leukopenia, anemia, thrombocytopenia) at HIGH DOSES
24
Q
What is Leflunomide?
A
- CYP-produced metabolite INH dihydroorotate dehydrogenase (DHODH), a mito enzyme that catalyzes a key step in de novo pyrimidine synthesis (like MTX)
- Cell cycle arrrest in T and B-cells: DEC lympho proliferation & Ig production suppressed
- Uricosuric effect from metabolite: INC renal elim of uric acid
- Elevated LFT’s with chronic use: caution advised in alcoholics, or w/heavy alcohol use
- Not used w/immune suppression or infection
- Category X drug
- NOTE: CYP activity in plasma/intestinal mucosa
26
Q
What are the monitoring parameters for the 4 classic DMARDs for RA (table)?
A
- Things that are different:
1. MTX: serum uric acid
2. MTX + Sulfa: serum creatinine/BUN
3. Leflu: pregnancy test, serum electrolytes
4. Hydro: opthalmologic exam
28
Q
How does long-term tx with CCS give rise to glucocorticoid-induced osteoporosis?
A
- Transient INC bone resorption in early tx due to stimulation of RANKL and MCF and downregulation of osteoprotegerin -> INC osteoclastogenesis and lifespan
-
Long-term: regulatory control of osteoblasts and osteocytes gives rise to DEC bone formation (CCS-induced osteoporosis)
1. INC PPARy2 expression + DEC Wnt signaling = DEC osteoblastogenesis; activation of caspase 3 = INC osteoblast/cyte apoptosis
30
Q
What are some of the AE’s associated with long-term medium/high dose CCS use?
A
- Only ones he noted were the adverse metabolic issues and the Cushingoid look, which can produce stark changes in physical appearance
32
Q
What is one way to avoid the general systemic effects of the CCS?
A
- Intra-articular injections provide local disease control and prevent widespread systematization of drug that occurs w/oral therapy
- By selecting drug w/correct solubility characteristics, application site can function as a depot, releasing drug over extended period of time
1. Most effective drugs are those w/limited solubility: Triamcinolone, Methylprednisolone
34
Q
What are the drug targets for the biologic RA drugs (image)?
A
35
Q
What are the MOA and mode of delivery for the biologic drugs for treating RA (table of 9)?
A
- Many of these are MAb’s, others function as false receptors for circulating TNF (which exists in a soluble and transmembrane bound form)
45
Q
What is Apremilast?
A
- Drug that arrived on the market last year
- Approval to treat psoriatic arthritis (improves joint tenderness, swelling) and plaque psoriasis (improves redness/scaliness)
- Distinct MOA: orally active phosphodiesterase inhbitor (PDE4), giving rise to reduction in pro-inflammatory mediators
- Oral drug: substrate of CYP3A4, 1A2, 2A6, and P-gp, w/extensive metabolism for renal/stool elim
- Most common AE’s: nausea, headache, weight loss (monitor during tx)
1. Rarely: depression, suicidal ideation (<1%; eval during routine office visits)
