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Drugs of arthritis
Lecture 5
54
Pharmacology
Professional
08/27/2012

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Term
Which non-opioid analgesic is used to treat OA?
Definition
Tylenol/Acetaminophen
Site of action: CNS. Inhibits COX only there
Term
Why doesn't Tylenol work at the site of inflammation?
Definition
Tylenol is inhibited by peroxides, no peroxides in the CNS.
Inhibits fever due to CNS action
Term
What is the IC50 score?
Definition
The amount it takes to inhibit to 50%. A lower number is more potent.
Term
What is NAPQI?
Definition
The highly reactive intermediate of tylenol found in the liver. Tied up by glutathione. If glutathione cannot process all of the NAPQI --> Liver toxicity
Term
What drug can be used to treat APAP toxicity?
Definition
Acetylcysteine
Term
What are the classifications of COX inhibitors?
Definition
- COX1 selective - Cox1 inhibitor with no activity on Cox2
- COX nonselective - Can inhibit both by fitting into both enzymes
- COX 2 Preferential - Affects COX2 more than Cox1, but will inhibit Cox1 in higher doses
- Cox-2 selective - Only inhibits Cox2 at maximum doses.
Term
Why were Cox2 inhibitors developed?
Definition
- Anti-inflammator effect
- No effect on platelets, GI, renal function
Term
How is cox activity compared with IC50?
Definition
If you are looking at Cox1/Cox2 - a low ratio tells you the drug is more effective on Cox1
If you are looking at cox2/cox1 - a high number indicates more selective for cox1
Remember - lower IC50 = less required to take effect.
Term
What effect will different NSAIDs have on platelet aggregation?
Definition
ASA>Diclofenac>Celebrex/control
ASA - irreversible platelet aggregation
Motrin - reversible
Term
Which NSAID has uricosuric properties?
Definition
ASA in high doses, but can't use due to gastric side effects.
Term
How do drugs move to sites of inflammation?
Definition
The drug is unionized, moves to the site of inflammation and becomes ionized at a basic pH (weak acid)
Term
Which NSAID produces the highest maximum benefits?
Are COX2 inhibitors better than non-selective?
Definition
None of them. They just take different doses to get there.
No, best anti-inflammatory effect achieved if you inhibit COX1 and 2
Term
How are ASA and sodium salicylate related?
Definition
Both act on neutrophils, but sodium salicylate has no effect on COX/platelets
Term
How does ASA affect NFkB?
What other mechanisms are prostaglandin independent?
Definition
Blocks phosphorylation of IkB by IKK --> no transcription
ASA also produces lipoxins when inhibiting COX2
Term
What is the main mechanisms of NSAIDs?
Definition
Inhibits prostaglandins by inhibiting COX enzymes --> less pain from BK, less inflammation
Inhibiting prostaglandins also inhibits IL-1 --> fever reduction.
Term
Are selective COX2 inhibitors better analgesics than non-selective?
Definition
No, but they last longer.
Term
What are the main side effects of NSAIDs?
Definition
Increased acid due to PG inhibition - PGs produce bicarb and protect mucous.
Renal function - increase in blood pressure, decreased renal perfusion
Reye's syndrome w/ ASA in children under 18
Term
What are potential drug interactions w/ NSAIDs?
Definition
- Decrease in RBF interferes w/ loop diuretic activity, which increase PGs.
- AceI - builds up BK while NSAIDs reduce BK
- Hyperkalemia
Term
Which drugs are COX non-specific?
Definition
ASA
Salsalate
Diflunisal/Dolobid - weak
Choline Salsalate/Trilisate
Term
Which drugs are Propionic Acids?
Non-specific COX inhibitors
Definition
IBU/advil
Fenoprofen/Nalfon
Flurbiprofen/Ansaid - S isomer
Ketoprofen/Orudis
Fenoprofen/Nalfon
Oxaprozin/Daypro
Naproxen/Aleve
Term
Which drugs are Acetic acids?
Non-specific COX inhibitors
Definition
Indomethacin/Indocin - potent
Sulindac/Clinoril - prodrug
Tolmetic/Tolectin
Nabumetone/Relafen - metabolite
Diclofenac/Voltaren
Diclofenac + Misoprostil/Arthrotec
Ketorolac/Toradol - analgesic only
Term
What drug is a Fenamate?
Non-specific COX inhibitor?
Definition
Meclofenamic acid/Meclomen
For dysmenorrhea
Term
What drugs are Pyranocarboxylic acids?
Non-specific COX inhibitor
Definition
Etodolac/Lodine - may be more selective than mobic
Oxicam
Piroxicam/Feldene
Term
What drug is a Preferential COX2 inhibitor?
Definition
Meloxicam/Mobic
Term
What drug is a Cox2 Specific inhibitor?
Definition
Celecoxib/Celebrex
Term
What drug depletes neuropeptides and how does it work?
Definition
Zostrix/Capsaicin - works on TRPV-1 receptors. Substance P.
Depolarize nerve ending --> release of neuropeptide and eventual depletion --> some pain but then desensitization
Term
What are neutraceuticals?
Definition
OTCs that are chondroprotective:
- Glucosamine - increased GAGs and hyaluronic acid, aggrecan. Inhibits MMPs, IL-1, iNOS
- Chondroitin - inhibits NFkB, decreases cartilage loss
Can be equivalent to IBU
Term
Which 3 class of drugs can reduce symptoms in RA?
Definition
- NSAIDs
- DMARDs
- Steroids
Term
How does NSAID use treat RA?
Definition
Less PGs, less neutrophils, may have a TNF and IL-1 effect.
Term
What is an example of a glucocorticoid?
Definition
Cortisol
Term
What is the HPA axis?
Definition
Hypothalamus --> anterior pituitary, ACTH released --> adrenal gland, cortisol released.
Cortisol is a negative feedback, controls itself
Term
What is the MOA of steroids?
Definition
- Genomic theory - enters cytoplasm to produce proteins
- Non-genomic theory - binds to cell membranes
Anti-inflammatory activity tied to glucocorticoid activity
EITHER NFkB blocked from going into nucleus or block NFkB binding to DNA
Term
What are the physiological effects of steroids?
Definition
tissue thinning, muscle wasting, diabetes, moon face and buffalo hump. Elevated mood, suppressed immune system
Cushing's syndrome
Term
What are sites of action for steroids?
Definition
- Vascular permeability
- Vasodilation
- Adhesion
- Chemotaxis
- Leukocytes
- Elimination of mediators
Term
How are steroids beneficial?
Definition
OA - reduce mediators, iNOS, MMPs
RA - prevents migration of macrophages and neutrophils into synovial fluid
SLE - blocks cytokines, reduces antibody complexes
Term
How do you compare steroid potency?
Definition
Everything is relative to cortisol, so divide mg equivalent by AIF potency = equivalent dose.
Term
What are the adverse effects of steroid drops?
Definition
Increase ocular pressure
Ocular infections
Term
What are DMARDs?
Definition
Disease modifying anti-rheumatic drugs
- Gold/Myochrysine or Solganol
- Penicillamine/Depen or Cuprimine
- Hydroxychloroquine/Plaquenil
- Methotrexate/Rheumatrex
- Sulfasalazine/Azulfidine
- Cyclosporine/Sandimmune
- Minocyline/Minocin
- Azathoprine/Imuran
- Leflonomide/Arava
Term
What drugs are in the class of biological agents?
Definition
- Etanercept/Enbrel - TNF, not antibody
- Infliximab/Remicade - TNF
- Adalimumab/Humira - TNF
- Anakinra/Kineret - IL-1
- Rituximab/Rituxan - CD20 on B cells
- Abatacept/Orencia - B7 on APCs
- Golimumab/Simponi - TNF
- Certolizumab pegol/Cimzia - TNF, not an antibody
- Tocilzumab/Actemra - IL-6
Term
What is the MOA of hydroxychloroquine?
Definition
Immunomodulator, interferes with antigen processing and the ability to produce antibodies.
Concentrates in neutrophils
Used in RA and SLE. Takes 2-4 months to work.
Term
What is the MOA of sulfasalazine?
Definition
Sulfa + salacylic acid
Decreases antibodies and inhibits T/B cells. Increased formation of adenosine
works in 1-2 months, not teratogenic
Term
What is the MOA of gold?
Definition
Decreases T cell activation and RF.
Very toxic, takes 6 months to work
Term
What is the MOA of MTX?
Definition
Inhibits DHFR - give folic acid to prevent this. Increased formation of adenosine --> anti-inflammatory. Low dose affects AICAR, inhibits adenosine deaminase, adenosine buildup. Decreased secretion of TNF, IL-1, IL-2, IL-6. Weekly dose, can cause severe fatigue.
Term
What is the MOA of Leflonamide?
Definition
Inhibits DHO dehydrogenase, reduces proliferation of T and B cells. Less toxic, still teratogenic. Alternative to MTX.
Term
What is the MOA of cyclophosphamide?
Definition
Inhibits mostly B cell activation, some T cells. Immunosuppressive, causes bladder inflammation and pulmonary fibrosis. Last resort.
Term
What is the MOA of azathioprine?
Definition
Decreases T and B cell activation - immunosuppressive. A purine antagonist. Bad in gout, some liver toxicity.
Term
What is the MOA of Mycophenolate?
Definition
Inhibits the enzyme that makes guanylic acid. Will still have some due to salvage, but lymphocytes have no feedback loop. Overall inhibition of purine synthesis. Similar to AZA in supressing B and T cells
Term
What is the MOA of cyclosporine?
Definition
Calcineurin must bind to calmodulin for IL-2 to be produced. Prevents that binding. Don't get the 3rd signal to activate T cells. Gingival hyperplasia
Term
Which drugs MOA are TNF antagonists?
Definition
- Etanercept/Enbrel - soluble TNF receptor. Can't use in crohn's.
- Infliximab/Remicade - humanized, used IV.
- Adalimumab/Humira
- Golimumab/Simponi
- Certolizumab pegol/Cimzia - pegylated. Decr immunogenicity, longer T1/2. No Fc = no phagocytosis
Term
What is the MoA of Anakinra/Kineret?
Definition
IL-1 receptor antagonist
Should not use in combo with a TNF antagonist due to side effects
Term
What is the MoA of Abatacept/Orencia?
Definition
CTLA4 + Fc --> competes with CD28 for B7, blocking the 2nd signal in T cell activation
Term
What is the MoA of Rituxan/Rituximab?
Definition
Complement mediated cell lysis. Affinity for CD20, activation of complement. MAJOR reactions, can lead to death
Term
What is the MoA of Tocilzumab/Actemra?
Definition
IL-6 receptor antagonist. Can be used with MTX
Term
What is Benlysta/Belimumab?
Definition
A new drug that targets circulating Blys from B cells, avoiding ADCC. Decreases B cell activation, decreased side effects
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