Pain, Inflammation and Anti-Inflammatory Flashcards
Inflammation
Inflammation is a process that begins following sub-lethal injury to tissue and ends with \_\_\_\_\_\_\_\_ destruction of tissue or with complete healing after removal of the injurious stimulus. It is characterized by five cardinal signs: rubor (redness) calor (increased heat) tumor (swelling) dolor (pain) -\_\_\_\_\_\_\_\_
permanent functio laesa (loss of function
Inflammation
-Elicits a series of events
-Humoral and Cellular (?)
These events bring about:
-Localization of injury
-Removal of noxious agent(s)
-Repair of_____ damage
________ of function in the injured tissue
Excessive/ Chronic inflammation is not beneficial :Rheumatoid arthritis, tuberculosis, psoriasis, mastitis etc.
physical
restitution
Inflammatory Mediators
-Generated at the _____ site
-Usually exist as precursors or sequestered in cells
-Cell damage results in release of _______ enzymes, -_________ and synthesis of various ________ ( Prostaglandins, Prostacyclines, Leukotreines, Thromboxanes)
-_________ have effects on blood vessels, nerve endings and blood cells
Two fundamental features of inflammation:
1. Increase permeability of the _______
2. Activation of ________
injury lysosomal arachidonic acid eicosanoids prostaglandins microvasculature leukocytes
Therapeutic Strategies
2 Goals of treatment:
-Relief of symptoms and maintenance of function
-Slowing of tissue damage
Drugs:
______: Relief of pain and Inflammation
_________: Long term control
_______: Decrease symptoms, slow bone damage in Arthritis and Decrease inflammation
NSAIDs
Corticosteroids
DMARDs
Anti-Inflammatory Agents
-Non-steroidal Anti-inflammatory Agents (NSAIDs):
Aspirin, Ibuprofen, Diclofenac, Piroxicam,
Celecoxib, Naproxen
-Steroidal Anti-inflammatory Agents:
Hydrocortisone, Betamethasone, Prednisolone
Triamcinolone, Fludrocortisone, Dexamethasone
-DMARDs (Disease Modifying Antirheumatic Drugs): Abatacept, Azathioprine, Cyclophosphamide, Methotrexate, Rituximab
idk
NSAIDs
NSAIDS: attenuate the inflammatory pain response
-Reduce biosynthesis of mediators of inflammation (______, ________)
-Cyclooxygenase (COX)-2 selective drugs: ______
Inhibition of _______ synthesis through selective inhibition of COX-2 isoenzyme
-COX -1 and Non-selective COX inhibitors: _____ GI complications. dyspepsia, ulceration, and upper GI ____ resulting in hematemesis
-Lower GI complications: small bowel, colon, and rectum leading to ulceration, overt or occult bleeding
-Cardiovascular effects of COX-2 inhibitors (MI/ Stroke)
prostaglandins, leukotrienes Celecoxib prostaglandin upper bleed
Cycloxygenase Enzyme
COX-1
Physiologic effects:
Platelets : production of ______
Kidney: regulate renal ______ in response to changes in blood volume and fluid & electrolyte transport
Gastric mucosa - maintain mucosal integrity
Regulate _______ tone
TXA2
blood flow
vasomotor
Cycloxygenase
COX-2
Physiologic
-_______ tract
Inducible (Pathologic)
-_______ and Pain by inflammatory mediators
Brain (_____): discovered in 2002
-found to be selectively inhibited by ________ andphenacetin and some ______
-Acetaminophen is a mild analgesic and antipyretic
-Suitable for mild to moderate pain.
-Its site of action has recently been identified as a COX-3 isoenzyme, a variant of the _____ enzyme
reproductive inflammation COX-3 acetaminophen NSAIDs COX-1
- __________ is a chronic, progressive, degenerative joint disease
Symptoms: Pain in DIP/ Morning stiffness/ Discomfort/ No systemic symptoms
-Diminished QOL
-Pain relieved by ____
-Radiographic findings: Narrowed ________
-Prevalence of OA is expected to increase primarily due to the world’s aging population and the increasing prevalence of
osteoarthritis
rest
joint space
Osteoarthritis
- Most common form of joint disease
- 90% population has radiographic features of OA in weight bearing joints by age ___!!
- Arthropathy includes degeneration of _____ and ______ of bone at articular margins
- Hereditary and mechanical factors involved
- _____ is felt in joint (Initially small, then large joints)
- No laboratory finding
- Radiology: Lipping of marginal bone, narrowing of joint space, thickened subchondral bone
40
cartilage, hypertrophy
crepitus
Osteoarthritis
-Several guidelines for the management of OA pain
-Continues to be ____ treated!!!
-Inadequate pain therapy commonly reduces quality of life.
-Lack of understanding of the principles of pain therapy
-Misconceptions in regard to pain medications
-Unwarranted fears of treatment side effects.
Patient-related factors:
-Inadequate patient education
-Reluctance to report pain/ take pain medications.
under
Pain of Osteoarthritis
Pain is classified as:
________: adaptive (protective) because it prevents further injury and/or promotes ______
________ pain: maladaptive (pathologic) with no protective function/ results from tissue damage
_______ pain: Direct injury or dysfunction of the nervous system (post-herpetic neuralgia, diabetic neuropathy)
_________ pain is associated with abnormal neural processing in the absence of neurologic deficit or peripheral abnormalities
nociceptive healing inflammatory pain neuropathic pain functional
Pain of Osteoarthritis
- OA pain mechanisms are unknown
- Peripheral inflammatory in origin caused by damage occurring around the ____ (capsule, ligaments, menisci, periosteum, subchondral bone)
- Severe OA pain associated with high expression of inflammatory _____ and ________ in the joint tissues.
- Involve both _______ and ______ sensitization of pain.
- Recent data suggests that there might be a neuropathic component
joint
cytokines, neuropeptides
peripheral, central
Management of Osteoarthritis
- _______ and ______ pain syndromes are generally responsive to analgesics, such as acetaminophen, NSAIDs, COX-2 selective inhibitors and opioids
- ______ and _____ pain syndromes often require the use of adjuvant analgesics such as ______ (Gabapentin and Pregabalin) and antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors
- _____ therapy may require combining different drug therapies
nociceptive, inflammatory
neuropathic, functional
anti-convulsants
optimal
Acetaminophen
-Acetaminophen: _____ and ______ drug
-It lacks potent _________ activity
-Recent reports suggest that acetaminophen acts as a _____ (endogenous cannabinomimetic substance)
-It activates the ________CB1 receptors in the central nervous system (FDA, 2009)
COX-3 inhibitor
-Recommended oral dose: 325 mg every 4-6 hours, as needed, to a maximum daily dose of 3250 gm
-Combined with ______( and COX-2 Inhibitors)
-Opioids (Codeine, hydrocodone)
analgesic, antipyretic anti-inflammatory prodrug cannabinoid NSAIDS
FDA advisory
- Acetaminophen toxicity is a leading cause of Acute ____ failure, resulting in an estimated 400 deaths in the US each year.
- Many of these events are happening because patients are unknowingly taking too much of the drug.
liver
Acetaminophen: March 2017
- FDA announced that it is limiting the maximum amount of Acetaminophen in products to _____ mg per tablet, capsule or other dosage unit.
- FDA : ‘This will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, increased need for liver transplant and death.’
325
Acetaminophen Toxicity
- Excessive use of Acetaminophen can damage the liver. Toxicity from Acetaminophen is not from the drug itself but from one of its metabolites, _____
- In the liver, the cytochrome P450 enzymes CYP 2E1 and CYP3A4 are responsible for the conversion of paracetamol to NAPQI
- Acetaminophen hepatotoxicity is, by far, the most common cause of acute liver failure in the United States
N-acetyl-p-benzoquinone (NAPQI).
Acetaminophen Toxicity
- The antidote is ________ also called N-acetylcysteine or ____)
- It acts as a precursor for ______ helping the body regenerate enough to prevent damage to the liver
- liver ____ is often required if damage to the liver becomes severe
Acetylcysteine
NAC
glutathione
transplant
NSAIDs (Propionic acid)
- Ibuprofen, Naproxen, Flurbiprofen
- ______, _______, ______
- Inhibit ____ mediated generation of pro-inflammatory eicosanoids
- Traditionally inhibit both COX 1 and COX 2
- Block the hydrophobic channel of the COX protein where ________ binds
- Result in dyspepsia, gastro pathology and hemorrhagic erosions
- Decrease ____ blood blow resulting in renal ischemia and papillary necrosis
anti-inflammatory, analgesic, antipyretic
COX
arachidonic acid
renal
NSAIDs: Oxicam-like Drugs
- Piroxicam
- _______ COX inhibitor
- Inhibits _______ and _______
- Effective for treatment of _____
- well absorbed, ____ t1/2 once a day dosing
- 30% patients report adverse effects
- Gastrointestinal effects
- Gastric Ulcer formation may occur
- Prolongs bleeding time due to__________?-Dizziness and Rash common
non-selective collagenase, proteoglycanase arthritis long thromboxanes
NSAIDs: Indomethacin
-______ derivatives( Indomethacin, Etodolac, Diclofenac and Ketorolac)
-Indomethacin (Indocin) is used when ___ is ineffective or not tolerated
-Inhibit ________ and promote the incorporation of arachidonic acid into triglycerides, thus reducing its availability for COX
-Used for Acute gouty arthritis, Rheumatoid arthritis and spondylitis
-Side effects include CNS effects
-Dizziness, Headache, Confusion
-Ocular effects: Blurred vision
Indomethacin promotes closure of ___ in premature infants
-SULINDAC : Chemically related to Indomethacin
Acetic acid
ASA
cycoloogenase
pda
NSAIDs: COX-2 Selective Inhibitors
- Celecoxib, Valdecoxib are sulfonic acid derivatives with ___ affinity for COX 2
- They have anti-inflammatory, antipyretic and analgesic properties without the ______/_______ damaging activity of NSAIDs
- Approved for OA/ RA/ ankylosing spondylitis, acute pain and dysmenorrhea and familial adenomatous polyposis (p53 genetic polymorphism/ mutations)
- Possibly fatal ________ events may occur
- Increased hypertension, edema, heart failure
- ______ (Vioxx) COX-2 selective NSAID marketed by Merck & Co.
- Worldwide over 80 million people were prescribed Rofecoxib
- 88,000 reported cardiac adverse effects
100x
antiplatelet, gastrointestinal
thromboembolic
Rofecoxib
OPIOIDS in OA
- Opioids: suited for moderate-to-severe pain
- Use of opioids in treatment of chronic _______ pain remains controversial!
- Development of ______ or ______ to opioids
- Opioid use :sedation, sleep disturbances, respiratory depression and upper airway obstruction, constipation, urinary retention, reduced immune function, and endocrine dysfunction.
- Tolerance, physical / psychological dependence
- _______: Opioid receptor agonist with weak SSRI
- US: Oxycodone, Hydrocodone, Codeine, Morphine, Methadone and transdermal Fentanyl.
non cancer
tolerance, hyperalgesia
Tramadol
Adjuvant Agents
_______: Amitriptyline : Exact mechanism unknown except increase __ levels
__________: Norepinephrine and serotonin reuptake inhibition thus enhancing endogenous pain modulating pathways
(Duloxetine, Venlafaxine)
Local ______: Sodium channel blockade
_______: Gabapentin and Pregabalin. Modulation of the alpha-2/delta-1 subunit of the voltage-dependent chloride channels centrally
NE
serotonin-norepinephrine
local anesthetics
GABA Mediators
Intra-Articular Injections
- Injections are available for treating ____ OA
- _______ and ________
- Short-term pain relief/ increased quadriceps strength
- Efficacy and utility of intra-articular Hyaluronate therapy is not well established.
- The Agency for Healthcare Research and Quality commissioned a systematic review of 42 trials derived primarily from 6 meta-analyses involving 5843 patients
- The expert group noted minimal positive effect s on pain and function from treatments compared with control saline injections.
knee
corticosteroids, hyaluronates
Monoclonal antibodies in OA
- _______(Pfizer) May Be Breakthrough Treatment Option for Osteoarthritic Knee Pain’ : Medscape 2009
- ‘Treatment with Tanezumab was associated with a reduction in joint pain and improvement in function, with mild and moderate adverse events in osteoarthritis of the knee’ : Late 2009
- FDA has cited safety concerns during Phase III: American Pain Society 2010
- Pfizer withdraws Tanezumab from US market (2010)
- ‘If you have been injured by Tanezumab, please be advised that the FDA is having an important meeting on this matter on September 13, 2011’ (Pfizer, 2011)
Tanezumab
Rheumatoid Arthritis
- A chronic, systemic, autoimmune inflammatory disease of unknown cause.
- Primarily attacks the joints but also skin, lungs, vessels and muscles
- Persistent ______ polyarthritis affecting hands and feet
- Extra-articular involvement of skin, heart, lungs, and eyes
- _______ targeting of joint proteins with local release of cytokines, TNF, growth factors
- Induction of ___/___ enzymes
- Macrophages release ______ and protease
- Lymphocytic activity results in immune complex formation
- Further damage and inflammation
symmetric
autoimmune
COX2/LOX
collegenase
Rhematoid Arthritis
- No test results are pathognomic for RA.
- The presence of both ______ antibodies* and ______r^ is highly specific for rheumatoid arthritis (RA)
- *Anti-cyclic citrullinated peptide (anti-CCP) antibody testing (in 2010 was added to the ACR/EULAR Rheumatoid Arthritis Classification Criteria)
- ^ RF: autoantibody against __ (elevated in other conditions – bacterial endocarditis; SLE etc)
- 3 cases per 10,000
- increasing with age and peaking at age 35-50 years.
- prevalent in some Native American groups ( 5-6%)
- Women are affected approx. 3 times more often than men
anti-CCP
rheumatoid factor
IgG
treatment of RA
______ care requires an integrated approach of pharmacologic and non-pharmacologic therapies.
Primary Objectives:
Reducing inflammation and pain
Preservation of _____ and prevent _____
Active patient (family) participation
Explaining the rationale or the therapy, the objective, design and implementation of the therapeutic program.
optimal
function, deformity
Non-pharmacologic
Many different therapies
-_______
Hot/cold applications; TENS; massage/Spa therapy, rest; Assistive devices (Splints)
-_______
diet, counseling, stress reduction (depression); relaxation techniques; Tai Chi, Yoga;
-Alternative Medicine
Supplements, Magnets, acupuncture, Homeopathy
-Surgery
Reconstruction (tendon, ligament); arthroplasty; synovectomy, osteotomy, joint debridement, Decompression of spinal/peripheral nerves
PT
rehabilitation
Pharmacological Treatment (RA)
-Treatment success requires ____ effective pharmacological intervention.
-Start _______ such as Methotrexate immediately
Pharmacologic agents:
________: COX-1 & COX-2 inhibitors
_______ (PO/ IA)
______ DMARDs (disease-modifying antirheumatic drugs)
______ DMARDs
Combination DMARDs _____ + ____ inhibitor)
early DMARDs NSAIDs Glucocorticoids Nonbiologic Biologic MTX, TNF
Glucocorticoids
-Corticosteroids are used in 60-70% patients of Rheumatoid Arthritis
-They cause _____ relief of pain
-They slow Bone _____ and prevent new bone erosion
-Commonly used in patients with RA to bridge the time until DMARDs are effective.
Intra-articular injections
-Symptomatic relief
-No more than four times a year (each joint)
-_______ may develop
-May result in secondary _____ infections and increase in blood ____
immediate erosion cushings syndrome fungal sugar
Disease modifying agents for Rheumatoid Arthritis (DMARDs)
Non-Biologic and Biologic DMARDs
Early therapy with ______ DMARDs has become the standard of care.
-may _____ the need for other anti-inflammatory or analgesic medications.
-Delay onset of symptoms: >3 to 6 months
-bridging therapy with ____ ± _____ to reduce pain and swelling.
Newer Biologic DMARD therapies are immunosuppressive in nature.
-May mask serious bacterial and sometimes ____ infections.
-Leukopenia & thrombocytopenia
non-biologic
eliminate
NSAIDs, corticosteroids
fungal
DMARDs: Methotrexate
-Methotrexate is an _____ used since the 1950s
-______ analogue that may increase Adenosine levels
- ______ is a potent endogenous antiinflammatory mediator that inhibits neutrophil adhesion, phagocytosis and superoxide generation
-Methotrexate also causes ______ of activated CD4 and CD8 T cells but not resting ones
-Given once a week..full effect in 4-6 weeks.
0CBC monthly and liver and renal function every 1-3 months
-Gastric irritation, stomatitis, pneumonitis (1%); Leukopenia, thrombocytopenia,
-_______ with fibrosis & cirrhosis.
Increase with alcohol, diabetes, obesity and renal ds
anti metabolite folic acid adenosine apoptosis hepatotoxicity
DMARDs: Leflunomide
-Activated lymphocytes proliferate and synthesize large quantities of cytokines, which requires synthesis of RNA or DNA
-Leflunomide is a ______ synthesis inhibitor, specifically blocking synthesis of UMP (Uridylate)
-Reduces _-cell and _-cell populations
Single daily 20 mg dose.
-Currently approved for use in RA, SLE and myasthenia gravis
-Also prolongs transplant ____ survival
pyrimidine
T, B
graft
DMARDs: Leflunomide
-Active metabolite undergoes extensive entero-hepatic circulation
-This drug takes up to 2 years to be undetectable in ____
-___ counts and ____ enzymes must be monitored.
Adverse effects:
Diarrhea and reversible alopecia
Stomatitis; xerostomia, oral candidiasis, enlarged salivary glands
Increased susceptibility to infection.
Hepatotoxicity; Leukopenia, thrombocytopenia (rare)
If Leflunomide must be removed quickly from a pts system, they should be given _______ (binds to___ and does what?)
plasma CBC liver cholestyramine bile acids
DMARDs: Hydroxychloroquine
______ agent – Mechanism unclear:
inhibits ______ of eosinophils, inhibits locomotion of neutrophils, and impairs complement-dependent antigen-antibody reaction
Full effect in 3-6 months.
-Relatively ____ toxicity than other DMARDs. Often used for mild disease or in combinations with other DMARDs.
Adverse effects:
Pigmentary ____ causing visual loss (rare) BUT may be very sensitive to bright lights.
Reversible neuropathies & myopathies
antimalarial
chemotaxis
lower
retinitis
DMARDs: Minocycline
______ – Mechanism:
matrix metalloproteinase inhibitor (MMPI)
-Anti-inflammatory effects may result from inhibition of inflammatory cell migration and transformation of lymphocytes
-Usually used in combination with ______
Adverse effects:
Mainly ______
Nausea and diarrhea
antibiotic
DMARDs
dizziness
DMARDs: Gold
-A chemically inert compound
-Acts by inhibition of ______ responsible for Inflammation
-Erratically absorbed ______
-_______ route preferred
-Highly plasma protein bound
0Excreted through Kidneys
Treatment with Gold: _______
macrophages
orally
intramuscular
chrysotherapy
DMARDs: Cytotoxic Drugs
-________ (Cytoxan)
-Decreases Bone ____ of arthritis
Prevents further progress of disease
-Used only in patients where other anti-inflammatory drugs have _____
Side effects are vast and limit use of these drugs
Dental: Mucositis, Glossitis, Ulcers
cyclophosphamide
erosion
failed
DMARDs: Penicillamine
-Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964
-Effective in acute , severe Arthritis
-Reduces pain, stiffness and swelling
It reduces numbers of _-lymphocytes, decreasing ___, decreasing rheumatoid factor, and preventing collagen from cross-linking
-Bone marrow suppression, dysgeusia, anorexia, vomiting and diarrhea are the most common side effects, occurring in ~20-30% of the patients treated with penicillamine
T, IL-1
Biologic DMARDs \_\_\_\_\_\_\_\_ Golimumab (Simponi); Etanercept (Enbrel); Infliximab (Remicade); Rituximab (Rituxan); Adalimumab (Humira); Certolizumab (Cimizia) \_\_\_\_\_\_ receptor antagonist Anakinra (Kineret) Interleukin _ receptor inhibitor Tocilizumab (Actemra) \_\_\_\_\_ activation inhibitor Abatacept (Orencia)
TNF
IL 1
IL 6
T-CELL
