Pain, Inflammation and Anti-Inflammatory Flashcards
(43 cards)
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
