22) NSAIDs, Gout, RA Flashcards
Inflammation
- Response to cell injury
- Primarily occurs in vascularized connective tissue
- Often involves the immune response
Inflammation causes
- Pain
- If cell injury, can result in a chronic condition of pain and tissue damage (like rheumatoid arthritis)
Drugs often used to control pain/inflammation
- NSAIDs
- Acetaminophen
Treatment strategies that target the immune processes
- Glucocorticoids
- Disease-modifying antirheumatic drugs (DMARDs)
Gout
- Metabolic with precipitation of uric acid crystals in joints
Treatment of Gout
- Aacute episode treatment targets inflammation
- Chronic gout treatment targets both inflammatory processes and the production and elimination of uric acid
Why NSAIDs exacerbate asthma?
- Inhibiting prostaglandins potentiates the leukotriene pathway
- Leukotriene pathway worsens asthma
Functions of the prostaglandins
- Stimulate hypothalamus to increase body temp
- Stimulate immune cells to cause inflammation
- Sensitize nerves to pain
- Produce protective mucous in the stomach
- Initiate blood clotting
- Constrict or dilate blood vessels
Prostaglandin function is inhibited by
- NSAIDs
Major difference between the MOA of aspirin and other NSAIDs
- Aspirin acetylates and thereby IRREVERSIBLY inhibits cyclooxygenase
- Inhibition produced by other NSAIDs is reversible
The irreversible action of aspirin results in
- Longer duration of antiplatelet effect
- Basis for its use as an antiplatelet drug
Arachidonic acid derivatives are important mediators of
- Inflammation
- Cyclooxygenase inhibitors reduce inflammation
NSAIDs also suppress
- Prostaglandin synthesis in the CNS stimulated by pyrogens (produce fever)
- Reduce fever (antipyretic action)
3 therapeutic dose ranges of aspirin
- The low range (<300 mg/d) = reduce platelet aggregation
- Intermediate doses (300–2400 mg/d) = antipyretic and analgesic effects
- High doses (2400–4000 mg/d) = anti-inflammatory effect
Release of phospholipids from damaged cell membrane initiates
- Arachidonic acid cascade COX
- Synthesizes prostaglandins
Analgesics act on
- Both PNS and CNS
Analgesics include
- Acetaminophen (Tylenol), known as Paracetamol in Europe (APAP)
- NSAIDs: salicylates (aspirin), ibuprofen, naproxen …
- Others non-OTC (e.g. Opioids as morphine/ oxycodone/ coxib/ and others)
OTC NSAIDs generic/brand names
- Ibuprofen (Advil)
- Naproxen (Aleve, All day relief, Naprosyn)
- Aspirin (Bufferin, Ecotrin, Bayer aspirin)
- Mefenemic acid (Ponstel)
Ibuprofen (Advil) classification
- Propionic acid derivative
All of the OTC NSAIDs site of action
- CNS and PNS
All of the OTC NSAIDs uses
- Analgesic
- Anti-inflammation
- Anti-pyretic
- Antiplatelet (Blood thinning)
Naproxen (Aleve, All day relief, Naprosyn) classification
- Propionic acid derivative
Aspirin (Bufferin, Ecotrin, Bayer aspirin) classification
- Salicylates: Acetyl salicylic acid (ASA)
Mefenamic acid (Ponstel) classificaiton
- Fenamate
Acetaminophen brand names
- Fever-all
- Tylenol
Acetaminophen classification
- Acetyl para-aminophenol (APAP)
Acetaminophen site of action
- CNS
Acetaminophen uses
- Analgesic
- Antipyretic
- NOT an anti-inflammatory
Aspirin MOA
- Non-selective and irreversible COX 1 and 2 inhibitor
Ibuprofen, Naproxen, and mefenamic acid MOA
- Non-selective and reversible COX 1 and 2 inhibitor
Aspirin, Ibuprofen, Naproxen, Mefenamic acid (NSAIDs) side effects
- Risk of bleeding (in ASA), bruising
- NSAIDs allergy (contraindication)
- GI ulcers, heartburn, nausea
- Renal monitoring: increase BUN, serum creatinine
- Exacerbate asthma
Aspirin DOA
- 4-6 h
Ibuprofen and Mefenamic acid DOA
- 6-8 h
Naproxen DOA
- 12 h
NSAIDs metabolism and excretion
- Hepatically (liver) metabolized
- Renally excreted
Metabolism definition
- Process where body breaks down and converts medication into active chemical substances
Symptoms of NSAID toxicity
- Ringing in the ears
- Nausea and vomiting
- Abdominal pain
- Fast breathing rate
- Fever
- Low blood glucose and potassium
Complications with NSAID toxicity
- Swelling in the brain
- Seizures
- Low blood sugar
- Cardiac arrest
Selective COX-2 inhibitor
- Celecoxib (Celebrex)
Selective COX-2 inhibitor advantage
- Reducedrisk of GI effects (gastric ulcers and serious GI bleeding)
COX-2 inhibitors risks and side effects
- Same risk of renal damage as COX inhibitors (nephrotoxicity)
- Increase risk of heart attacks or stroke, hypertension
- Increase GI bleeding
- Anemia
Celebrex cannot be given to
- Patients with sulfur allergues (sulfa drug)
Celecoxib (Celebrex) metabolism
- Hepatic
APAP details
- MOA unknown
- Reduces COX activity
- Liver metabolized, renal excretion
- DOA = 4-6 h
APAP side effects
- Nausea, vomiting
- Constipation
- Increased aspartate aminotransferase
- Rash, pruritus
- Hypokalemia, hyperglycemia
- Hepatotoxicity
In cases of APAP overdose,
- The sulfate and glucuronide pathways become saturated
Under normal conditions, NAPQI is detoxified by
- Conjugation with glutathione
More APAP is shunted to the cytochrome P450 system to produce
- NAPQI
- As a result, hepatocellular supplies of glutathione become depleted
APAP causes NAPQI to remain in its toxic form in the liver
- Reacts with cellular membrane molecules
- Hepatocyte damage and death
- Acute liver necrosis
APAP when following a therapeutic dose in normal patients
- Mostly converted to nontoxic metabolites by conjugation with sulfate and glucuronide (phase II metabolism)
- Small portion oxidized via cytochrome P450 system
Acetaminophen toxicity
- More than 4 g per 24 hours
Signs and symptoms of acetaminophen toxicity occure in 3 phases
- Phase 1 (hours after overdose)
- Phase 2 (24-72h)
- Phase 3 (3-5 days)
- Phase 1 acetaminophen toxicity (hours after overdose)
- Nausea and vomiting
- Pale appearance
- Sweating
Phase 2 acetaminophen toxicity (24-72h)
- Jaundice, signs of liver damage (i.e. right upper quadrant pain followed by acute renal failure)
Phase 3 acetaminophen toxicity (3-5 days)
- Liver necrosis
- Low blood sugar
- Coagulation problems
- Brain swelling
- Multiple organ failure and death
Liver damage results from one of APAP metabolites
- N-acetyl-p-benzoquinone imine (NAPQI)
Acetaminophen overdose antidote/treatment
- N-acetylcysteine (NAC)
- IV form not the OTC oral product (that becomes GSH)
ASA vs. APAP structure
- ASA = salicylate
- APAP = para-amino phenol derivative
ASA vs. APAP indication
- ASA = analgesic, antipyretic, anti-inflammatory
- APAP = analgesic, antipyretic
ASA vs. APAP gastric side effects
- ASA = yes (inhibition of COX-1 in the gastric area)
- APAP = not major
ASA vs. APAP at low doses
- ASA = has anti-platelet activity (mediated by COX-1)
- APAP = no anti-platelet activity
ASA vs. APAP antidote
- ASA = no specific
- APAP = N-acetylcysteine (NAC)
DMARDs
- Disease-modifying antirheumatic drugs
- Anti-inflammatory actions in several connective tissue diseases
- Can slow, or even reverse joint damage
DMARDs activity/progression
- Slow acting because it may take 6 weeks to 6 months for their benefits to become apparent
Corticosteroids
- Can be considered anti-inflammatories with intermediate rate of action (ie, slower than NSAIDs but faster than other DMARDs)
- Too toxic for routine chronic use
Corticosteroid use
- Temporary control of severe exacerbations
- Long-term use in patients with severe disease not controlled by other agents
Glucocorticoid side effects
- Decreased growth in children
- Glaucoma
- Centripetal distribution of body fat
- Osteoporosis (negative calcium balance)
- Increased risk of infection (impaired wound healing)
- Hirsutism
- Increased appetite
- Emotional disturbances (euphoria, depression)
- Peptic ulcer
- Hypertension
- Peripheral edema
- Hypokalemia
Glucocorticoid hyperglycemia/diabetes side effect mechanism
- Gluconeogenesis
Glucocorticoid central obesity, moon face, buffalo hump side effect mechanism
- Dramatic redistribution of body fat
Glucocorticoid muscle weakness and wasting side effect mechanism
- Breakdown of proteins
- Diversion of amino acids to glucose production
Glucocorticoid weight gain side effect mechanism
- Increased appetite (CNS effect)
- Increased need for insulin over time (because of gluconeogenesis which results from weight gain)
- Mineralocorticoid activity (Na+/water retention)
Glucocorticoid osteoporosis side effect mechanism
- Decreased reabsorption of calcium by the kidney
Glucocorticoid avascular necrosis of femur head side effect mechanism
- Increased levels of serum lipids
- Results in both increased formation of microemboli in bone nutrient arteries, and fat-related blockage of venous flow from bone (lipolysis)
- IRREVERSIBLE
Glucocorticoid skin bruising and poor wound healing side effect mechanism
- Anti-proliferative effect
Glucocorticoid hirsutism and acne side effect mechanism
- Due to ACTH-mediated increase of adrenal androgens
Glucocorticoid increased infections side effect mechanism
- Immunosuppression
Glucocorticoid hypomania, depression, psychosis side effect mechanism
- Normal cortisol levels maintains emotional balance
DMARDs names
- Abatacept (T-cell modulator)
- Anti-IL-1
- Anti-IL-6
- Anti-TNF-alpha
- Belimumab
- Cyclosporine
- Hydroxychloroquine, chloroquine
- Leflunomide
- Methotrexate
- Penicillamine
- Rituximab
- Sulfasalazine
- Gol compounds
- Tofacitinib
Abatacept MOA
- Interfere with activity of T-lymphocytes
Abatacept toxicity when used for RA
- Infection
- Exacerbation of COPD
Anti-IL-1 drug names
- Anakinra
- Rilonacept
- Canakinumab
Anti-IL-1 drugs MOA
- Recombinant human IL-1 receptor antagonist
- Acts as a cysteine inhibitor
Anti-IL-1 drugs toxicity when taken for RA
- Infection
- Neutropenia
Anti-IL-6 drug names
- Tocilizumab
Tocilizumab MOA
- IL-6 antagonist
Tocilizumab (anti-IL-6 drug) toxicity when taken for RA
- Upper respiratory tract infections
- Hypertension
- Increase LFT
Anti-TNF-alpha drug names
- Infliximab
- Etanercept
- Adalimumab
- Golimumab
- Certolizumab
Anti-TNF-alpha drugs MOA
- Biological agent
- Inhibits action of TNF-alpha
Anti-TNF-alpha drugs toxicity when taken for RA
- Infection
- Lymphoma
- Hepatotoxicity
- Hematological effects
- Cardiovascular toxicity
Belimumab MOA
- Anti-B cell activating factor (MAb)
- Inhibits B lymphocyte stimulator (BLyS)
Belimumab toxicity when taken for RA
- Nausea, vomiting
- Respiratory tract infection
DMARD drugs that interfere with T-lymphocytes
- Cyclosporine
- Hydrocychloroquine, chloroquine
- Leflunomide
- Sulfasalazine
Cyclosporine toxicity when taken for RA
- Nephrotoxicity
- Hypertension
- Liver toxicity
Hydroxychloroquine, chloroquine toxicity when taken for RA
- Diarrhea
- Dermatitis
- Hematological abnormalities
Leflunomide toxicity when taken for RA
- Rash
- GI disturbance
- Myopathy
- Neuropathy
- Ocular toxicity
Methotrexate MOA
- Cytotoxic drug that reduces the number of immune cells
Methotrexate toxicity when taken for RA
- Teratogenic
- Hepatotoxicity
- GI
- Skin reaction
Penicillamine toxicity when taken for RA
- Nausea
- Mucosal ulcers
- Hematotoxicity
- Hepatotoxicity
- Teratogenicity
Rituximab MOA
- Interfere with the activity of B-lymphocytes
Rituximab toxicity when taken for RA
- Proteinurea
- Dermatitis
- GI
- Hematological
Sulfasalazine toxicity when taken for RA
- Cardiac toxicity
Gol compounds MOA
- Interfere with the activity of macrophages
Tofacitinib MOA
- Janus kinase inhibitor
Tofaciitinic toxicity when taken for RA
- Infection
- Neutropenia
- Anemia
- Increased LDL and HDL
Colchicine
- A selective inhibitor of microtubule assembly
Paclitaxel
- Stabilizes and protects microtubule against disassembly
Drugs used in gout
- Microtubule assembly inhibitors
- Uricosurics
- Xanthine oxidase inhibitors
- Uricase
Microtubule assembly inhibitors
- Colchicine
- Taken orally
Colchicine side effects
- Diarrhea
- Liver and kidney damage with overdose
Uricosurics
- Probenecid
- Lesinurad
- Both taken orally
Uricosurics (probenecid, lesinurad) MOA
- Inhibition of renal reabsorption of uric acid
Xanthine oxidase inhibitors
- Allopurinol
- Febuxostat
- Both taken orally
Xanthine oxidase inhibitors (allopurinol, febuxostat) MOA
- Allopurinol = irreversible inhibior
- Febuxostat = reversible inhibitor
Xanthine oxidase inhibitors (allopurinol, febuxostat) side effects
- GI upset
- Bone marrow suppression
Uricases
- Pegloticase
- IV administration
Pegloticase MOA
- Recombinant mammalian uricase
- Converts uric acid to soluble form allantoin
Pegloticase side effects
- Rapid change in uric acid levels can precipitate gout
