Chemical:

1.histamine

2.serotonin

3. prostaglandins (PGE2, PGI2, PGD2)

4.bradykinins

5.leukotrienes (LTs)

Chemotactic:

1. platelet-activating factor (PAF)

2. complement factor C5a, LTB4

Immunologic:

1. IL-1

2. tumor necrosis factor (TNF) in concert with other cytokines

3.growth factors (IL-2, IL-6, IL-8)

Others:

1. endothelial intercellular adhesion molecule-1 (ICAM-1),

2. oxygen radicals

Nitric oxide

may caused by

1. infection (viral/bacterial)

2. inflammation

3. graft rejection

4. malignancy

Infection, inflammation, etc., can enhance the formation of cytokines such as IL-6, IL-1β, TNFα and interferons (act as endogenous pyrogens)

initial phase of thermoregulatory response: Mediated by ceramide release (triggers IL-1β formation) in neurons of the pre-optic area of the hypothalamus

later phase response:

1. Is mediated by induction of cyclooxygenase (COX-2) and formation of PGE2

2. PGE2  acts on EP receptors on thermosensitive neurons which triggers the hypothalamus to elevate body temperature by increase heat generation and decrease heat loss

Peripheral terminals of primary afferent fibers that sense pain (nociceptors)can be activated by stimuli such as heat, acids and pressure

During tissue injury, inflammatory mediators (e.g., bradykinin, H+, serotonin, LTs, ATP, PGs, nerve growth factor) increase the sensitivity of nociceptors and potentiate pain perception

Neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) may also be involved in the generation of pain

PGE2 and PGI2 reduce the threshold of the stimulation of nociceptors leading to peripheral sensitization

PGE2, PGD2, PGI2 and PGF2α contribute to central sensitization (an increase in the excitability of spinal dorsal horn neurons that cause hyperalgesia and allodynia

TRUE

FALSE

COX-2 increases PGE2 biosynthesis which stimulates pain pathways

5-LOX-derived leukotrienes activate the surrounding endothelium to recruit inflammatory cells

Release of cytokines such as TNF, growth factors and interleukins which induce COX-2 expression

Macrophages release collagenase and proteases while lymphocyte activity leads to the formation of the immune complex (both processes further damage joint tissue)

True

False

Salicylates: acetylsalicylic acid (aspirin) and its derivative

Propionic acid derivatives: ibuprofen, naproxen, ketoprofen and flurbiprofen

Acetic acid derivatives: indomethacin, diclofenac, nabumetone, sulindac and etodolac

Oxicam derivatives: piroxicam, meloxicam

Fenamate derivatives: mefenamic acid

NSAIDs inhibit COX leading to a decrease production of PGs and thromboxanes

COX-1: a constitutive enzyme involved in physiologic activities such as vascular homeostasis, maintenance of renal and GI blood flow

Non-selective NSAIDs inhibit both COX-1 and COX-2

COX-2: an inducible enzyme involved in inflammation,  fever and pain.  It can be induced by cytokines and endotoxins

Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity

A decrease in the release of vasodilator PGE2 and PGI2 means less vasodilation and indirectly, less edema

Inhibition of the migration of leukocytes and macrophages into inflammationsites

Stabilization of lysosomal membranes

Effective against pain of low to moderate intensity

Decreased PG generation means less sensitization of nociceptive nerve endings to the action of bradykinin, histamine and other chemical mediators

Effective when inflammation has caused peripheral and/or central sensitization of pain perception

Due to a decrease in the COX-2 mediated PGE2 generation in response to bacterial or inflammatory pyrogens (which is responsible for elevating the hypothalamic set-point for temperature control)

NSAID do not influence normal body temperature or when it is elevated by such factors such as exercise or increases in ambient temperature

Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective PGI2 and PGE2

Inhibition of PG-induced inhibition of gastric acid secretion

Local irritation from contact of orally administered drug with gastric mucosa

Increased generation of products of the lipoxygenase pathway

COX-2 selective NSAIDs can cause myocardial infarction, stroke and thrombosis

Due to depression of COX-2 dependent PGs (PGI2) formed in the vasculature and kidney without an effect on COX-1 catalyzed formation of platelet thromboxane TXA2

PGI2 inhibits platelet aggregation and constrains the effect of prothrombotic and atherogenic stimuli by TXA2

Promote retention of salt and water by

1. Inhibiting PG-induced inhibition of reabsorption of chloride

2. inhibition of action of ADH

Promote hyperkalemia via

1. Suppression of PG-induced secretion of renin

2.Increased reabsorption of K⁺

Chronic uses of high doses of NSAIDs can lead to analgesic nephropathy (a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule and sterile pyuria)

No effect on renal function or blood pressure in normal human subjects

In patients with congestive heart failure, hepatic cirrhosis, chronic renal disease and hypovolemia, inhibition of vasodilatory PG production leads to a decrease in renal blood flow and glomerular filtration rate

TRUE

FALSE

true

false

true

false

Acts by acetylating COX-1 and COX-2 leading to inhibition of their activity

Acetylated COX-2 can form 15-epi-lipoxins which have potent anti-inflammatory actions

Antipyretic dose < anti-inflammatory dose

Large doses of salicylates have been used for anti-inflammatory and anti-rheumatic actions

Salicylates are metabolized by the liver into salicyluric acid (glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide

Kidney excretion via carrier facilitated transport mechanism for weak organic acids

Rate of urinary excretion is higher in alkaline than in acid urine

Rate of urinary excretion is also enhanced  by a higher rate of urine flow (polyuria)

Salicylate clearance is reduced, and salicylate exposure is significantly increased in the elderly

Plasma t1/2 for aspirin is about 20 minutes and for salicylate is 2-3 h.  After a large dose, plasma t1/2 of salicylate may rise to 15-30 h

Direct stimulation of the respiratory center in the medulla in medium to large doses

Hyperventilation is characterized by an increase in the depth and a pronounced increase in respiratory rate

The plasma CO2 tension (PCO2) falls, and primary respiratory alkalosis ensues

Increase in O2 consumption and CO2 production (especially in skeletal muscle) in anti-inflammatory doses: Mechanism is due to salicylate-induced uncoupling of oxidative phosphorylation

Hyperventilation is characterized by an increase in depth of respiration and only a slight increase in rate

Increased alveolar ventilation balances the increased CO2 production and thus plasma PCO2 does not change or decreases slightly

Increased renal excretion of bicarbonate which is accompanied by Na+ and K+ excretion

Plasma bicarbonate is lowered, and blood pH returns to normal

This is the stage of compensatory respiratory acidosis often seen in adults given intensive salicylate therapy

The enhanced production of CO2 outstrips its alveolar excretion because of direct salicylate-induced depression of respiration

Plasma PCO2 increases

Blood pH decreases

Metabolic acidosis is caused by the accumulation of strong acids such as sulfuric and phosphoric acids

true

false

In large doses, salicylates can cause hepatic injury after several months of treatment.  The injury is reversible after discontinuation of treatment

Salicylates may play a role in the severe hepatic injury and encephalopathy associated with Reye’s syndrome (consequence of viral infection in children

Large doses of salicylates may cause hyperglycemia and glycosuria and  can deplete liver and muscle glycogen

Retention of salt and water, as well as acute reduction in renal function (↓ RBF and GFR) in patients with congestive heart failure, renal disease and hypovolemia

true

false

True

false

low dose (1-2 g/day)

intermediate (2-3g/day)

large doses (>5g/day)

true

false

Absorption of salicylates can be reduced by emesis, gastric aspiration and administration of activated charcoal

Administration of intravenous fluids to correct acid-base imbalance

hemodialysis

true

false

true

false

true

false

Nabumetone is a ketone prodrug

Compared to other NSAIDs, it has a preferential activity against COX2

Converted in liver to active metabolite, 6-methoxy-2-napthylacetic acid

Low incidence of GI disturbances

Uses: rheumatoid arthritis and osteoarthritis

Has a greater selectivity (about 100 times) for COX-2 than COX-1 isoenzyme

Has anti-inflammatory, antipyretic and analgesic properties similar to traditional NSAIDs but does not share the anti-platelet actions of COX-1 inhibitors

Relative to traditional (non-selective) NSAIDs, the safety profile of selective COX-2 inhibitors is uncertain due to the uncovering of increased thrombogenicity with clinical use

Celecoxib is the only FDA approved drug in this class

Uses: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and primary dysmenorrhea

true

false

true

false

true

false

Has no effect on the respiratory system

Has no effect on platelet aggregation

Has no effect on uric acid excretion or on acid-base balance

Does not cause gastric irritation or bleeding

true

false

Principal toxicity associated with over dosage is potentially fatal hepatic necrosis

Mechanism involves covalent binding of the toxic alkylating metabolite, NAPQI to sulfhydryl groups in glutathione (GSH) to form mercapturic acid

After GSH is depleted, NAPQI combines with sulfhydryl groups on hepatic proteins leading to hepatic necrosis.  Depletion of GSH renders hepatocytes highly susceptible to oxidative stress and apoptosis

Early symptoms of hepatic damage include nausea, vomiting, diarrhea and abdominal pain

Treatment includes activated charcoal or/and N-acetylcysteine

The main inflammatory conditions in which NSAIDs are effective include rheumatoid arthritis, osteoarthritis and soft tissue rheumatism

NSAIDs have minimal effects on the progression of joint deformity

Disease-modifying anti-rheumatic drugs (DMARDs) reduce the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction

DMARDs include a diverse group of small molecule non-biological and biological (mainly antibodies and binding proteins) agents

methotrexate - A dihydrofolate reductase inhibitor that inhibits cytokine production and purine nucleotide biosynthesis leading to immunosuppressive and anti-inflammatory actions

leflunomide - Is an immunomodulatory drug that inhibits the activity of  autoimmune lymphocytes by acting on dihydroorotate dehydrogenase (DHOD) which important for pyrimidine syn, a requirement for activated proliferating lymphosytes

hydroxychloroquine - a anti-malaria drug with unknown MOA

cyclosporine (calcineurin inhibitor; immunosuppressant) and azathioprine (purine synthase inhibitor; immunosuppressant)

A dihydrofolate reductase inhibitor that inhibits cytokine production and purine nucleotide biosynthesis leading to immunosuppressive and anti-inflammatory actions

Can slow the appearance of new erosions within joints

Doses of methotrexate needed for RA is much lower than that need for CA chemotherapy (weakly dose)

Common side effects associated with RA therapy are mucosal ulceration and nausea

Drugs in this class includes adalimumab, infliximab, certolizumab, etanercept and golimumab

These drugs can decrease signs and symptoms of RA, reduce the progression of structural damage and improve physical conditions of patents

recombinant monoclonal antibody - active SC

Drug Interactions: avoid live vaccines, warfarin, cyclosporine and theophylline

Acts by binding to endogenous TNFα and blocking its activit

True

False

Drugs in this class include baricitinib and tofacitinib

modulate immune cell activity in response to binding of inflammatory mediators to cellular membranes

By inhibiting Janus kinase, these drugs block cytokine signaling thus preventing the inflammation and activation of immune system associated with RA

Cytokines, growth factors, interferons can increase Janus kinase activity and activation of the immune system