§Thermal or physical trauma

§Noxious chemicals

§Infectious agents

damage-

pathogen

associated molecules that are recognized by cells charged with immune surveillance

associated molecules that does not recognized by cells charged with immune surveillance

may be exaggerated

sustained with no apparent benefit and with severe adverse consequences

hypersensitivity, autoimmune diseases, chronic inflammation

Resolution with or without tissue degeneration and fibrosis

Infiltration of leukocytes and phagocytic cells

Transient local vasodilation and increased capillary permeability

Resolution with or with tissue degeneration and fibrosis

Transient local vasodilation and decreased capillary permeability

chemical

chemotactic

immunologic

others

histamine

serotonin

prostaglandins (PGE2, PGI2, PGD2)

bradykinins

leukotrienes (LTs)

LTB4

oxygen radicals and nitric oxide

platelet-activating factor (PAF),

complement factor C5a

endothelial intercellular adhesion molecule-1 (ICAM-1

IL-1, tumor necrosis factor (TNF) in concert with other cytokines and growth factors (IL-2, IL-6, IL-8)

prostaglandins (PGE2, PGI2, PGD2

endothelial intercellular adhesion molecule-1 (ICAM-1

endothelial intercellular adhesion molecule-1 (ICAM-1

platelet-activating factor (PAF),

platelet-activating factor (PAF), complement factor C5a, LTB4

oxygen radicals and nitric oxide

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

IL-1, tumor necrosis factor (TNF) in concert with other cytokines and growth factors (IL-2, IL-6, IL-8)

histamine, serotonin, prostaglandins (PGE2, PGI2, PGD2) bradykinins and leukotrienes (LTs)

Set point for temperature regulation in the hypothalamus is elevated in fever

the immune system’s protective response to an injurious stimulus.

Inflammation

Graft rejection

Infection (viral or bacterial origin)

Malignancy

disease

IL-6

IL-1β

TNFα

interferons

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

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

PGE2 acts on EP receptors on thermosensitive neurons which triggers the hypothalamus to elevate body temperature

Mediated by ceramide release (triggers IL-1β formation) in neurons of the post-optic area of the hypothalamus

PGE2 acts on AP receptors on thermosensitive neurons which triggers the hypothalamus to elevate body temperature

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

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

Increasing heat generation and Decreasing heat loss

decreasing heat generation and Decreasing heat loss

Acids

Heat

Pressure

Base

Coldness

bradykinin

H+

serotonin

LTs, ATP, PGs

nerve growth factor

increase the sensitivity of nociceptors and potentiate pain perception.

decrease the sensitivity of nociceptors and potentiate pain perception.

substance P

calcitonin

CGRP

CFP

PGE2

increasing the threshold of the stimulation of nociceptors leading to peripheral sensitization

reduce the threshold of the stimulation of nociceptors leading to central sensitization

increasing the threshold of the stimulation of nociceptors leading to central sensitization

reduce the threshold of the stimulation of nociceptors leading to peripheral sensitization

contribute to central sensitization

a decrease in the excitability of spinal dorsal horn neurons that cause hyperalgesia and allodynia

contribute to peripheral sensitization

an increase in the excitability of spinal dorsal horn neurons that cause hyperalgesia and allodynia

Chronic

systemic

autoimmune

inflammatory disease

central system

COX-2 increases PGE2 biosynthesis which stimulates pain pathways.

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

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

COX-2 decreases PGE2 biosynthesis which stimulates pain pathways.

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

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

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

Chronic inflammation develops.

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

Non-selective NSAIDS (traditional or tNSAIDs)

Selective NSAIDS (traditional or tNSAIDs)

COX-2 selective inhibitors

COX-1 selective inhibitors

Acetic acid derivatives:

Oxicam derivatives:

Fenamate derivatives:

Salicylates

Propionic acid derivatives

acetylsalicylic acid (aspirin) and its derivatives

mefenamic acid

Celecoxib

piroxicam, meloxicam

indomethacin, diclofenac, nabumetone, sulindac and etodolac

indomethacin

ibuprofen

naproxen

ketoprofen

flurbiprofen

diclofenac,

etodolac

indomethacin

sulindac

nabumetone

piroxicam

Celecoxib

meloxicam

naproxen

ketoprofen

mefenamic acid

acetylsalicylic acid

Celecoxib

nabumetone

mefenamic acid

Celecoxib

acetylsalicylic acid

meloxicam

piroxicam

Infection, toxins, injury, inflammation

Immune response mediators

IL-1, IL-2, TFN, IFN

Leukocytes

Monocytes, neutrophils, Lymphocytes

Endothelium, glial cells, mesenchymal cells

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as neurotransmitter)

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as a neurotransmitter)

Fever

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

Leukocytes

Monocytes, neutrophils, Lymphocytes

Endothelium, glial cells, mesenchymal cells

Infection, toxins, injury, inflammation

Immune response mediators

IL-1, IL-2, TFN, IFN

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as neurotransmitter)

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

Leukocytes

Monocytes, neutrophils, Lymphocytes

Endothelium, glial cells, mesenchymal cells

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as neurotransmitter)

Infection, toxins, injury, inflammation

Immune response mediators

IL-1, IL-2, TFN, IFN

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

Fever

Leukocytes

Monocytes, neutrophils, Lymphocytes

Endothelium, glial cells, mesenchymal cells

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as neurotransmitter)

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

fever

fever

Hypothalamic Endothelium

Production of PGE2

Rise in cAMP (acts as neurotransmitter)

Elevated Set Points

Activation of vasomotor center neurons

Peripheral vasoconstriction and heat production

Pyrogenic Cytokines

IL-1, TNF, IFN

Gp 130 receptor ligands

Leukocytes

Monocytes, neutrophils, Lymphocytes

Endothelium, glial cells, mesenchymal cells

homogeneous group of compounds which share certain therapeutic actions and some side effects.

antipyretic dose < anti-inflammatory dose

heterogeneous group of compounds which share certain therapeutic actions and some side effects.

site of action is in the brain (subcortical) or periphery

inhibit COX leading to a decreased production of PGs and thromboxanes.

inhibit COX leading to increased production of PGs and thromboxanes.

stimulate COX leading to a decreased production of PGs and thromboxanes.

stimulate COX leading to a increased production of PGs and thromboxanes.

COX-1: an inducible enzyme involved in inflammation, fever and pain. It can be induced by cytokines and endotoxins.

COX-2: a constitutive enzyme involved in physiologic activities such as vascular homeostasis, maintenance of renal and GI blood flow.

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

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

cox-1

cox-2

competitive

non-competitive

reversible

ir-reversible

active site inhibitors of COX enzymes

COX-1

COX-2

irreversibly inhibiting COX activity

reversibly inhibiting COX activity

Anti-inflammatory action, Reno-vascular action

Analgesic action, Pregnancy

Antipyretic action, Hypersensitivity reactions

Gastric or intestinal ulceration

Cardiovascular system

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

stimulation of the migration of leukocytes and macrophages into inflammation sites

Stabilization of lysosomal membranes

Inhibition of the migration of leukocytes and macrophages into inflammation sites

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

Effective against pain of low to moderate intensity

non-effective when inflammation has caused peripheral and/or central sensitization of pain perception

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

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

Due to a increase 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

do influence normal body temperature or when it is elevated by such factors such as exercise or increases in ambient temperature

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

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

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

Inhibition of PG-induced inhibition of gastric acid secretion.

stimulation of PG-induced inhibition of gastric acid secretion.

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

Increased generation of products of the lipoxygenase pathway.

Local irritation from contact of orally administered drug with gastric mucosa.

decreased generation of products of the lipoxygenase pathway.

Local irritation from the contact of parenta administered drug with the gastric mucosa.

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

COX-1 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.

Due to depression of COX-2 dependent PGs (PGI2) formed in the vasculature and kidney with 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

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

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

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.

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

Inhibition of action of ADH

stimuation PG-induced inhibition of reabsorption of chloride

Inhibiting PG-induced inhibition of reabsorption of chloride

stimuation of action of ADH

Increased reabsorption of K+

decreased reabsorption of K+

Suppression of PG-induced secretion of renin

Suppression of PG-1 induced secretion of renin

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

Non- 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

Chronic uses of low 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

Non- Chronic uses of low 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

can prolong gestation.

Myometrial COX-2 expression and levels of PGE2 and PGF2α increase significantly in the myometrium during labor

in late pregnancy can decreased the risk of postpartum hemorrhage.

Myometrial COX-2 expression and levels of PGE2 and PGF2α decreased significantly in the myometrium during labor

in late pregnancy can increase the risk of postpartum hemorrhage.

§Vasomotor rhinitis

§Generalized urticaria

§Bronchial asthma

Sulfonylurea hypoglycemics

Methotrexate

Warfarin

Lithium

reduce renal excretion of lithium.

reduce the effectiveness of ACE inhibitors.

reduce the effectiveness of DA inhibitors.

reduce the effectiveness of ATP inhibitors.

rare disorder characterized by hypokalemic, hypochloremic metabolic alkalosis with normal BP and hyperplasia of the juxtaglomerular apparatus

rare disorder characterized by hypokalemic, hypochloremic metabolic alkalosis with higt BP and hyperplasia of the juxtaglomerular apparatus

leading to increased PGE2 biosynthesis).

leading to decreased PGE2 biosynthesis).

Children are particularly prone to intoxication.

adult are particularly prone to intoxication.

Death occurs from respiratory failure after a period of unconsciousness

Death does not occurs from respiratory failure after a period of unconsciousness

contain salicylism

mild form of intoxication

toxic form of intoxication

characterized by: headache, dizziness, tinnitus, difficulty in hearing, mental confusion, sweating, thirst, hyperventilation, nausea and vomiting

characterized by: headache, dizziness, tinnitus, difficulty in hearing, mental confusion, sweating, thirst, hyperventilation, nausea and vomiting, dirrhea

pronounced CNS disturbances (e.g., generalized convulsions and coma), skin eruptions and marked alterations in acid-base balance (respiratory and metabolic acidosis).

Fever is prominent in children

Dehydration occurs as a result of hyperpyrexia, sweating, vomiting and hyperventilation

Hypoglycemia may be a serious consequence of poisoning in children.

death can occur due to CVS

§Symptomatic treatment of mild cases of poisoning.

§Administration of intravenous fluids to correct acid-base imbalance.

§Hemodialysis

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

§to reduce the risk of death and myocardial infarction in patients with coronary artery disease.

aspirin and salicylic acid

methyl salicylate,

sulfasalazine,

olsalazine

balsalazide

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

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

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

Acetylated COX-1 can form 15-epi-lipoxins which have potent anti-inflammatory actions

effect on immunological process in mesenchymal and connective tissues

antipyretic dose < anti-inflammatory dose

site of action is in the brain (subcortical) or periphery

antipyretic dose < anti-inflammatory

site of action is in the brain (subcortical) or periphery

effect on immunological process in mesenchymal and connective tissues

effect on immunological process in mesenchymal and connective tissues.

antipyretic dose < anti-inflammatory dose

site of action is in the brain (subcortical) or periphery

effect on immunological process in mesenchymal and connective tissues

Non-specific stabilization of capillary permeability during immunological insults

Effect on connective tissue mucopolysaccharides that act as barriers to the spread of inflammation

specific stabilization of capillary permeability during immunological insults

respiration

acid-base electrolyte balance

hepatic and renal effects

GI and uricosuric acid effects

hematologic effects

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

Direct effect: Plasma CO2 tension (PCO2) falls, and primary respiratory alkalosis ensues.

Indirect effect: Increase in O2 consumption and CO2 production in skeletal muscles leading to hyperventilation

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

Therapeutic doses of salicylates produce changes in the acid-base and electrolyte pattern.

Therapeutic doses of salicylates does not produce changes in the acid-base and electrolyte pattern.

Compensation for the initial event, respiratory alkalosis is achieved.

Compensation for the initial event, respiratory acidosis is achieved.

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

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

Plasma bicarbonate is higher, and blood pH returns to normal.

Plasma bicarbonate is lowered, and blood pH returns to normal.

Plasma bicarbonate is lowered, and blood pH returns to normal.

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

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

Epigastric distress, nausea and vomiting

Gastric ulceration, GI hemorrhage and erosive gastritis

Epigastric distress, nausea and vomiting.

Gastric ulceration, GI hemorrhage and erosive gastritis

Gastric damage caused by salicylates may be due to:

Direct irritant effect on mucosa (e.g., by an undissolved tablet

Gastric damage caused by salicylates may be due to: Inhibition of biosynthesis of protective prostaglandins (PGE2 and PGI2)o

§Inhibition of biosynthesis of protective prostaglandins (PGE2 and PGI2)

Due to acetylation of the active site of COX in platelets leading to a reduction in the biosynthesis of TXA2

A single dose of aspirin can prolong bleeding time of normal persons for a period of 4 to 7 days

Aspirin is used widely for the prophylaxis of thromboembolic disease

Inhibition of biosynthesis of protective prostaglandins (PGE2 and PGI2)

Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency and hemophilia should avoid the use of aspirin

Low doses (1-2 g/day):

↓ urate excretion; ↑plasma urate concentration

Large doses (> 5 g/day):

Uricosuria; ↓ plasma urate concentration

Large doses (> 5 g/day):

↓ urate excretion; ↑plasma urate concentration

Intermediate doses (2-3 g/day):

No effect

Low doses (1-2 g/day):

No effects

Salicylic acid is applied topically as a keratolytic agent for warts, corns and fungal infections

Methyl salicylate is a common ingredient of ointments and deep-heating liniments used in the management of musculoskeletal pain.

Aspirin is used to reduce the risk of death and myocardial infarction in patients with coronary artery disease

Rheumatoid arthritis

Analgesia and Antipyresis

ibuprofen

flurbiprofen.

ketoprofen

naproxen

Aspirin

Ibuprofen is the most commonly used traditional (non-selective) NSAID in the U.S.

Aspirin is the most commonly used traditional (non-selective) NSAID in the U.S.

Naproxen has a long t1/2 and is 20 times more potent than aspirin in inhibiting COX

Naproxen directly inhibits leukocyte function and causes less severe GI effects than aspirin

Asprin has a long t1/2 and is 20 times more potent than aspirin in inhibiting COX

rheumatoid arthritis

osteoarthritis

ankylosing spondylitis

acute gouty arthritis

migraine and primary dysmenorrhea.

indomethacin

sulindac

etodolac

diclofenac

ketorolac

In addition to inhibiting COX, these compounds also promote the incorporation of un-esterified arachidonic acid into triglyceride, thus reducing the availability of the substrate for COX and LOX

In addition to stimuation COX, these compounds also promote the incorporation of un-esterified arachidonic acid into triglyceride, thus reducing the availability of the substrate for COX and LOX

more potent inhibitors of COX than aspirin

Indomethacin directly inhibits the motility of polymorphonuclear leukocytes to inflammation sites

Sulindac directly inhibits the motility of polymorphonuclear leukocytes to inflammation sites

rheumatoid arthritis

ankylosing spondylitis

osteoarthritis

acute gouty arthritis

acute gouty arthritis

indomethacin

sulindac

etodolac

diclofenac

ketorolac

Ketorolac

diclofenac

piroxicam

meloxicam

Piroxicam shows some COX-2 selectivity.

Meloxicam shows some COX-2 selectivity.

Piroxicam can inhibit the activation of neutrophils, apparently independent of its action on COX

Meloxicam can inhibit the activation of neutrophils, apparently independent of its action on COX

Has a long t1/2; permits once a day dosing.

rheumatoid arthritis and osteoarthritis

Have similar efficacy as aspirin, naproxen, indomethacin and ibuprofen.

ankylosing spondylitis, acute gouty arthritis and other musculoskeletal disorders

meloxicam

piroxicam

mefenamic acid

Aspirin

ibuprofen

inhibition of COX, fenamates (especially meclofenamate) can also block PG receptors

stimuation of COX, fenamates (especially meclofenamate) can also block PG receptors

inhibition of COX- 1, fenamates (especially meclofenamate) can also block PG receptors

stimuation of COX-1 , fenamates (especially meclofenamate) can also block PG receptors

osteoarthritis.

primary dysmenorrhea

rheumatoid arthritis

ankylosing spondylitis

meloxicam

mefenamic acid

Nabumetone

piroxicam

preferential activity against COX-2

preferential activity against COX-1

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

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

Low incidence of GI disturbances

osteoarthritis

rheumatoid arthritis

primary dysmenorrhea

other musculoskeletal disorders

Celecoxib

Nabumetone

mefenamic acid

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

Has a less 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

Has anti-inflammatory, antipyretic and analgesic properties similar to traditional NSAIDs but does 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.

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

Due to prolonged inhibition of vascular COX-2 within endothelial cells leading to decreased PGI2 formation.

Due to prolonged stimulation of vascular COX-2 within endothelial cells leading to decreased PGI2 formation.

Celecoxib is the only FDA approved drug in this class.

osteoarthritis

rheumatoid arthritis

ankylosing spondylitis

primary dysmenorrhea

Celecoxib

Acetaminophen

Nabumetone

mefenamic acid

active metabolite of phenacetin.

Has analgesic and antipyretic actions similar to those of the salicylates but has a weak anti-inflammatory actions.

weak effect on COX may be due to the fact that acetaminophen can only inhibit the enzyme in an environment that is low in peroxides

during inflammation, high concentrations of peroxides are generated by leukocytes

Due to prolonged inhibition of vascular COX-2 within endothelial cells leading to decreased PGI2 formation

Inhibits the generation of nitric oxide because its anti-nociceptive actions can be reversed by L-arginine

Inhibits the generation of nitric oxide because its anti-nociceptive actions can be reversed by A-arginine

more effective against COX in the brain than in the periphery (could explain its antipyretic efficacy).

less effective against COX in the brain than in the periphery (could explain its antipyretic efficacy).

Has no effect on platelet aggregation.

Has no effect on the respiratory system.

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

Does not cause gastric irritation or bleeding.

have no effect on CVS

Active orally.

small proportion of acetaminophen undergoes cytochrome P-450-mediated N-hydroxylation to form N-acetyl-benzoquinone-imine (NAPQI), a highly reactive intermediate that is toxic to both the liver and kidneys in high concentrations.

NAPQI reacts with –SH groups and is rendered harmless.

small proportion of acetaminophen undergoes cytochrome P-450-mediated N-hydroxylation to form N-acetyl-benzoquinone-imine (NAPQI), a highly reactive intermediate that is toxic to both the liver and kidneys in low concentrations.

NAPQI reacts with –FH groups and is rendered harmless.

Principal toxicity associated with over dosage is potentially fatal hepatic necrosis

Principal toxicity associated with under 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

Mechanism involves ionic 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.

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

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

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

Activated charcoal

deactivated charcoal

Use of N-acetylcysteine to detoxify NAPQI.

N-acetylcysteine acts by replenishing hepatic stores of GSH

N-acetylcysteine acts by replenishing hepatic stores of FSH

mild to moderate pain such as headache, myalgia, postpartum pain

osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and primary dysmenorrhea

other circumstances in which aspirin is an effective analgesic

soft tissue rheumatism

rheumatoid arthritis

osteoarthritis

NSAIDs have minimal effects on the progression of joint deformity

increase the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction.

reduce the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction.

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

diverse group of large molecule non-biological and biological (mainly antibodies and binding proteins) agents

Methotrexate (dihydrofolate reductase inhibitor)

Leflunomide (pyrimidine synthase inhibitor)

Leflunomide(dihydrofolate reductase inhibitor)

Methotrexate- pyrimidine synthase inhibitor)

Hydroxychloroquine (anti-malarial)

Cyclosporine (calcineurin inhibitor; immunosuppresant)

Hydroxychloroquine (dihydrofolate reductase inhibitor)

Cyclosporine (pyrimidine synthase inhibitor)

Leflunomide (anti-malarial)

Methotrexate (purine synthase inhibitor; immunosuppressant)

Hydroxychloroquine (pyrimidine synthase inhibitor)

Azathioprine (purine synthase inhibitor; immunosuppressant)

Cyclosporine (calcineurin inhibitor; immunosuppresant)

Azathioprine (pyrimidine synthase inhibitor)

Adalimumab (Ab, TNF-α antagonist)

Adalimumab (Ab, IL-1β antagonist)

Infliximab (Ab, IL-1β antagonist)

Infliximab (Ab, TNF-α antagonist)

Canakinumab (Ab, IL-1β antagonist)

Etanercept (Ab, IL-1β antagonist)

Etanercept (TNF-α antagonist)

Canakinumab(TNF-α antagonist)