lipid mediators of inflammation

&
Chronic
inflammation/immunosuppression

NSAIDs & DMARDs

Newman Osafo, BPharm, PhD

Department of Pharmacology, FPPS, CHS, KNUST
nosafo.pharm@knust.edu.gh
 OBJECTIVES:

 After studying this material and attending lectures you should be able
to:
 Know the biochemical pathways for eicosanoids production
 Know the effects produced by the eicosanoids and their mechanism of action.
 Understand the consequences of blockade of synthesis or action of the
eicosanoids.
 Describe the mechanisms of action of the NSAIDs and the DMARDs.
 Know the therapeutic uses of NSAIDs and the DMARDs in relation to RA

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 The eicosanoids are derived from the regulated action of acyl hydrolase
on constituent membrane phospholipids to generate fatty acid
precursors.

 The enzymatic activity of interest is PLA2 liberating arachidonic acid.

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ARACHIDONIC ACID METABOLISM:

LOX inhibitor
Zileuton

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ACTIONS OF THE EICOSANOIDS:
 Prostaglandins contribute to the symptoms of inflammation along with
other autacoids such as histamine and bradykinin.

 PGE2 and PGI2 cause vasodilation of arterioles and venules causing

increased blood flow which leads to erythema = REDNESS

 Oedema is also caused in part by prostaglandins

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Pain:
 PGs directly sensitize pain fibers so they respond to normally innocuous stimuli
(hyperalgesia).
 Subdural injection of PGE1 with small amounts of bradykinin or histamine is
very painful.

Fever:
 A common cause is the production of pyrogens released by neutrophils fighting
a bacterial infection (IL-1).
 Pyrogens are thought to cause release of PGs in the preoptic area of the
hypothalamus. The net effect is an imbalance in heat production and loss
leading to fever.
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 Inhibition of PG synthesis in the CNS causes cutaneous
vasodilation and increases heat loss thus, reducing the fever.

 A general reduction of PG synthesis in the brain and in inflamed

tissues probably also reduces the symptoms of fever.

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 THE INFLAMMATORY RESPONSE

 Increase Prostaglandin Synthesis results in...

 Increased capillary permeability (mediates local

erythema and edema)
 Increased sensitivity of pain receptors
 Increased platelet aggregation
 Increased Body temperature
 Potential hypertension, neurologic disorders and
respiratory dysfunction

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 THERAPEUTIC EICOSANOIDS

Drug Name Analog of Clinical Use

Pulmonary hypertension, useful in
Epoprostenol PGI2 hemodialysis to harvest platelets
Medical abortion, relax uterine cervix in
Dinoprostone PGE2 preparation for induction of labor
Misoprostol PGE1 Peptic ulcer, Medical abortion
Maintain a patent (open) ductus
arteriosus in neonates with certain
Alprostadil PGE1 cardiac malformations until emergency
surgery; erectile dysfunction
(Caverject)
Carboprost PGF2 Labor induction

Latanoprost PGF2 Glaucoma

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 INHIBITORS OF EICOSANOID PRODUCTION

Zileuton NSAIDS (including

Phospholipase A2
aspirin)
5-ASA (IBD)
Arachidonic acid
Lipoxygenase Cyclooxygenase (COX)

Lipoxygenase products Prostaglandins & thromboxanes

montelukast, (leukotrienes)
zafirlukast

Inflammatory effects Inflammatory effects Homeostatic

(esp. in asthma) functions

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NON-STEROIDAL ANTI-
INFLAMMATORY AGENTS [NSAIDS]
 Aspirin and other Salicylates
 Non-selective COX Inhibitors
 propionic acids e.g., ibuprofen, ketoprofen, naproxen
 oxicam derivatives e.g., piroxicam,
 indole derivatives e.g., indomethacin, sulindac, etodolac
 Selective COX-2 Inhibitors

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 NSAIDS
 Analgesia

 All drugs in this class relieve pain, but the type of pain is
important. These drugs are most effective against mild to
moderate pain, particularly pain due to inflammation.
 Postoperative pain often responds favorably to aspirin and
related drugs. Myalgia, arthralgia and neuralgia also
respond well.
 In contrast to the opiates, aspirin-like drugs are not
addictive and do not alter sensory perception (except for
perception of cutaneous pain).
 Pain emanating from the hollow viscera is not relieved.

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NSAIDS

 Antipyresis
 The anti-inflammatory drugs reduce fever, but this
application is limited to the less toxic agents,
aspirin; and acetaminophen*.

 Relief of fever with drugs does not eliminate the

cause of the fever

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NSAIDS

 Anti-inflammatory Action
 Treatment of inflammatory disease such as RA,
ankylosing spondylitis and osteoarthritis is a major
clinical use. Aspirin is still the reasonable DOC for
newly diagnosed RA but does not satisfy the
patients need for a "prescription".
 The pain and inflammation of arthritis are relieved, but
the progressive degeneration of the joints is not
prevented.

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 MECHANISM OF NSAID ACTION
[EICOSANOID SYNTHESIS
INHIBITION]
 Eicosanoids include
 Prostaglandins, Thromboxanes and Leukotrienes
 Cells subjected to trauma increase production of Prostaglandins
 Synthesis of Prostaglandins and Thromboxanes are catalyzed by
the enzyme Cyclooxygenase

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Non-steroidal anti-inflammatory drugs (NSAIDs)

 All NSAIDs inhibit the cyclooxygenase (COX) required for

conversion of arachidonic acid to endoperoxide
intermediate (PGG2 and PGH2).
 arachidonic acid →endoperoxide →PGG2 →PGH2
→prostaglandins + prostacyclin + thromboxane
 Some NSAIDs even block synthesis of leukotrienes
 Inhibition of Cyclooxygenase eliminates a cells inflammatory response including
 Pain
 Fever
 Platelet Aggregation

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 Structural differences of cyclooxygenase:
 COX1: mostly expressed in tissues.
 COX2: is synthesized by inflammatory factors at the site of
inflammation.

 NSAIDs inhibit PG and TX synthesis, they are potent inhibitors

of cyclooxygenase and eliminate all PGs and TX in every cell
they reach

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 ASPIRIN
 Unique among the NSAIDs in irreversible blockade of COX

 Is rapidly deacetylated by esterases producing salicylate which

has antipyretic, anti-inflammatory and analgesic effects.

 Blockade of prostaglandin synthesis at the thermoregulatory

centers in the hypothalamus and at the peripheral target sites
PGE2 is thought to sensitize nerve endings to the action of bradykinin, histamine and other
 e.g.,
chemical mediators released locally by the inflammatory process

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 Prevent the sensation of pain receptors to both
mechanical and chemical stimuli
 Also depress pain stimuli at subcortical sites
 No effect on normal body temperature

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 For the management of pain of low to moderate intensity
arising from integumental structures rather than that arising
from the viscera

 NSAIDs are superior to opioids for the management of pain

in which inflammation is involved

 Combination of opioids and NSAIDs are effective in treating

pain caused by a malignancy.

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 ADVERSE EFFECTS

Gastrointestinal Distress
 Normally PGI2 inhibits gastric acid secretion and PGE2 and PGF2
stimulate synthesis of protective mucus in both the stomach and small
intestine
 BUT in the presence of aspirin prostanoids are not formed
 epigastric distress, ulceration, haemorrhage

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 Proton pump inhibitor are used in the treatment of
gastric damage induced by NSAIDs or as a prevention
during chronic treatment by NSAIDs

 Agents such as Flurbiprophen-conjugated to NO are

currently being developed to decrease the mucosal
damage produced by NSAIDs.

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 EFFECT OF ASPIRIN
(NSAIDS) ON PLATELETS
 Normally TXA2 enhances platelet aggregation, whereas PGI2
decreases it
 Low doses=60-80 mg daily of aspirin can irreversibly inhibit TX
production in platelets without markedly affecting TXA2 production
in the endothelial cells of the blood vessel
 The lack of TX persists for the lifetime of the platelet (3-7 days)
 TXA2 platelet aggregation is reduced, producing an
anticoagulant effect with a prolonged bleeding time.

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 EFFECT OF ASPIRIN (NSAIDS) ON
KIDNEY

 Normally PGE2 and PGI2 are responsible for maintaining renal

blood flow

 During the treatment by NSAIDs decreased synthesis of PGs

can result in retention of sodium and water – can cause
oedema and hyperkalaemia in some patients.

 Interstitial nephritis can also occur with all NSAIDs

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 THERAPEUTIC USE OF ASPIRIN (NSAIDS)

 Antipyretic, analgesic, anti-inflammatory

 Rx of gout, rheumatic fever, RA
 Salicylic acid is used topically to treat corns, calluses,
epidermophytosis
 Cardiovascular applications of aspirin (salicylates): to
inhibit platelet aggregation. Low doses of aspirin
prophylactically to decrease the incidence of transient
ischemic attack and unstable angina in men as well as
that of coronary thrombosis
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 PHARMACOKINETICS OF SALICYLATES

 Absorption - Rapidly absorbed from the stomach and upper

intestine. Aspirin is rapidly hydrolyzed to salicylate by enzymes
circulating in the plasma, liver and erythrocytes. Salicylic acid and
methyl salicylate, which are used in analgesic ointments, are
rapidly absorbed from the skin.

 Distribution - widely distributed throughout the fluids of the body

including the synovial fluid, an important site of antiarthritic-pain
action. Salicylate does not readily enter the CSF due to the high
fraction in the plasma that is ionized. Salicylate and aspirin are
highly bound to plasma proteins.

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 Metabolism - Salicylates are metabolized by the liver primarily
to glycine conjugates and are excreted by the kidneys.

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 ADVERSE EFFECTS

 GIT: epigastric distress, nausea, vomiting, microscopic GIT

bleeding

 Blood: prolonged bleeding time  should not be taken for at

least one week prior to surgery. When salicylates are
administered, anticoagulants may have to be given in reduced
doses.

 Respiration: Higher synthesis of leukotrienes  irritation of

respiratory tract. In toxic doses salicylates cause respiratory
depression and a combination of uncompensated respiratory and
metabolic acidosis. 28
 Hypersensitivity: Urticaria, bronchoconstriction or anaphylaxis,
angioneurotic oedema

 Reye syndrome: Happens during viral infection. Often fatal,

culminating in hepatitis with cerebral oedema. Especially in children
contraindicated till 12 years, they should use acetaminophen to
reduce fever
 RS marked by fatty degenerative liver failure and non-inflammatory
encephalopathy.

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 TOXICITY OF SALICYLATES & TREATMENT

 Mild intoxication: it is called salicylism.

 Nausea, vomiting, marked hyperventilation, headache, mental
confusion, dizziness, tinnitus.

 Severe intoxication: commonly happens in children.

 CNS disturbances, skin eruptions and serious acid-base imbalance.

 Acute accidental or intentional overdose is the most common cause of

severe toxicity in older patients

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 Salicylate intoxication is a potentially fatal medical emergency.

 Treatment depends on the symptoms and may include gastric

lavage, reducing hyperthermia and treating acid-base imbalance
with bicarbonate solution and glucose to reverse metabolic acidosis.
Blood transfusion and vitamin K may reverse haemorrhage, and
dialysis may be necessary to clear plasma salicylate.

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 INDOLES
 Indomethacin, sulindac
 Potent and effective anti-inflammatory agent used to treat RA, musculoskeletal pain
and is used intravenously for the Rx of patent ductus arteriosus.

 Pharmacological profile like the salicylates.

 Orally effective, highly bound to plasma proteins and metabolized in the liver.
Elimination is via renal and biliary mechanisms.

 Crosses the placenta and is available in breast milk, it should not be given to
pregnant or breast-feeding mothers.

 Sulindac - reduced adverse effects.

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 metabolized to a sulfide which is the active drug.
 FENAMATES
 Mefenamic acid and Meclofenamate
 Pharmacological Effects - Mefenamic acid inhibits cyclooxygenase and has
analgesic, antipyretic and anti-inflammatory actions.
 Meclofenamate may also block PG receptors.
 Adverse Effects. The major limiting adverse effect is potentially severe
gastrointestinal irritation leading to severe diarrhea.
 Mefenamic acid is extensively bound to plasma proteins and can displace several
drugs including the oral anticoagulants.

 These agents decrease fertility in animal studies. No data is available in humans.

Should not be given to pregnant or breast-feeding mothers.

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 BENZOPYRROLE.
 Tolmetin
 Has anti-inflammatory, analgesic and antipyretic activity.
 It is a more potent anti-inflammatory drug than aspirin, but less potent than
indomethacin. The primary use of the drug is in treatment of RA
 Adverse effects include gastrointestinal and CNS effects, tinnitus and
rashes.
 Tolmetin is excreted in breast milk and should be avoided by nursing
mothers.

 Tolmetin binds extensively to plasma protein but is unusual for the

nonsteroidal anti-inflammatory drugs in that it does not increase clotting
time if given with warfarin.
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 PROPIONIC ACID
DERIVATIVES.
 Ibuprofen, Naproxen, Ketoprofen, Fenoprofen, Flurbiprofen, Oxaprozin

 Have analgesic, antipyretic and anti-inflammatory effects.

 This group has advantages over aspirin and indomethacin in treating arthritis
because side effects are less frequent and less severe.
 The major adverse effect is gastrointestinal distress which is less severe than with
aspirin or indomethacin. Increased bleeding time is also a potentially important side
effect.
 The propionic acid derivatives are all highly bound to plasma proteins and there is
potential for serious drug-drug interaction with warfarin and possibly oral
hypoglycemics.

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 OXICAMS
 Piroxicam
 Nonsteroidal anti-inflammatory, analgesic, antipyretic agent used to treat
osteoarthritis.
 Meloxicam
 Relatively selective for COX2 than COX1 inhibition but at high doses it is
non-selective.
 Long plasma half-life (50 h) allows once-a-day dosing for chronic arthritics.
 This can be an advantage if patient compliance is a problem.
 Very high plasma protein binding (99%).
 G.I. distress is most common side effect.

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 PHENYLACETIC ACIDS
 Diclofenac, aceclofenac
 Anti-inflammatory, analgesic, antipyretic agent used to treat arthritis.
 In addition to inhibition of COX activity, diclofenac appears to block the release of
arachidonic acid in leukocytes which may participate in its anti-inflammatory effects.
 Diclofenac undergoes significant (50%) first-pass effect and exhibits very high
plasma protein binding (99%). In addition, this drug appears to accumulate in
synovial fluid explaining its longer therapeutic effect than plasma T1/2.
 In addition to GI side effects, hepatic toxicity is known, and hepatic transaminases
should be followed. This drug is useful in the treatment of RA, osteoarthritis and
ankylosing spondylitis.
 Diclofenac is embryotoxic in animal studies and should be avoided in pregnant
women or in nursing mothers.

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 OTHERS
 Nimesulide
 Sulfonanilide, weak inhibitor of PG synthase but good blocker of leukocyte function.
 Also blocks metalloproteinase activity on articular chondrocytes.
 useful in patients who are allergic to aspirin or other NSAIDs.

 Ketorolac
 Potent agent with the usual spectrum of activities, analgesic, antipyretic and anti-
inflammatory.
 Chemically related to indomethacin and is 40x as potent an anti-inflammatory as
ibuprofen.
 The major advantage offered with this drug is that it can be given by im injection or orally.
It is indicated for use in the treatment of pain but is not recommended for use beyond 1-2
weeks.
 Dazoxiben, Primogrel and Ridogrel
 Thromboxane synthase inhibitors being developed for treatment of vascular ischemia and
thrombosis. Ridogrel also blocks TX receptor as well as blocking the synthase.
 May be useful for the prophylaxis of MI. 38
 Etodolac
 less GI side effects compared to aspirin. Uses and precautions are the same as
for other NSAIDs.

 Nabumetone (Relafen)
 Not a very good COX inhibitor but it is a good anti-inflammatory.
 May work through other pathways and thus, could be useful in combination
with other NSAIDs.
 Recent evidence suggests that this drug is an inhibitor of COX-2, the inducible
form of cyclooxygenase as well as COX-1.
 It is a pro-drug that is converted to the active form in the liver.

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 Zileuton
 5-lipoxigenase inhibitor developed for ulcerative colitis, asthma
and allergic rhinitis

 Etanercept
 Competitively inhibits TNF-alpha receptor (TNFR)
 Etanercept renders the cytokine inactive, resulting in reduced
inflammatory activity.
 Given by sc. injection.

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 DRUG INTERACTIONS OF
NSAIDS
 Drug interactions of clinical significance include avoidance of concurrent therapy
with agents that cause hypoprothrombinemia, thrombocytopenia or gastric
ulceration.

 Propionic acids (ibuprofen et al.) can compete with phenytoin for protein
binding.

 The concurrent use of cephalosporin antibiotics and NSAIDs may increase the
risk of bleeding.

 In general, the use of two NSAIDs is unwarranted due to the increase incidence
of gastric side effects.
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 DRUG INTERACTIONS OF
NSAIDS
 Concurrent use of NSAIDs and lithium can result in increases in plasma lithium
concentrations of as much as 50% due to decrease in the clearance of lithium by
NSAIDs.
 Methotrexate use in conjunction with NSAIDs is cautioned. Specifically,
methotrexate should not be used with phenylbutazone due to the risk of
agranulocytosis or bone marrow depression.
 It is recommended that NSAIDs be withheld for 24 to 48 hours prior and for 12
hours following methotrexate dosing.
 Indomethacin may cause  renal excretion aminoglycosides or digitalis leading to 
plasma levels and potential toxicity.
 Probenecid increases the plasma concentration of NSAIDs.

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 DRUG INTERACTIONS OF
NSAIDS
 Anticoagulants such as coumarin, heparin or thrombolytic agents such as
plasminogen activator, streptokinase or urokinase.
 The fenamates and the salicylate congener diflunisal are less likely to cause this
antithrombotic effect.

 Indomethacin inhibits the hepatic glucuronidation and clearance of zidovudine.

Also been implicated in the worsening of depression, parkinsonism and epilepsy
and thus, should be avoided in such patients

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COX-2 SELECTIVE INHIBITORS
- COXIBS
 COX-2
 Enzyme induced by inflammatory cytokines
 Induced during tissue injury
 Results in Prostaglandins causing pain and inflammation

 COX-2 Inhibitors e.g. Celecoxib (Celebrex), Etoricoxib

(Arcoxia), Rofecoxib (Vioxx), Valdecoxib (Bextra)
 No effect on platelet aggregation
 Rofecoxib and valdecoxib taken off some markets due to
their associated strokes and heart attacks.

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 CELECOXIB
 Useful in the treatment of RA and osteoarthritis.
 Appears to be free of COX-1 antagonistic properties.
 Orally effective.
 Complexes to some extent with food or co-administration of
antacids. Highly protein bound. 60% of the drug is
eliminated in the feces/ 30% in the urine.
 Significantly less GI damage is claimed
 Renal insufficiency, increase the risk of hypertension

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 ETORICOXIB
 Useful in the treatment of RA, gouty and osteoarthritis.
 106x more selective for COX-2.
 Has less interference with cardioprotective COX-1-mediated
antiplatelet activity of low-dose aspirin in vitro than
celecoxib.
 Significantly less GI damage
 Renal insufficiency, increase the risk of hypertension

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47
48
 CHRONIC
INFLAMMATION
 DMARDs
 Used in autoinflammatory diseases (e.g., RA, SLE, IBD) to slow down
disease progression.
 They reduce evidence of disease progression
 They are not typical anti-inflammatory agents

 Include the following:

 TNF alpha inhibitor: Adalimumab, infliximab, etanercept
 IL-1-induced apoptosis suppressor: Chloroquine

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 CHRONIC INFLAMMATION
 Include:
 TNF alpha-induced apoptosis inhibitor: Sulphasalazine,
hydroxychloroquine
 5-LOX inhibitor: zileuton, Minocycline
 Purine metabolism inhibitor: Methotrexate
 Gold compounds: Auranofin
 Janus Kinase (JAK) pathway inhibitors: Baricitinib,
Tofacitinib
 PDE4 inhibitors: effective in psoriatic arthritis with its
mechanism not well defined. Apremilast.
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 CHRONIC INFLAMMATION
 Long term reaction associated with organ transplantation and autoimmunity.
 IMMUNOSUPPRESSION
 Calcineurin inhibitors
 A calcium dependent serine-threonine phosphatase. In T cells normally bound to
FKBP-12.
 It acts to dephosphorylate Nuclear factor of activated T-cells (NF-AT), which
translocates to the nucleus to regulate the expression of cytokines like IL-2. The
constitutive phosphorylation of NF-AT prevents its passage into the nucleus
 Cyclosporin – binds to cytosolic cyclophilin which as a complex inhibits
calcineurin
 Tacrolimus/FK506 – binds to FKBP12, which in turn inhibits calcineurin.
 By reducing NF-AT transcriptional activity, reduces T-cell proliferation

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 Others
 Sirolimus/Rapamycin – blocks mammalian target of rapamycin
(mTOR) signalling pathway – preventing maturation of APC and
inflammatory cell proliferation
 Azathioprine and Mycophenolate mofetil – inhibitors of cell
proliferation

 Transplantation – typical drug regimen would include calcineurin

inhibitors, such as cyclosporin or tacrolimus; glucocorticoids, such as
cortisol, dexamethasone; and inhibitors of T cell proliferation such as
azathioprine or mycophenolate mofetil

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 METHOTREXATE
 Pivotal DMARD in RA management
 MTX affects cell survival by decreasing folate availability
 Effective in early arthritis and has been shown to reduce the progression of
erosion.

 GI disorders common (ulcers, nausea, vomiting, etc.)

 Rare but life-threatening haematological disorders
 Pulmonary toxicity
 Fetal death and congenital abnormalities common in pregnancy

53
 SULFASALAZINE
 A combo of mesalazine or 5-ASA and sulfapyridine
 Suppresses neutrophil activities such as chemotaxis, degranulation.
 Inhibits PGE2 synthetase and extracellular release of PLA2
 Suppress activation of T, B and NK cells with decreased pro-inflammatory
cytokines and immunoglobulin production.

 GI disorders common
 Reversible oligospermia and bone marrow toxicity

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 ANTIMALARIALS
 The 4-aminoquinolones: chloroquine (CHQ) and HCQ are commonly used
 Low incidence of adverse effect.
 In SLE, considered as universal therapy
 Play a role in lysosomal acidification leading to TLR inhibition

 HCQ identified to prevent thrombosis (Annexin A5 activity).

 Retinopathy, myopathy, tinnitus, cardiomyopathy and psychotic behavior

 GI disorders
 Skin pigmentation of oral mucosal membranes
 Haemolysis in G6PD deficiency (rare)
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 AZATHIOPRINE
 Used in IBD, SLE and RA
 A prodrug of 6-MP, acts as antagonist of endogenous purines.
 Suppresses activation of MAPK and NF-kB

 GI disorders common
 Neutropenia common in Thiopurine methyltransferase (TPMT) deficient
individuals
 Long term therapy increases risk of malignancies

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 CYCLOSPORIN A
 Preferred in refractory disease given the significant risk of toxicity on
long term therapy
 It impairs production of IL-2 and reduces lymphocyte proliferation >>>
A calcineurin inhibitor

 GI toxicity common
 Hypertrichosis, gingival hyperplasia, hyper- kalemia, magnesemia,
uricemia
 HPT and renal dysfunction
 Inhibitors of CYP3A4 such as CCB, macrolide antibiotics, azole
antifungals increase the serum concentration in 2-5 folds

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 OTHER DMARDS
 Intramuscular gold therapy: improve swollen joint count, pain and
disability. Early use retards joint erosion. Used less due to risk of
cytopenia and proteinuria.

 D-penicillamine: withdrawn due to no advantage over placebo in RA

coupled with adverse side effects.

 Minocycline: inhibits matrix metalloproteinases and decreases synovial

T cell proliferation and cytokine production. Side effects include vertigo
and liver toxicity and drug-induced SLE. Also known to inhibit 5-LOX.

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 IL-1 RECEPTOR INHIBITORS
 Plasma IL-1 levels are increased in patients with active
inflammation

 Anakinra is an approved recombinant, non-glycosylated

form of human IL-1RA for the management of joint disease
in rheumatoid arthritis.

 Others: Rilonacept, Canakinumab

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 OTHER IL RECEPTOR
INHIBITORS
 Tocilizumab, an IL-6R antagonist, is approved for treatment of
rheumatoid arthritis and systemic juvenile idiopathic arthritis

 Siltuximab, another IL-6R antagonist, is approved for treatment of

multicentric Castleman disease if the patient is HIV positive

 Ustekinumab is a human IL-12R and IL-23R antagonist indicated for the

treatment of plaque psoriasis and psoriatic arthritis.

 Secukinumab is a human anti-IL-17A antagonist indicated for treatment

of plaque psoriasis.
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