Non-steroidal Anti-Inflammatory Drugs

Dr.HAZAR 2011

Definition of the drugs & their categories

The inflammatory response & inhibition

side effects

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Nonsteroidal Anti-Inflammatory Drug

• A therapeutic agent which relieves pain and fever by inhibiting the inflammatory response.

• These drugs are available over the counter and by prescription.

• Some common examples include aspirin, ibuprofen, Celebrex, and less commonly acetaminophen (Tylenol).

Categories of NSAIDs• There are two major categories for non-

steroidal anti-inflammatory drugs• The first is non-selective anti-

inflammatory drugs.• The second is selective anti-inflammatory

drugs, COX-2 inhibitors.

The Inflammatory Response• The body’s response to a stimuli which

causes pain and/or tissue damage.• Physiologically capillaries become

“leaky” through vasodilation.• The response is initiated by the chemical

messengers prostaglandins.

The innate immune response

• The innate response occurs immediately on injury or infection. It comprises vascular and cellular elements. Mediators generated by cells or from plasma modify and regulate the magnitude of the response.

• Tissue macrophages, bearing Toll receptors, recognise specific pathogen-associated molecular patterns on the microorganism and release cytokines, particularly interleukin (IL)-1 and tumour necrosis factor (TNF)-α, as well as various chemokines.

• IL-1 and TNF-α act on local postcapillary venular endothelial cells, causing: – vasodilatation and fluid exudation – expression of adhesion molecules on the cell surfaces.

• Exudate contains enzyme cascades that generate bradykinin (from kininogen), and C5a and C3a (from complement). Complement activation lyses bacteria.

• C5a and C3a stimulate mast cells to release histamine, which dilates local arterioles.

• Tissue damage and cytokines release prostaglandin PG I2 and PGE2 (vasodilators) and leukotriene (LT) B4 (chemotaxin).

• Cytokines stimulate synthesis of vasodilator nitric oxide , which increases vascular permeability.

• Using adhesion molecules, leucocytes roll on, adhere to and finally migrate through vascular endothelium towards the pathogen (attracted by chemokines, IL-8, C5a, and LTB4), where phagocytosis and killing takes place.

The adaptive response

• The adaptive (specific, acquired) immunological response boosts the effectiveness of the innate responses. It has two phases, the induction phase and the effector phase, the latter consisting of (i) antibody-mediated and (ii) cell-mediated components.

• During the induction phase, naive T cells bearing either the CD4 or the CD8 coreceptors are presented with antigen, triggering proliferation: – CD8-bearing T cells develop into cytotoxic T cells that

can kill virally infected cells – CD4-bearing Th cells are stimulated by cytokines to

develop into Th1 or Th2 cells – Th2 cells control antibody-mediated responses by

stimulating B cells to proliferate, giving rise to antibody-secreting plasma cells and memory cells

– Th1 cells develop into cells that release cytokines that activate macrophages; these cells, along with cytotoxic T cells, control cell-mediated responses.

• The effector phase depends on antibody- and cell-mediated responses.

• Antibodies provide: – more selective complement activation – more effective pathogen phagocytosis – more effective attachment to multicellular parasites,

facilitating their destruction – direct neutralisation of some viruses and of some bacterial

toxins.

• Cell-mediated reactions involve: – CD8+ cytotoxic T cells that kill virus-infected cells – cytokine-releasing CD4+ T cells that enable macrophages to

kill intracellular pathogens such as the tubercle bacillus – memory cells primed to react rapidly to a known antigen.

• Inappropriately deployed immune reactions are termed hypersensitivity reactions.

• Anti-inflammatory and immunosuppressive drugs are used when the normally protective inflammatory and/or immune responses escape control.

Prostanoids

• The term prostanoids encompasses the prostaglandins and the thromboxanes.

• Cyclo-oxygenases (COXs) oxidise arachidonate, producing the unstable intermediates prostaglandin (PG) G2 and PGH2.

• There are two main COX isoforms: COX-1, a constitutive enzyme, and COX-2, which is often induced by inflammatory stimuli.

• PGI2 (prostacyclin), predominantly from vascular endothelium, producing vasodilatation and inhibition of platelet aggregation.

• Thromboxane (TX) A2, predominantly from platelets, causing platelet aggregation and vasoconstriction.

• PGE2 is prominent in inflammatory responses and is a mediator of fever. Main effects are: – EP1 receptors: contraction of bronchial and

gastrointestinal tract (GIT) smooth muscle – EP2 receptors: relaxation of bronchial,

vascular and GIT smooth muscle – EP3 receptors: inhibition of gastric acid

secretion, increased gastric mucus secretion, contraction of pregnant uterus and of GIT smooth muscle, inhibition of lipolysis and of autonomic neurotransmitter release.

• PGF2α found in uterine (and other) smooth muscle, and corpus luteum, producing contraction of the uterus and luteolysis (in some species).

• PGD2 is derived particularly from mast cells causing vasodilatation and inhibition of platelet aggregation

Clinical uses of prostanoids

• Gynaecological and obstetric – termination of pregnancy: gemeprost or misoprostol

(a metabolically stable prostaglandin (PG) E analogue) – induction of labour: dinoprostone or misoprostol – postpartum haemorrhage: carboprost.

• Gastrointestinal – to prevent ulcers associated with non-steroidal anti-

inflammatory drug use: misoprostol

• .

• Cardiovascular – to maintain the patency of the ductus

arteriosus until surgical correction of the defect in babies with certain congenital heart malformations: alprostadil (PGE1)

– to inhibit platelet aggregation (e.g. during haemodialysis): epoprostenol (PGI2), especially if heparin is contraindicated

– primary pulmonary hypertension: epoprostenol

• Ophthalmic – open-angle glaucoma: latanoprost eye drops

Platelet-activating factor

• PAF is released from activated inflammatory cells by phospholipase A2 and acts on specific receptors in target cells

Pharmacological actions include

• vasodilatation, increased vascular permeability, chemotaxis and activation of leucocytes (especially eosinophils), activation and aggregation of platelets, and smooth muscle contraction.

• PAF is implicated in bronchial hyperresponsiveness and in the delayed phase of asthma.

Bradykinin

• BK is a nonapeptide 'clipped' from a plasma α-globulin, kininogen, by kallikrein.

• It is converted by kininase I to an octapeptide, BK1-8 (des-Arg9-BK), and inactivated by kininase II (angiotensin-converting enzyme) in the lung.

Pharmacological actions

– vasodilatation (largely dependent on endothelial cell nitric oxide and prostaglandin

– increased vascular permeability – stimulation of pain nerve endings – stimulation of epithelial ion transport and

fluid secretion in airways and gastrointestinal tract

– contraction of intestinal and uterine smooth muscle.

• There are two main subtypes of BK receptors: B2, which is constitutively present, and B1, which is induced in inflammation.

• There are selective competitive antagonists for both B1 receptors (des-Arg Hoe 140; pA2:8) and B2 receptors (icatibant, pA2:9).

Cytokines

• Cytokines are polypeptides released during inflammation that regulate the action of inflammatory and immune system cells.

• The cytokine superfamily includes the interferons, interleukins, tumour necrosis factor (TNF), growth factors, chemokines and colony-stimulating factors.

• Utilising both autocrine or paracrine mechanisms, they exert complex effects on leucocytes, vascular endothelial cells, mast cells, fibroblasts, haemopoietic stem cells and osteoclasts, controlling proliferation, differentiation and/or activation.

• Interleukin (IL)-1 and TNF-α are important primary inflammatory cytokines inducing the formation of other cytokines.

• Interferon (IFN)-α and IFN-β have antiviral activity, and IFN-α is used as an adjunct in the treatment of viral infections. IFN-γ has significant immunoregulatory function and is used in the treatment of multiple sclerosis

Leukotrienes• 5-Lipoxygenase oxidises arachidonate to

give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is converted to leukotriene (LT) A4. This, in turn, can be converted to either LTB4 or to a series of glutathione adducts, the cysteinyl-leukotrienes LTC4, LTD4 and LTE4.

• LTB4, acting on specific receptors, causes adherence, chemotaxis and activation of polymorphs and monocytes, and stimulates proliferation and cytokine production from macrophages and lymphocytes.

• The cysteinyl-leukotrienes cause: – contraction of bronchial muscle – vasodilatation in most vessels, but coronary

vasoconstriction.

• LTB4 is an important mediator in all types of inflammation; the cysteinyl-leukotrienes are of particular importance in asthma.

Prostaglandins• Prostaglandins were isolated from human

semen in 1936 by Ulf von Euler. He named them Prostaglandins because he believed they came from the prostate gland.

• The Swedish scientist received the Nobel Prize in medicine in 1970 for this work.

• Since his work in this area it has been determined that they exist and are synthesized in almost every cell of the body.

• They are synthesized in the same cell on which they act.

Biosynthesis of Prostaglandins• The goal is to inhibit the biosynthesis of

prostaglandins in order to relieve the symptoms caused by the inflammatory response.

• Prostaglandins are synthesized from arachidonic acid in a pathway mediated by the Cyclooxygenase enzymes.

ROLE OF PROSTAGLANDINS

PHYSIOLOGIC

TEMPERATURE CONTROL

BRONCHIAL TONE

CYTOPROTECTION

INTESTINAL MOBILITY

MYOMETRIAL TONE

SEMEN VIABILITY

PATHOLOGIC

FEVERASTHMAULCERSDIARRHEADYSMENORRHEA INFLAMMATION

BONE EROSION

PAIN

FUNCTION OF PROSTAGLANDINS IN INFLAMMATION

• PGE2, PGI2

VASODILATION,

ACT SYNERGISTICALLY WITH OTHER MEDIATORS

HISTAMINE, COMPLEMENT, LTB4

BRONCHODILATATION

INHIBITION OF PLATELET AGGREGATION

• TXA2

PROMOTION OF PLATLET AGGREGATION

COX Enzyme:Prostaglandin Effects

COX-1: beneficial COX-2: harmful

Peripheral injury site Inflammation

Brain Modulate pain perception

Promote fever (hypothalamus)

Stomach protect mucosa

Platelets aggregation

Kidney vasodilation

COX Expression Function Inhibitors

COX-1constitutively throughout the body

organ pain, platelet function, stomach

protection

NSAIDs including aspirin

COX-2Inducible and constitutively in brain, kidney

Inducible:  inflammation, pain, feverConstitutive:  synaptic

plasticity

NSAIDs, COX 2 inhibitors including celecoxib

(Celobrex )

COX-3Constitutively, high

in brain, heart

pain pathways, not inflammation pathways

acetaminophen some NSAIDs

Non-steroidal anti-inflammatory drugs NSAIDs

• three major pharmacologically desirable actions, stemming from the suppression of prostanoid synthesis in inflammatory cells through inhibition of the cyclo-oxygenase (COX)-2 isoform of the arachidonic acid COX. They are as follow.

• An anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, oedema. Accumulation of inflammatory cells is not reduced.

• An analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated vasodilatation

• An antipyretic effect: interleukin-1 releases prostaglandins in the central nervous system, where they elevate the hypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this. Some important examples are aspirin , ibuprofen , naproxen , indomethacin, piroxicam and paracetamol. Newer agents with more selective inhibition of COX-2 (and thus fewer adverse effects on the gastrointestinal tract) include celecoxib and etoricoxib

EFFECTS OF NSAIDS • INHIBITION OF – CYCLOOXYGENASE ENZYMES – LIPOXYGENASE ENZYMES – SUPEROXIDE GENERATION – LYSOSOMAL ENZYME RELEASE – NEUTROPHIL ACTIVITY – LYMPHOCYTE FUNCTION – CYTOKINE RELEASE – CARTILAGE METABOLISM

Effects of COX Inhibition by Most NSAIDS

COX-1

Gastric ulcers

Bleeding

Acute renal failure

COX-2

Reduce inflammation

Reduce pain

Reduce fever

NSAIDs : anti-platelet—decreases ability of blood to clot

General unwanted effects of NSAIDs

• Due to inhibition of the constitutive housekeeping enzyme cyclo-oxygenase (COX)-1 isoform of COX, are common, particularly in the elderly, and include the following.

• Dyspepsia, nausea and vomiting. Gastric damage may occur in chronic users, with risk of haemorrhage. The cause is suppression of gastroprotective prostaglandins in the gastric mucosa.

• Skin reactions. Mechanism unknown.

• Reversible renal insufficiency. Seen mainly in individuals with compromised renal function when the compensatory prostaglandin E2-mediated vasodilatation is inhibited.

• 'Analgesic-associated nephropathy'. This can occur following long-continued high doses of NSAIDs (e.g. paracetamol) and is often irreversible.

• Liver disorders, bone marrow depression. Relatively uncommon.

• Bronchospasm. Seen in 'aspirin-sensitive' asthmatics

Clinical uses of NSAIDs

• For analgesia (e.g. headache, dysmenorrhea, backache, bony metastases, postoperative pain): – short-term use: aspirin , paracetamol or

ibuprofen – chronic pain: more potent, longer

lasting drugs (e.g. diflunisal , naproxen , piroxicam )

– to reduce the requirement for narcotic analgesics (e.g. ketorolac postoperatively).

•In addition to its anti-inflammatory actions, aspirin   inhibits platelet aggregation, and its main clinical importance now is in the therapy of myocardial infarction. •It is given orally and is rapidly absorbed; 75% is metabolised in the liver. •Elimination follows first-order kinetics with low doses (half-life 4 hours), and saturation kinetics with high doses (half-life over 15 hours). •Unwanted effects:

•with therapeutic doses: some gastric bleeding (usually slight and asymptomatic) is common •with large doses: dizziness, deafness and tinnitus ('salicylism'); compensated respiratory alkalosis may occur •with toxic doses (e.g. from self-poisoning): uncompensated respiratory acidosis with metabolic acidosis may occur, particularly in children •aspirin  

has been linked with a postviral encephalitis (Reye's syndrome) in children.

•If given concomitantly with warfarin, aspirin   can cause a potentially hazardous increase in the risk of bleeding.

• For anti-inflammatory effects (e.g. rheumatoid arthritis and related connective tissue disorders, gout and soft tissue disorders). – Note that there is substantial individual

variation in clinical response to NSAIDs and considerable unpredictable patient preference for one drug rather than another.

• To lower temperature (antipyretic): paracetamol.

Aspirin (acetylsalicylic acid)

• is the oldest non-steroidal anti-inflammatory drug. It acts by irreversibly inactivating both cyclo-oxygenase (COX)-1 and COX-2.

• In addition to its anti-inflammatory actions, aspirin inhibits platelet aggregation, and its main clinical importance now is in the therapy of myocardial infarction.

• It is given orally and is rapidly absorbed; 75% is metabolised in the liver.

• Elimination follows first-order kinetics with low doses (half-life 4 hours), and saturation kinetics with high doses (half-life over 15 hours).

• Unwanted effects: – with therapeutic doses: some gastric bleeding (usually

slight and asymptomatic) is common – with large doses: dizziness, deafness and tinnitus

('salicylism'); compensated respiratory alkalosis may occur

– with toxic doses (e.g. from self-poisoning): uncompensated respiratory acidosis with metabolic acidosis may occur, particularly in children

– aspirin has been linked with a postviral encephalitis (Reye's syndrome) in children.

• If given concomitantly with warfarin, aspirin can cause a potentially hazardous increase in the risk of bleeding.

Reye’s • Seen in children under 15 after an acute

viral illness• Results in encephalopathy, fatty

infiltration of the liver, pancreas, kidneys, spleen, and lymph nodes

• Cause is unknown

Aspirin in non-inflammatory conditions

• Aspirin-previously thought of as an old anti-inflammatory workhorse-is now approaching the status of a wonder drug that is of benefit not only in inflammation, but in an increasing number of other conditions. These include:

• cardiovascular disorders: through the antiplatelet action of low-dose aspirin

• colonic and rectal cancer: aspirin (and COX-2 inhibitors) may reduce colorectal cancer-clinical trial results are awaited

• Alzheimer's disease: again, clinical trial results are awaited

• radiation-induced diarrhoea.

Paracetamol (Acetaminophen)

• has potent analgesic and antipyretic actions but rather weaker anti-inflammatory effects than other NSAIDs. It may act through inhibition of a CNS -specific (COX) isoform such as COX-3, although this is not yet conclusive.

• It is given orally and metabolised in the liver (half-life 2-4 hours).

• Toxic doses cause nausea and vomiting, then, after 24-48 hours, potentially fatal liver damage by saturating normal conjugating enzymes, causing the drug to be converted by mixed function oxidases to N-acetyl-p-benzoquinone imine. If not inactivated by conjugation with glutathione, this compound reacts with cell proteins and kills the cell.

• Agents that increase glutathione (I.V acetylcysteine or oral methionine ) can prevent liver damage if given early.

G.I.T Effects of NSAIDS(Ibuprofen=1)

NSAIDS• Propionic acid derivatives such as

ibuprofen, ketoprofen (Orudis), naproxen and fenoprofen (Nalfon)

• Acetic acid derivatives include indomethacin (Indocin), sulindac (Clinoril) and tolmetin (Tolectin)---these drugs have more severe adverse reactions than the proprionic acid derivatives

NSAIDS• IV indomethacin is approved for the tx of

patent ductus arteriosus in premature infants.

• Remember: patent ductus is a communication between the pulmonary artery and the aorta

NSAIDS• ketoralac is used only for pain. Is the only

NSAID that can be given by injection. Use limited to 5 days as can cause bleeding.

• Oxicam drugs include meloxacam and piroxicam

• celecoxib• Affect bleeding only while drug is still in

the system

Effects of Nonsteroidals on Other Drugs

• Decrease effects of ACEI, beta blockers and diuretics

• Affect sodium and water retention• Inhibit renal prostaglandin synthesis