autacoids & anti- inflammatory agents cecile a. jimeno. md

Autacoids & Anti-inflammatory Agents

Cecile A. Jimeno. MD

Definitions

Hormone (Bayliss & Starling): a chemical substance that was secreted, without benefit of a duct, directly into the bloodstream and which acted at long range, often slowly, on distant organs or tissues

Definitions

Neurotransmitters: released by neurons, not endocrine glands, and acted briefly and at short range on adjacent neurons or target cells

HOW TRUE? HOW TIDY?

Spurious classification of the body’s chemical messengers

Moving from “orderly inexactitude” towards a “confused precision”

What’s the Issue?

Some substances which were not neurotransmitters acted briefly as short range and on adjacent cells (e.g. histamine on mast cells) ans these were termed local hormones or paracrine secretions

Autocrine secretions: act in cells which secrete them e.g cytokines

What’s the Issue? “Hormones” “neurotransmitters” and

“local hormones” [autacoids or paracrine secretions] are not separate categories in terms of function and locus of action: categories overlap

_________________________________________Predominantly neurotransmitters (acteylcholine)

Predominantly hormones (e.g. sex steroids)

Mediators of

inflammation

“Autacoids”

a varied group of endogenous substances occurring in minute amounts and possessing distinct chemical structure with distinct biologic/ pharmacologic activity

Autos = self; Akos = medicinal agent or remedy (Greek).

AUTACOIDS Naturally occurring substances Localized in tissues Do not normally circulate Diverse physiological and pharmacological

activities Differ from hormones and neurotransmitters Short duration of action Usually involved in response to injury Sites of action restricted to the synthesis

area

Examples of autacoids

Amines: histamine, serotonin (5HT)

Polypeptides: kinins, oxytocin, angiotensin II, vasopressin, atrial natriuretic factor, endothelins.

Fatty acids: prostaglandins, leukotrienes, thromboxanes, platelet activating factor (PAF).

Others: endothelium-derived relaxing factor (NO), cytokines (proteins).

Histamine

Signal for local immune responses, also a neurotransmitter

Synthesized by the decarboxylation of histidine

Either stored or quickly inactivated by histamine-N-methyltransferase and diamine oxidase

Release from mast cells is stimulated by IgE antibodies in response to foreign antigens

Pathophysilogical actions of Histamine

Involved in allergic reactions

Mediate type 1 hypersensitivity reactions: hives and hay fever.

Emesis: mediation of motion sickness.

Histamine shock (hypotension): systemic anaphylaxis.

Selected Actions of Histamine in Humans

Organ Tissue Action Receptor

RESPIRATORY

Bronchiolar smooth muscle

Contraction (more prominent)

Relaxation

H1

H2

GASTROINTESTINAL

Oxyntic mucosa

GI smooth muscle

Gallbladder smooth muscle

Acid and pepsin secretion, If

Relaxation & Contraction

(more prominent)

Relaxation (?)

H2

H1

H2 (?)

CUTANEOUS NERVE ENDINGS (Sensory)

Pain & itching

(esp to insect bites & needle stings)

H1, H2 (?)

ADRENAL MEDULLA Epinephrine release H1

BASOPHILS Inhibition of IgE – dependent degranulation

H2

BIOGENIC AMINESSEROTONIN

Source: plants (banana, pineapple, plums) & animals (mollusks, arthropods, mammals (platelets, not in mast cells).

Biosynthesis: Hydroxylation of tryptophan, then decarboxylation to serotonin(5-hydroxy tryptamine;5-HT). Rapidly absorbed into secretory granules. Accumulated in platelets, degradation by oxidative deamination.

Uses: No therapeutic use. Antagonists are highly useful.

SEROTONIN actions

Neurotransmitter in the CNS Precursor of melatonin Induces sleep, Intestinal motility Involved in Temperature regulation Affects mood and behavior (humans) Deficiency causes depression Hemostasis : Platelet aggregation &

vasoconstriction

Serotonin

Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol.

GI tract: small intestine very sensitive to serotonin → intense rhythmic contractions due to direct & indirect (ganglia in wall) effects.

Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally).

1. Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI2 – mediated)

2. Heart: direct inotropic & chronotropic effects

3. Reflex mechanisms due to change in BP

4. Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension

Serotonin: Cardiovascular system

Pain perception

Sleep/Wakefulness

Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc.

Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones.

Serotonin in the Central Nervous System

BRADYKININ

A nonapeptide formed after tissue damage, viral infections and

allergic response.

Bradykinin (activate B1 and B2 receptors; t½ = 15 s)

Vasodilatation (direct or via NO, Pgs) → Increased capillary pressure

Venular permeability → edema.

Contract smooth muscles: intestine, uterus, veins, bronchioles.

Bradykinin (activate B1 and B2 receptors; t½ = 15 s)

Ion transport and fluid secretion in airways and GIT → allergic rhinitis, diarrhea, pancreatitis.

Role in chronic inflammation (e.g., hereditary angioedema, gout, rheumatoid arthritis, inflammatory bowel disease).

Pain at site of injection – stimulate nociceptive afferents.

Ang Mga Bida

Eicosanoids

Eicosanoids

Unlike histamine, are not found preformed in the tissues

Generated de novo from phospholipids

Control of many physiological processes

Most important mediators and modulators of the inflammatory reaction

MEMBRANE DERIVED AGENTSEICOSANOIDS

Derived from Arachidonic acid (AA), a 20 carbon essential fatty acid

AA is esterified to phospholipids of the cell membranes

Biosynthesis depends on enzyme availability Synthesis is regulated and initiated by physical

& chemical stimuli These stimuli cause release of AA from the

cellular stores

EicosanoidsExamples

Prostaglandins Thromboxanes Leukotrienes

Epoxyeicosatrienoic acids.

Functions

Inflammation Fever regulation of BP blood clotting immune system

modulation control of reproductive

processes & tissue growth

regulation of sleep/wake cycle.

MEMBRANE DERIVED AGENTSBiosyntheiss of EICOSANOIDS

Physical & chemical stimuli interact with membrane-bound G protein receptors ----- activates phopholipase C and/or phospholipase A2 which increases concentration of intracellular Ca

Phospholipase A2 hydrolyzes ester bond of phopholipids (AA release)

Phospholipase C cleaves the bond and forms diglyceride

Diglyceride lipase releases diglyceride arachidonate from diglycerides

The released arachidonate is oxygenated by several enzymes: major enzymes are cyclooxygenase and lipoxygenase

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Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase A2

Cycloo

xyge

nase Lipoxygenase

ProstaglandinsThromboxanesProstacyclins

LeukotrienesOthers

IsoprostanesCyt. P450products

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Leukotrienes

Leukotrienes have roles in inflammation.

They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis.

Also implicated in asthmatic constriction of the bronchioles.

Some leukotrienes act via specific G-protein coupled receptors (GPCRs) in the plasma membrane.

Modulators of the pathways

NSAID’s and Corticosteroids (COX Inhibitors)

Lipoxygenase Inhibitors (Zileuton)

TXA2 Synthase Inhibitors

Receptor Antagonists (TXA2)

LTD4 Receptor Antagonist (Montelukast)

Analogues (PGE2, PGI2, Archidonic Acid)

Eicosanoid Alphabet Names of the first 2 eicosanoids derives from

the names of the first 2 prostaglandins based on the separation procedure

PGE – partitioned into Ether

PGF – into the phosphate buffer (Fosfat in Swedish)

PGA and PGB – which are artefacts, based on their stability in Acids and Bases

Other letters of the alphabet were just filled in

Prostanoids

encompasses the prostaglandins and thromboxanes

Cyclo-oxygenase (COX) acts on arachidonate to give rise to cyclic endoperoxides (PGG2 and PGH2)

In turn, give rise to PGI2(vascular endothelium), TXA2 , PGE2 , PGF2 , PGD2

Actions of the Prostanoids

PGD2 : vasodilatation, inhibition of platelet aggregation, relaxation of gastrointestinal muscle, uterine relaxation, modification of release of hypothalamic/pituitary hormones

PGF2: mypmetrial contractions (humans)

PGI2 (prostacyclin): vasodilatation, inhibition of platelet aggregation, renin release and natriuresis, via effects on tubular absorption of sodium

Actions of the Prostanoids TXA2: vasoconstriction, platelet aggregation

PGE2 : EP1 receptors - contraction of bronchial

and GI smooth mm

EP2 receptors- bronchodilation, vasodilatation , stimulation of intestinal fluid secretion & relaxation of GI smooth mm

EP3 – contraction of int smooth mm, inhibition of gastric acid secretion and increased gastric mucus secretion, stimulation of contraction of pregnant human uterus

Action of NSAID’s & steroids on mediators derived from arachidonic acid (eicosanoids)

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Platelets

Vascular endothelium

macrophages

Pharmacological/Physiological EffectsI. Cardiovascular System

1. TXA2: vasoconstrictor.

2. PGE2 and PGI2: vasodilators.

3. LTC4 and D4: increased vascular permeability. ↓Cardiac contractility. ↓ blood pressure.

4. Protective effect of vasodilator prostaglandins especially in kidney.

5. Renin release

Pharmacological/Physiological Effects

III. Pulmonary

1. LTC4 and D4: Bronchoconstriction + ↑mucus secretion + ↑vascular permeability

1. PGE2 , PGI2: bronchodilators.

IV. GI Tract

1. PGE2 + LT’s contract

smooth muscle

2. PGE2: watery diarrhea,

vomiting & cramps (↑cAMP)

3. PGE2+ PGI2: inhibit gastric

acid secretion; Cytoprotective effect (↑ mucosal blood flow; ↑cAMP; ↑ mucus secretion; ↑ protein synthesis)..

Role of

Prostanoids in

InflammationMOA of NSAID’s

Role of Prostanoids in Inflammation

Inflammatory response is always accompanied by the release of prostanoids from local tissues and blood vessels, predominantly PGE2

though PG12 can also be found

In chronic inflammation, cells of the monocyte-macrophage series also release PGE2 and TXA2

Mediators of acute inflammation and their effects

Mediator (Autacoids)

Vaso-

dilation

Vascular

permeability

Chemotaxis Pain

Histamine ++ ↑ ↑ ↑ - -

Serotonin +/- ↑ - -

Bradykinin +++ ↑ - +++

Prostaglandins +++ ↑ +++ +

Leukotrienes - ↑ ↑ ↑ +++ -

OTHERS: Nitric Oxide, Platelet Activating Factor 45

Summary 1. Autacoids are part of a heterogenous group

of substances that participate in homeostasis.

2. Autacoids have different sources, fates, and biologic activities.

3. Autacoids play an imp’t role in health and disease.

4. Understanding the pharmacologic properties of these agonists, antagonists & inhibitors using prototype drugs is important to effectively utilize these agents in the clinical setting.

Pharmacologic Mgt of Inflammation and Pain: Focus on NSAID’s

Cecilia A. Jimeno, M.D.

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Objectives

• To review the pathophysiology of inflammation• To differentiate between steroids, salicylates,

NSAID’s and opioids• To discuss the structure and mechanisms of

actions of NSAID’s• To enumerate the adverse effects and toxicity

from NSAID’s

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3 Phases of Inflammatory Response

1 Acute transient phase – local vasodilation & increased capillary

permeability (floodgates open)

2 Delayed, subacute phase– infiltration of leukocytes & phagocytic cells

(chemotaxis & diapedesis)

3 Chronic proliferative phase– tissue degeneration & fibrosis (± repair)

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1. Acute: calor, rubor, tumor, dolor

2. Immune response- activation of immunologically competent cells in response to foreign organisms or antigenic substances liberated during the acute phase

3. Chronic inflammation – release of a number of mediators that are not prominent in the acute response

Phases of the inflammatory response

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Mediators of acute inflammation and their effects

Mediator (Autacoids)

Vaso-

dilation

Vascular

permeability

Chemotaxis Pain

Histamine ++ ↑ ↑ ↑ - -

Serotonin +/- ↑ - -

Bradykinin +++ ↑ - +++

Prostaglandins +++ ↑ +++ +

Leukotrienes - ↑ ↑ ↑ +++ -

OTHERS: Nitric Oxide, Platelet Activating Factor 51

Chronic inflammation

• Chronic inflammation e.g. in RA can result in pain and destruction of bone & cartilage leading to severe disability

• Cell damage, fibrosis and contractures in the joints and peri-articular tissues

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Some mediators of chronic inflammation e.g. RA

Mediator Sources Primary effectsInterleukins-1,-2 and -3

Macrophages, T-lymphocytes

Lymphocyte activation. Prostaglandin production

GM-CSF T-lymphocytes, endothelial cells, fibroblasts

Macrophage & granulocyte activation

TNF-α Macrophages Prostaglandin production

Interferons Macrophages, endothelial cells, T-lymphocytes

Many

PDGF Macrophages, endothelial cells, fibroblasts, platelets

Fibroblast chemotaxis, proliferation

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Primary goals of treatment

• Pain relief

• Slowing, or arrest, of the tissue-damaging process

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Pharmacotherapy of Inflammation & Pain

• Non-steroidal anti-inflammatory drugs (NSAIDs)

• Corticosteroids• Disease-modifying antirheumatic drugs

(DMARDS)• Other Analgesics: Opiates, Opioids• Drugs used in gout

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Definition: NSAID’s

• Weak inorganic acids [or pro-drug for the acidic active drug e.g. nabumetone] linked to an aromatic residue which inhibit the COX enzymes involved in arachidonic acid metabolism.

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Definition: STEROIDS

• All endogenous products derived from cholesterol are steroids

• All pharmacologic agents which have similar structure and action

• GLUCOCORTICOIDS = Corticosteroids

• Have actions on glucose, proteins & fat (substrate) & bone (mineral) metabolism

•Anti-inflammatory & immunosuppressant actions

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID’s)

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Non-steroidal Anti-inflammatory Drugs (NSAID’s)

• Any anti-inflammatory drug that is not classified as steroids

• Most prescribed drugs for ‘rheumatic’ musculoskeletal complaints

• Often taken without prescription (OTC) for minor aches & pains

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General properties of NSAID’s

1. All are weak inorganic acids; the exception (nabumetone) is a ketone pro-drug that is metabolized to the acidic active drug

2. Chemically, the acidic moiety is linked to an aromatic residue;

3. Most of the drugs are well absorbed, and food does not substantially change their bioavailability

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General Effects of NSAID’s

• All NSAID’s have the following actions:1. Antipyretic (Temperature lowering)

2. Analgesic (Pain relief)

3. Anti-inflammatory (Decrease swelling and other signs & symptoms of inflammation)

• However, the extent to which they exert these effects differs from one agent to another

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General Indications

• Any etiology of pain or inflammation• Rheumatoid arthritis• Psoriatic arthritis• Osteoarthritis• Localized musculoskelatal syndromes (e.g.

sprains, strains, low back pain)• Gout • Mild to moderate pains of any etiology

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• Most are well absorbed orally

• Most are highly metabolized in the liver: CYP3A or CYP2C families of P450 enzymes

• Route of excretion: renally BUT nearly all NSAID’s undergo varying degrees of biliary excretion & reabsorption

• Degree of GI tract irritation correlates with the amt of enterohepatic circulation

• Most of the are highly protein bound, usually to albumin: SO?

Pharmacokinetics of NSAID’s

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• All currently available NSAID’s can have significant side effects esp. in the elderly

• Since aspirin the original NSAID has a number of side effects, many NSAID’s have been developed to improve upon aspirin’s efficacy and decrease toxicity

NSAID’s

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NSAID’s: Mechanism of Action

• Inhibit the cyclooxygenase (COX) enzyme suppressing inflammation, alleviating pain and lowering fever

• COX localized to the endoplasmic reticulum are responsible for the formation from arachidonic acid of a group of local hormones comprising the prstaglandins, prostacyclins & thromoboxanes

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• All NSAID’s (except aspirin effects on platelets) are reversible inhibitors of COX enzymes

• These enzymes possess an elongated pore into which the substrate arachidonic acid is inserted and converted into an active product

• NSAID’s penetrate into this pore and prevent access for arachidonic acid, leading to reversible blockade of the enzyme

Pharmacodynamics

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The COX Enzymes

Two types of COX enzymes1. COX 1 – a constitutive enzyme expressed

in most tissues (kidney, GIT, including platelets); prostanoids it produces are involved in cell-cell signaling & in tissue homeostasis (GOOD COX)

1. COX 2 – induced in inflammatory cells when they are activated by inflammatory cytokines (peptides released from inflammatory tissues) – primarily interleukin 1 and TNF α

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COX enzyme

COX-1 is essential for thromboxane formation in blood platelets, and for maintaining integrity of the gastrointestinal epithelium.

COX-2 levels increase in inflammatory diseases such as arthritis.

Inflammation is associated with up-regulation of COX-2 & increased amounts of particular prostaglandins.

COX enzyme

COX-2 expression is increased in some cancer cells.

Angiogenesis (blood vessel dev’t), which is essential to tumor growth, requires COX-2.

Overexpression of COX-2 leads to increased expression of VEGF (vascular endothelial growth factor).

Regular use of NSAIDs has been shown to decrease the risk of developing colorectal cancer.

• Endothelium, brain, spinal cord• Kidney (Macula densa), ovaries, uterusCOX-2 also in

Mechanism of Action of NSAID’s

3 major actions of NSAID’s (esp. anti-inflammatory): mainly due to the inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis (both PG and TXA2)

Most NSAID’s are inhibitors of both enzymes, with varying degrees of inhibition of each

Inhibition of COX1: adverse effects e.g. GI bleeding

Coxibs have selective action on COX 2

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Nonselective vs COX 2 Inhibitors

COX-2 inhibitors are anti-inflammatory & block pain, but are less likely to cause gastric toxicity associated with chronic use of NSAIDs that block COX-1. 

A tendency to develop blood clots when taking some of these drugs has been attributed to:  decreased production of an anti-thrombotic (clot

blocking) prostaglandin (PGI2) by endothelial cells lining small blood vessels

lack of inhibition of COX-1-mediated formation of pro-thrombotic thromboxanes in platelets.

Some evidence suggests the existence of a third isoform of PGH2 Synthase, designated COX-3, with roles in mediating pain and fever, and subject to inhibition by acetaminophen/paracetamol.

Acetaminophen has little effect on COX-1 or COX-2, and thus lacks anti-inflammatory activity.

Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting.

Many people take a daily aspirin for its anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets.

This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme.

NSAID’s: Shared Therapeutic Effects

1. Antipyretic 2. Analgesic, for low-to-mod intensity like dental

pain, postop pain or pain from inflammatory conditions. Not visceral pain.

3. Anti-inflammatory, symptomatic relief in musculoskeletal disorders (eg, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis)

(EXCEPT paracetamol, which is effective vs brain COX only, not anti-inflammatory in peripheral tissues)

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Other mechanisms of Action of other NSAID’s• Inhibition of chemotaxis

• Down-regulation of interleukin-1 production

• Decreased production of free radicals and superoxide

• Interference with calcium-mediated intracellular events

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Adverse effects of NSAID’s

ARACHIDONIC ACIDARACHIDONIC ACID

Nephropathy, decreased excretion of NaCl and H2O, edema, increased BP, impaired wound healing, diarrhea, disturbed uterine motility

Gastric mucosal damage with ulcer formation, bleeding and perforation

Non-selective COX inhibitors

COX

Prostaglandin decreased

Lower incidence of gastric complications

Selective COX-2 inhibitors

Lipo-oxygenases

Leukotrienes increased

(depending on supply of arachidonic acid)

Bronchoconstriction, bronchial asthma, proinflammatory effect

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ADVERSE EFFECTS (due to COX-1 inhibition)

1. Gastric or intestinal ulceration due to loss of cytoprotective PGI2 & PGE2 (less risk with highly selective COX-2 inhibitors)

2. Disturbance in platelet function (TXA2)

3. Prolongation of gestation/spontaneous labor

4. Premature closure of ductus

5. Renal function changes: increased water retention; critical in CHF, cirrhosis, chronic renal dis, hypovolemic

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Other Effects of NSAID’s: Kidneys

• COX-inhibitors prevent the synthesis of PGI2 and PGE2 - prostaglandins that are responsible for maintaining renal blood flow, particularly in the presence of circulating vasocontrictors

• All the NSAID’s except ASA can also directly cause interstitial nephritis

• ALL NSAID’s are potentially NEPHROTOXIC

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• TXA2 enhances platelet aggregation, whereas PGI2 inhibits it

• Plalelet aggregation is the first step in thrombus production e.g. in atherosclerotic plaque

• Low doses of ASA (> 60 to 80 mg daily) can irreversibly inhibit thromboxane production in platelets w/o markedly affecting TXA2 production in the endothelial cells of the blood vessels

Prototype: Aspirin (ASA)Effects on platelets

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Focus on the Prototype: ASA• Acetylation of salicylic acid significantly reduces

its ability to induce mucosal injury• Anti-inflammatory activity: use dose > 3 g daily• Anti-pyretic & analgesic dose is much lower• At low dosage (60-200 mg), following absorption

into the portal circulation causes a long-lasting, irreversible blockade of COX-1 mediated thromboxane synthesis in platelets because of irreversible acetylation of the enzyme: WHAT FOR?

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• Platelets (3 to 7 days life span): no nucleus & cannot synthesize new enzyme unlike endothelial cells

• Basis for the anti-coagulant properties of ASA• ASA increases the bleeding time• Also explains other side-effects e.g. increased

tendency for hemorrhagic strokes

Effects on platelets

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Focus on the Prototype: ASA• Common Adverse Effects (at usual doses):

gastric upset, gastric & duodenal ulcers• Uncommon effects: hepatotoxicity, asthma,

rashes, renal toxicity• GI-bleeding is dose-related• Salicylism: vomiting, tinnitus, decreased hearing,

vertigo at higher doses• Higher doses causes metabolic acidosis,

respiratory depression, cardiotoxicity & glucose intolerance

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GENERAL CLASSIFICATION OF NSAID’S

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General Chemical Classification

• Non-selective COX Inhibitors : aspirin, indomethacin, diclofenac, ibuprofen, mefenamic acid, nabumetone

• Selective COX-2 Inhibitors :

highly selective - celecoxib, etoricoxib

preferential - meloxicam

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Selective COX-2 inhibitors

• Efficacy of COX-2 selective drugs equals that of the other NSAID’s, while gastrointestinal safety may be improved

• On the other hand, COX-2 inhibitors may increase the incidence of edema and hypertension

• Celecoxib and eterocoxib

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The Vioxx story

• Rofecoxib (Vioxx) and valdecoxib (bextra), two previously marketed highly selective COX-2 inhibitors have been withdrawn form the market (voluntarily) due to their association with increased cardiovascular thrombotic events

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The Vioxx story

• 2005: Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the FDA concluded that “there was not enough evidence to withdraw the COX-2 inhibitors but “black-box” warnings concerning the cardiovascular risks should be added to the product label”.

• Additionally, it was recommended that all other NSAID product labels be revised to include cardiovascualr risks

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Chemical Classification of Analgesic, Antipyretic, and NSAID’s

Salicylic acid derivatives (= SALICYLATES) Aspirin, sodium salicylate, diflunisal, salicylsalicylic

acid, sulfasalazine

Para-aminophenol derivatives: Acetaminophen

Indole and indene acetic acidsIndomethacin, sulindac, etodolac

Heteroaryl acetic acids: Tolmetin, diclofenac, ketorolac

Arylpropionic acidsIbuprofen, naproxen, flurbiprofen, ketoprofen

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Chemical Classification of Analgesic, Antipyretic, and NSAID’s

Anthranilic acids (fenamates)Mefenamic acid, meclofenamic acid

Enolic acidsOxicams (piroxicam, tenoxicam, meloxicam), pyrazolidinediones (phenylbutazone)

Alkanones: Nabumetone

Coxibs:Rofecoxib, Celecoxib, Valdecoxib, Eterocoxib

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Pharmacologic properties of aspirin and NSAIDs

Drug Half-life

(hrs)

Recommended anti-inflam. dosage

Comments

Mefenamic acid

3 250-500 mg tid to qid COX/PhLipaseA

Meloxicam 20 7.5 – 15 mg daily “preferentially” selective

Nabumetone 26 1000-2000 mg daily Expensive

Naproxen 14 375 mg bid Photosensitivity

Piroxicam 57 20 mg daily Greatest ulcer risk

Valdecoxib 8-11 10 mg qd Withdrawn in the US due to CV risk & SJ syndrome

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Adverse effects of NSAID’s

ARACHIDONIC ACIDARACHIDONIC ACID

Nephropathy, decreased excretion of NaCl and H2O, edema, increased BP, impaired wound healing, diarrhea, disturbed uterine motility

Gastric mucosal damage with ulcer formation, bleeding and perforation

Non-selective COX inhibitors

COX

Prostaglandin decreased

Lower incidence of gastric complications

Selective COX-2 inhibitors

Lipo-oxygenases

Leukotrienes increased

(depending on supply of arachidonic acid)

Bronchoconstriction, bronchial asthma, proinflammatory effect

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Anti-pyretic analgesics: Paracetamol/ acetaminophen

• P-aminophenol or pyrazolone derivatives with clinically useful analgesic and antipyretic efiicacy

• Act by inhibiting prostaglandin synthesis in the CNS: anti-pyretic & analgesic

• Less effect on cyclo-oxygenase in peripheral tissues: hence, weak anti-inflammatory activity

• Mild pain e.g. headache, fever or conditions which do not require anti-inflammatory actions

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Anti-pyretic analgesics

• Lack side effects of aspirin• Do not affect platelet function or increase blood

clotting• Examples: Acetaminophen (paracetamol),

phenazone and dipyrone

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• Rapidly absorbed from GIT• With significant first pass metabolism in the

luminal cells of intestine & liver• Excreted in the kidney• Adverse effects

– At normal therapeutic doses, NONE– Infrequent rash & minor allergic reactions– Large doses: renal tubular necrosis & hypoglycemic

coma (Rare), hepatic necrosis

Acetaminophen (Paracetamol)

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