Download stuNSAIDs[2011

Non-steroidal AntiInflammatory Drugs
Dr.HAZAR 2011
1
Definition of the drugs & their categories
2 The inflammatory response & inhibition
3
side effects
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 nonsteroidal anti-inflammatory drugs
• The first is non-selective antiinflammatory 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 antiinflammatory 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 (angiotensinconverting 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 (desArg 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 cysteinylleukotrienes 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 cysteinylleukotrienes 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
PATHOLOGIC
FEVER
ASTHMA
ULCERS
DIARRHEA
DYSMENORRHEA
INFLAMMATION
BONE EROSION
PAIN
PHYSIOLOGIC
TEMPERATURE CONTROL
BRONCHIAL TONE
CYTOPROTECTION
INTESTINAL MOBILITY
MYOMETRIAL TONE
SEMEN VIABILITY
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
COX-1
Expression
constitutively
throughout the
body
Function
organ pain, platelet
function, stomach
protection
Inhibitors
NSAIDs including
aspirin
NSAIDs, COX 2
Inducible: inflammatio
inhibitors
n, pain, fever
including
Constitutive: synaptic
celecoxib
plasticity
(Celobrex )
COX-2
Inducible and
constitutively in
brain, kidney
COX-3
Constitutively, high pain pathways, not
inflammation
in brain, heart
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 cyclooxygenase (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
COX-2
Reduce inflammation
Bleeding
Reduce pain
Acute renal failure
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 E2mediated 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
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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).
• 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 cyclooxygenase (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 antiinflammatory 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