Transcript NSAIDs.ppt

Pharmacological
actions.
Mechanism of
action.
Common
unwanted effects.
Classification
Individual drugs
1-Antipyretic
effect:2-Analgesic
effects:3-Anti-inflammatory
effect:-
Centre in the
hypothalamus.
Fever → ↑setpoint
NSAIDs reset the
thermostat.
Temperature-regulating
mechanisms (dilatation of
superficial blood vessels,
sweating, (
Normal temperature is
not affected by NSAIDs.
Endotoxins →
release from
macrophages of a
pyrogen [IL-1]
hypothalamus,
→PGEs
PGEs →elevation of
the set-point for
temperature.
NSAIDs
effective against
pain associated
with
inflammation.
arthritis,
bursitis,
pain of muscular
and vascular origin
toothache,
dysmenorrhoea,
pain of postpartum
states
pain of cancer
metastases in bone.
NSAIDs ↓
components of the
inflammatory
response → COX2.
vasodilatation
oedema
pain
no effect on
lysosomal
enzyme release,
toxic oxygen
radical
production, ↓
tissue damage in
chronic
inflammatory
conditions.
Three isozymes
COX-1 constitutively
expressed , widely
distributed, has
‘housekeeping’
function.
COX-2 ,inducible in inflammatory cells by inflammatory
stimulus.
Expression is stimulated by growth factors, tumour
promoters,cytokines ,endotoxins.
Cox-3 may be implicated in fever.
Cox-3 is expressed in the brain, ↓paracetamol
Indomethacin & sulindac inhibit primarily COX-1.
Meclofenamate & ibuprofen are equipotent on COX-1
&COX-2.
Celecoxib & rofecoxib↓ COX-2
1GASTROINTESTINA
L DISTURBANCES
result mainly from
inhibition of COX-1.
dyspepsia, diarrhoea ,
nausea ,vomiting,
gastric bleeding and
ulceration.
Therapeutic doses of
NSAIDs in healthy
individuals .
susceptible patients →acute
renal insufficiency.
Prostanoids involved in the
maintenance of renal blood
dynamics
mefenamic acid
and sulindac.
Skin reactions
include
mild rashes,
urticaria
photosensitivity
reactions.
Quiz?
• Cyclooxygenase-1 and-2 are
responsible for
• (A) The synthesis of prostaglandins
from arachidonate
• (B) The synthesis of leukotrienes
from arachidonate
• (C) The conversion of ATP to cAMP
• (D) The metabolic degradation of
cAMP
• (E) The conversion of GTP to cGMP
Salicylates:- e.g. aspirin.
p-Aminophenol e.g. paracetamol.
Propionic acid e.g. ibuprofen
Indole derivatives e.g. indomethacin
Phenylacetic acid e.g. diclophenac
Oxicam e.g. piroxicam, meloxicam.
Fenamate:- Meclophenamic acid
Naphthylacetic acid e.g. nabumetone
Nonselective COX Inhibitors
COX-2 Selective Inhibitors
COX-1 inhibition, in general, is
instantaneous and competitively
reversible.
COX-2 inhibition is time dependent, i.e. its
effect increases with time.
The COX-2-selective drugs have minimal
gastrointestinal toxicity.
COX-2 inhibitors no impact on
platelet aggregation.
Cardiovascular thrombotic events
→ COX-2 inhibitors.
COX-2 is constitutively active
within the kidney.
Prototype is
aspirin.
Mechanism of
action:inhibition of
arachidonate
cyclooxygenase
Aspirin ,week
acid , unionized
in acid
environment ,
most of it is
protein –bound.
t½ at low dose
3h, high dose
15h.
Hydrolyzed by
esterases.
25% oxidized ,
some conjugated to
glucouronic , glycine
& sulphuric acid,
25% excreted
unchanged.
Rate of excretion is
higher in alkaline
urine.
ADR:-GIT side
effects,
dyspepsia,
nausea,
vomiting,
mucosal
damage
hemorrhage
Analgesia
associated
nephropathy.
Bronchospasm in
aspirin- sensitive
asthmatics
Reye's syndrome is
a potentially fatal
disease .
Associated with
aspirin consumption
by children with viral
diseases such as
chicken pox.
Skin reactions.
Impaired
haemostasis.
Acute toxicity:local effects :gastritis with
focal erosions.
Systemic effects:- salicylism.
Large therapeutic doses alter acidbase balance  hyperventilation &
respiratory alkalosis.
Larger doses respiratory
acidosis.
Interfere with CHO
metabolism 
metabolic acidosis.
Hyperpyrexia,
dehydration
Disturbance of
haemostasis.
Kidney failure
CNS:- initially stimulation
with excitement then
coma & respiratory
depression.
Treatment:-correction of acid-base
disturbances.
Therapy for dehydration & hyperthermia.
Maintenance of kidney function.
Gastric lavage & forced alkaline
diuresis.
Minor musculoskeletal
disorders → bursitis,
synovitis, tendinitis,
myositis, and myalgia.
Fever and headache.
Inflammatory disease, such as acute
rheumatic fever, rheumatoid arthritis,
osteoarthritis, and certain rheumatoid
variants, such as ankylosing
spondylitis
Prophylaxis of myocardial infarction and
ischemic stroke.
Colon cancer.
Quiz?
• Aspirin may precipitate asthma in
sensitive subjects. The most likely
explanation is that aspirin:
• A. Decreases the threshold of
bronchial reactivity to prostaglandin
F2α
• B. Has beta adrenoceptor blocking
activity
• C. Releases histamine from mast cells
• D. Increases the formation of
leukotriene D4 in lung tissue
• E. Increases renal clearance of
endogenous adrenaline
Quiz?
• Which one of the following
effects does not occur in
salicylate intoxication?
• (A) Hyperventilation
• (B) Hypothermia
• (C) Metabolic acidosis
• (D) Respiratory alkalosis
• (E) Tinnitus
2-Paracetamol:Pharmacokinetics:-given
orally , well absorbed, peak
plasma concentration
reached in 30-60min ,
variable proportion is bound
to plasma protein
Drug is inactivated in the
liver, conjugated with
glucuronic & sulphuric acid
,t½=2-4h, toxic dose 4-8h.
Unwanted effects:-
therapeutic doses
side effects are few,
allergic skin
reactions,
In toxic doses
hepatotoxicity.
Drug is
metabolized by to
toxic metabolite
(N-acetyl-pbenzoquinone
immine), 
necrosis in the
liver & kidneys
Initial symptoms, nausea ,vomiting .
Treatment:- gastric lavage, oral activated
charcoal.
If patient is seen soon ,liver damage can be
prevented by:1]giving agents which glutathione formation
in the liver e.g. acetylcysteine [p.o. or IV]
2]agents that conjugation reaction
[methionine , cysteamine].
After 12h these agents are useless & may
precipitate hepatic coma
Allergy to aspirin
Salicylates are poorly
tolerated,
hemophilia
history of peptic ulcer,
bronchospasm
precipitated by aspirin,
children with viral
infections,
concomitantly with
probenecid
A 25 –year-old male is seen in the
emergency department. He is
disoriented but he states that he has
nausea ,vomiting ,abdominal pain and
diarrhoea since he took “too many pain
pills”. Before he can tell you more , he
loses consciousness. Liver function test
was as follows:Alanine inotransaminase 243 IU/L
normal (5-40)
Aspartate transaminase 317 IU/l normal
(10-40)
Q1
•
1)
2)
3)
4)
The pain pills are most
likely:Aspirin
Ibuprofen
Paracetamol
A combination of codeine
and aspirin
Q2
•
1)
2)
3)
4)
5)
What non specific measures
could be taken:Emesis
Gastric lavage
Activated charcoal
Cathartic
Forced diuresis
Q3
•
1)
2)
3)
4)
5)
The specific antidote is:Naloxone
Diphenoxylate
N-acetyle-L-cysteine
Neostigmine
pralidoxime
Q4
•
How would ordering a
plasma concentration of
paracetamol help in
management of this
patient?
Ibuprofen inhibits COX-1 and
COX-2 about equally.
t ½=2hours
analgesic, antipyretic ,in
treatment for rheumatoid
arthritis and degenerative
joint disease.
A topical cream preparation.
Closing patent
ductus
arteriosus in
preterm infants
A liquid gel preparation → postsurgical
dental pain.
Ibuprofen & platelet inhibition induced by
aspirin.
ADR:-nausea,
heartburn,
epigastric pain,
rash, and dizziness, visual changes,
prolongation of bleeding times.
Equal selectivity for
COX-1 and COX-2.
Used in rheumatoid
arthritis, osteoarthritis,
ankylosing spondylitis,
dysmenorrhea.
t ½=1.1hours
A topical gel
containing 3%
diclofenac is
effective for solar
keratoses.
Combined with either misoprostol or
omeprazole.
A 0.1% ophthalmic preparation →
postoperative ophthalmic
inflammation.
ADR:-GIT disturbances ,
headache,
reversible elevation of serum
transaminases.
long half-life [ 57hours].
At high concentrations it inhibits
polymorphonuclear leukocyte migration,
decreases oxygen radical production, and
inhibits lymphocyte function.
Indicated for rheumatoid arthritis and
osteoarthritis.
ADR:- GI reactions, edema, dizziness,
headache, rash, and changes in hematological
parameters.
Meloxicam is reported to be a selective COX-2
inhibitor
Meloxicam is introduced for the treatment
of osteoarthritis, rheumatoid arthritis and
certain acute conditions.
Although meloxicam is sometimes
reported to be a selective COX-2 inhibitor,
it is considerably less selective than
celecoxib or rofecoxib, low frequency GI
side effects
Used for rheumatoid arthritis, osteoarthritis, and pain
management.
t ½ =26 hours
Its long half-life allows for once-daily dosing.
It is metabolized in the liver to 6-methoxy-2naphthylacetic acid , a strong COX inhibitor that is
chemically similar to naproxen.
Renal impairment may double its t ½ .
Lower incidence of GIT side effects → prodrug.
May cause pseudoporphyria and photosensitivity in
some patients.
Other ADRs are lower-bowel complaints, rashes, and
CNS disturbances.
Celecoxib is highly
selective COX-2
inhibitor.
t ½=11hours, 27% of the
dose is excreted
unchanged.
Used for osteoarthritis
and rheumatoid arthritis.
Contraindicated in individuals with hypersensitivity
to sulfonamides or other NSAIDs.
It should be used with caution in persons with
hepatic disease.
Interactions occur with other drugs that induce
CYP2C9 (e.g rifampin) or compete for metabolism
by this enzyme (e.g. warfarin, fluconazole,
leflunomide).
ADR:-mild to moderate GI effects such as
dyspepsia, diarrhea, and abdominal pain.
Serious GI and renal effects have occurred rarely
May cause hypertension and oedema.
Quiz?
• A 45-year-old surgeon has developed
symmetric early morning stiffness in
her hands. She wishes to take a
nonsteroidal anti-inflammatory drug to
relieve these symptoms and wants to
avoid gastrointestinal side effects.
Which one of the following drugs is
most appropriate?
• (A) Aspirin
• (B) Celecoxib
• (C) Ibuprofen
• (D) Indomethacin
• (E) Piroxicam
A21-year-old college student
presented to her university’s student
health center with an acute
exacerbation of asthma. Her
respiratory rate was increased, and
she was in obvious respiratory
distress, with wheezes audible on
both sides of the chest.The
examination of the nasal passages
revealed mucosal edema and a polyp
on the right. There was marked
swelling about the eyes, and her
upper lip was swollen (angioedema).
Her fingertips were slightly cyanotic. Her
peak expiratory flow rate was 25% of the
predicted normal value. Oxygen was
given by face mask. She was given
1:1000 aqueous epinephrine 0.3 mL
subcutaneously, diphenhydramine HCl
50 mg intramuscularly, and prednisone
40 mg by mouth. Subsequently she was
given nebulized albuterol, and the peak
flow rate improved to 75% of
predicted.When questioned further, she
said she had taken a friend’s ibuprofen
for menstrual cramps.