Seiyun University college of medicine and health

sciences
Pharmacology IIi
time :2hrs
first semester
fourth year
2023– 2024

analgesic , antipyretic
and anti inflammatory
drugs (NSAIDs)
Pharm.D Aisha Salem Bakhdar
References
Bertram G. Katzung*
Basic and clinical pharmacolog 12th edition

K.D. Tripathi*
Essential of medical pharmacolgy 8th edition

Michael J. Neal*
Medical Pharmacology at a Glance 7th edition
 Introduction
 Algesia(pain):is an ill-defined unpleasant
sensation , usually evoked by an external or internal
noxious stimulus.

 Analgesic : is a drug that selectively relieves pain by

acting in the CNS or on peripheral pain mechanisms.
 Introduction
 Analgesic drugs:
 I.narcotic analg. II.nonnarcotic analg.
 Significant tolerance No tolerance
 Physical dependence Without
 Relief most types of pain Mild or moderate
 Central Peripheral(most)
 Abuse liability No abuse
 Ex: morphine Ex: aspirin
MOA
 isomers of COX enzyme 3
COX-3 COX-2 COX-1

Brain At the site of Platelet

.inflammation Stomach
Kidney
 Classification
A. Nonselective COX inhibitors:
1. Salicylates: Aspirin.
2. Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen , Flurbiprofen .
3. Fenamate: Mefenamic acid.
4. Enolic acid derivatives(oxicams): Piroxicam,
Tenoxicam.
5. Acetic acid derivatives: Ketorolac,
Indomethacin ,Diclofenac , Nabumetone.
6. Pyrazolone derivatives: Phenylbutazone ,
 Classification
B. Preferential COX-2 inhibitors
Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac.
C. Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic-antipyretics only:
1. Paraaminophenol derivative: Paracetamol
(Acetaminophen).
2. Pyrazolone derivatives: Metamizol (Dipyrone),
Propiphenazone.
3. Benzoxazocine derivative: Nefopam.
 Pharmacological Action
CNS:
Analgesic action they decrease PGS centrally and
peripherally.
Antipyretic action 1.they decrease PGE2 synthesis
in the heat regulation center of hypothalamus.
2.They increase heat loss through
VD of skin vessels and sweating.
 Pharmacological Action
 Inflammation
 Anti inflammatory and anti rheumatic

They decrease PGS synthesis reducing vascular

permeability and edema.

Blood
Aspirin in small dose (75-150mg/day) decrease PLT
aggregation due to inhibit TXA2 .
Pharmacological Action
 GIT
Acute or chronic ulcer ,internal bleeding due to decrease
stomach PGS levels .
Kidney
Decrease renal blood flow due to decrease kidney PGS
level.
Respiratory system
acid – base imbalance (Aspirin)
Therapeutic Uses

 1. mild to moderate pain due to

inflammation and injury ex: headache ,
toothache and common cold.
 2. fever

 3. rheumatoid arthritis

 4.anti thrombotic (Aspirin)

 5.dysmenorrhea

 6.post-operative pain
S/E
 Gastrointestinal
Nausea, anorexia, gastric irritation, peptic ulceration,
gastric bleeding/perforation.
 Renal

Na+ and water retention, chronic renal failure,

nephropathy.
 Hepatic

 Raised liver enzymes transaminases (SGOT , SGPT) in

adult
 Reye`s syndrome (Aspirin) in children
S/E
 CNS
 Headache, mental confusion, vertigo, behavioural

Disturbance.
CVS:
Rise in BP, risk of MI (especially with COX2 inhibitors)
 Haematological

Bleeding, thrombocytopenia, haemolytic anaemia.

 Others

Teratogenic , Bronchospasm , skin rashes.

 C/I
1.peptic ulcer
2.bronchial asthma
3. gout (aspirin)
4. pregnancy
5. allergy
6.renal disease
7.bleeding tendency
8. Aspirin not used in infant and children
 Aspirin (acetylsalicylic acid
ASA)
 Pharmacokinetics
Absorption :
rapidly absorbed from the stomach and upper
small intestine
has a pKa of 3.5
Distribution :
Rapidly and widely distributed ,cross placenta and enters breast milk.
Metabolism: by liver
Excretion: Amount excreted unchanged By the kidney depends on urine
PH.
1st order elimination (low dose)
Zero order elimination (high dose)
 Aspirin
Compared to other NSAIDS Aspirin only inhibit COX
.enzyme irreversibly so has long duration of action
:Note
.Aspirin must be stopped 7-10 days before surgery
 In pregnancy: Aspirin is classified as FDA pregnancy

category C risk during the first and second trimesters and

category D during the third trimester.
 Aspirin should be avoided during pregnancy and

breastfeeding.
 PROPIONIC ACID
DERIVATIVES
Ibuprofen
(400 mg) has been found equally or more efficacious
than a combination of aspirin (650 mg) + codeine
(60 mg) in relieving dental surgery pain, but is
a weaker antiinflammatory; not suitable for acute
gout and other similar conditions.
Flurbiprofen
* more effective than ibuprofen, but gastric side effects
are also more.
*It is used as an ocular antiinflammatory as well.
 PROPIONIC ACID
DERIVATIVES
Naproxen
* The antiinflammatory activity is stronger and it is particularly
potent in inhibiting leucocyte migration — may be more valuable
in acute gout.
* It is also recommended for rheumatoid arthritis and ankylosing
spondylitis.
* Because of longer t½ regular use can effectively suppress
platelet function.
*Naproxen carries lower thrombotic risk than
diclofenac ,etoricoxib, etc.
* Dose should be reduced in the elderly .
FENAMATE (Anthranilic acid derivative)

Mephenamic acid
*An analgesic, antipyretic and weaker antiinflammatory drug,
which inhibits synthesis of PGs as well as antagonises some of
their actions.
*Mephenamic acid exerts peripheral as well as central analgesic
action.
*Uses :
Mephenamic acid is indicated primarily as analgesic in muscle, joint
and soft tissue pain where strong antiinflammatory action is not
needed.
It is quite effective in dysmenorrhoea.
ENOLIC ACID DERIVATIVES (Oxicams)

Piroxicam
* It is a long-acting potent NSAID with antiinflammatory
potency similar to indomethacin and good analgesic
antipyretic action.
* It is a nonselective, reversible inhibitor of COX;
lowers PG concentration in synovial fluid and
inhibits platelet aggregation—prolonging bleeding
time.
 ENOLIC ACID DERIVATIVES (Oxicams)

Piroxicam
Uses :
Due to slow onset of action piroxicam is suitable for use
as
long-term antiinflammatory drug in rheumatoid and osteo
arthritis.
But is not a first choice drug for any condition because of
relatively higher toxicity.
 ACETIC ACID DERIVATIVES
Ketorolac
* This arylacetic acid NSAID has potent analgesic but
modest
Antiinflammatory activity.
In postoperative pain it has equalled the efficacy of
morphine, but does not interact with opioid receptors and is
free of opioid side effects.
* Like other NSAIDs, it inhibits PG synthesis and relieves
pain
primarily by a peripheral mechanism.
 ACETIC ACID DERIVATIVES
In short-lasting pain, it has compared favourably with
aspirin.

Use :
is frequently used in postoperative, dental and acute
musculoskeletal pain.
It may also be used for renal colic and migraine.
 ACETIC ACID DERIVATIVES

Indomethacin
*This indole acetic acid derivative is a potent
antiinflammatory drug with prompt antipyretic action.
*Indomethacin relieves only inflammatory or tissue injury
related pain.
*It is a highly potent inhibitor of PG synthesis
and suppresses neutrophil motility.
 ACETIC ACID DERIVATIVES
Nabumetone
*It is a prodrug—generates an active metabolite (6-MNA)
which inhibits both COX-1 and COX-2.
* It possesses analgesic, antipyretic and antiinflammatory
activities; effective in the treatment of rheumatoid and
osteo-arthritis as well as in soft tissue injury.
* Nabumetone has caused a lower incidence of gastric
erosions, ulcers and bleeding.
 B. Preferential COX-2 inhibitors

Diclofenac sodium
An analgesic antipyretic antiinflammatory drug, similar in
efficacy to naproxen.
It inhibits PG synthesis and is somewhat COX-2 selective.
The antiplatelet action is not appreciable due to sparing of
COX-1.
* Renal adverse effects were common in high risk patients.
Aceclofenac
A moderately COX-2 selective congener of diclofenac
 B. Preferential COX-2 inhibitors

Meloxicam
* This newer congener of piroxicam has a COX-2/COX-1
selectivity ratio of about 10.
* Since measurable inhibition of platelet TXA2 production
(a COX-1 function)
* occurs at therapeutic doses of meloxicam, it has been
labelled ‘preferential COX-2 inhibitor’
*Efficacy of meloxicam in osteo- and rheumatoid arthritis is
comparable to piroxicam.
*Plasma t½ is 15–20 hours permiting single daily dose.
 SELECTIVE COX-2 INHIBITORS (Coxibs)

Celecoxib
* The COX-2 selectivity of celecoxib is modest and similar
to that of diclofenac.
* It exerts antiinflammatory, analgesic and antipyretic
actions with low ulcerogenic potential.
* Comparative trials in rheumatoid arthritis have
found it to be as effective as naproxen or
diclofenac, without affecting COX-1 activity in
gastroduodenal mucosa.
 SELECTIVE COX-2 INHIBITORS (Coxibs)

Etoricoxib
* This newer COX-2 inhibitor has the highest COX-2
selectivity.
* It is suitable for once-a-day treatment of
osteo/rheumatoid/acute gouty arthritis, ankylosing
spondylitis, dysmenorrhoea, acute dental surgery pain and
similarconditions, without affecting platelet function or
damaging gastric mucosa.
 Paracetamol
 MOA:
Inhibit COX3 enzyme that synthesized of prostaglandins that
may serve as mediators of pain and fever in CNS.
Has no significant anti inflammatory properties or GI toxicity.
Pharmacological action:
* Analgesic
* Anti pyretic
 Safe in:

Children , Bronchial asthma , Peptic ulcer , Pregnancy

 Maximum daily dose up to 4g/day
 Paracetamol
 Pharmacokinetics
Absorption: Well absorbed orally
Distribution: In all over the body
Metabolism: in liver
Phenacetin(active) paracetamol (active) NAPQI
(toxic metabolite) detoxified by Glutathione system
(G-SH )
 Excretion: in urine

 S/E: Hepatotoxicity
Paracetamol toxicity
 Paracetamol toxicity
 ttt:
 G : gastric lavage
 S : SH- donor ex: N- acetylcysteine (NAC)
 20 hrs protocol of:
 150mg/kg/1h
 50mg/kg/4hrs
 100mg/kg/15hrs
 H: heamodialysis
 ??? Q

N-acetyl cysteine is beneficial in acute paracetamol

poisoning because:
A. It reacts with paracetamol to form a nontoxic complex
B. It inhibits generation of the toxic metabolite of
paracetamol
C. It is a free radical scavenger
D. It replenishes hepatic glutathione which in turn binds
the toxic metabolite of paracetamol