A

Oleh :
Dimas P.Nugraha
Departemen farmakologi FK UR

Mechanisms of Pain and

Nociception
Nociception is the mechanism
whereby noxious peripheral stimuli
are transmitted to the central
nervous system. Pain is a subjective
experience, not always associated
with nociception.

Mechanisms of Pain and

Nociception
Polymodal nociceptors (PMN) are the
main type of peripheral sensory
neuron that responds to noxious
stimuli. The majority are nonmyelinated C-fibres whose endings
respond to thermal, mechanical and
chemical stimuli.

Pain
mechanis
ms and
pathway
s

Natural painkillers
They

are produced naturally in the

body.
Endorphins and enkephalins are
the natural opiates found in the part
of the brain and the spinal cord that
transmit pain impulses. They are
able to bind to neuro-receptors in the
brain and produce relief from pain.
The temporary loss of pain
immediately after an injury is
associated with the production of

Pain sensation can be influenced or modified as follows:

Elimination of the cause of pain

Klasifikasi
Berdasarkan pada kekuatan efek,
mekanisme kerja dan efek samping,
obat analgetik di kelompokkan dalam
3 golongan :
1. Analgetik mirip Opioid / analgetik
narkotik/Hipnoanalgetik
Efek kuat dan bekerja sentral
Penggunaan terapi untuk nyeri kuat,
sampai yang paling kuat, nyeri tumor.
Contoh semua opiat dan derivat
semisintetiknya

2. Analgetik Non opioid

Berefek lemah hingga sedang dan bekerja
perifer
Mempunyai efek antiinflamasi, antipiretik
dan sebagian antirematik
Senyawa asam : derivat as.salisilat
(as.asetil salisilat), derivat as.arilasetat
(diklofenak, indometasin), derivat asam
arilpropionat (ibuprofen)NSAIDs
Senyawa bukan asam : anilda
(parasetamol), pirazolon yang tidak asam
(metamizol)

3. Analgetik nonopioid tanpa efek

antipiretik
Flupirtin
Nefopam

Non-steroidal anti-inflammatory
drugs (NSAIDs)
An analgesic effect: decreased
prostaglandin generation means less
sensitisation of nociceptive nerve
endings to inflammatory mediators
such as bradykinin and 5hydroxytryptamine.
Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation.

Eicosanoids and inflammation

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-plateletdecreases ability of blood to clot

COX

Expression

Function

Inhibitors

COX-1

organ pain, platelet

constitutively
function, stomach
throughout the body
protection

COX-2

Inducible: inflammation, NSAIDs, COX 2

Inducible and
pain, fever
inhibitors including
constitutively in brain, Constitutive: synaptic celecoxib
kidney
plasticity
(Celobrex )

COX-3

Constitutively, high in pain pathways, not

acetaminophen
inflammation pathways some NSAIDs
brain, heart

NSAIDs including
aspirin

The Salicylates: Aspirin

Aspirin (acetylsalicylic acid) was first
isolated in 1829 by Leroux from willow
bark.
It can cause irreversible inactivation of
cyclo-oxygenase, acting on both COX-1
and COX-2.

Salicylates

Aspirin is rapidly and almost completely absorbed from the stomach an

Salicylates
Pharmacologic Effects
Analgesic
It is used to treat mild to moderate pain,
including dental pain.

Antipyretic
Aspirin reduces fever because of its ability
to inhibit prostaglandin synthesis in the
hypothalamus.
Aspirin reduces fever by inducing
peripheral vasodilation and sweating.

Salicylates
Pharmacologic Effects
Antiinflammatory
This effect is also from aspirins ability to
block prostaglandin synthesis.
Aspirin reduces redness and swelling at the
inflamed area.

Antiplatelet
Aspirin irreversibly binds to platelets.
Aspirin inhibits both prostacyclin and
thromboxane A2 depending on the dose
used. This helps prevent blood from clotting.
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Salicylates
Uses
Mild to moderate pain
Fever
Inflammation
Prevention of stroke or heart attack
Antiplatelet effects

10

Salicylates
Adverse Reactions
Aspirins adverse reactions are many. These
reactions have limited aspirins everyday use.
The many adverse reactions of aspirin include:
Gastrointestinal They are a direct result of
direct gastric irritation and blockage of
prostaglandins.
Bleeding Bleeding time is prolonged
because of aspirins effects on platelets and
prostaglandins.
7

Salicylates
Adverse Reactions
Reye syndrome
Hepatotoxicity
Renal toxicity
Hypersensitivity
Patients with asthma are at a higher risk
for hypersensitivity or allergic reactions.

Treatment of Aspirin
poisoning
Inducing emesis or administering gastric

Salicylates

Propionic acid derivatives

Ibuprofen, naproxen, ketoprofen, oxaprozin

Naproxen and Ibuprofen

They have prominent anti-inflammatory
action.
Therapeutic uses: rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis,
acute tendinitis, dysmenorrhea, et al.
Adverse effect: gastrointestinal effects,
dermatologic problems, thrombocytopenia.
apply to long-term treatment because
they are better-tolerated.

Acetic acid derivatives

Indomethacin
Pharmacologic effects :
(1)Inhibit COX nonselectively .
(2)Inhibit phospholipase A and C.
(3)Reduce PMN migration.
(4)Decrease T cell and B cell
proliferation.
(10-40 time more potent antiinflammatory than aspirin)

Indomethacin
Adverse effect:
(1)Gastrointestinal complaint:
(2)CNS effects: 25%-50%
(3)Hematologic reactions:
(4)Hypersensitivity reactions: asthma
(aspirin- sensitive patients may
exhibit cross-reactions to
indomethacin).

Oxicam derivatives

Fenamates
Mefenamic

Heteroaryl acetic acids

Diclofenac , tolmetin, ketolarac.
Approved for long-term use in the treatment of
RA, osteoarthritis, and ankylosing spondylitis
Diclofenac is more potent than indomethacin
or naproxen
Ketorolac is a potent analgesic but has
moderate anti-inflammatory effects. available
for oral administration, for intramuscular use in
the treatment of postoperative pain, and for
topical use for allergic conjunctivitis.

 Ketorolac can cause fatal peptic

ulcers as well as GI bleeding and/or
perforation of the stomach or
intestines.
Ketolarac to be avoided in pediatric
patients; patients with mild pain, and
those with chronic conditions, the
dose should not exceed 40 mg/day

Selective COX-2 inhibitor

Celecoxib, Meloxicam and Rofenxib
more selective for COX-2 than for
COX-1.
Adverse effects are slighter than
other NSADs.
Long-term studies of the incidence of
clinically significant gastrointestinal
ulcers and bleeding are not yet
completed.

Celecoxib
Celecoxib is significantly more
selective for inhibition of COX-2 than
of COX-1
Celecoxib should be avoided in
patients with chronic renal
insufficiency, severe heart disease,
volume depletion, and/or hepatic
failure.
Celecoxib is contraindicated in
patients who are allergic to

Clinical uses of the NSAIDs

For analgesia in painful conditions (e.g.
headache, dysmenorrhoea, backache,
bony metastases of cancers, postoperative
pain):
The drugs of choice for short-term analgesia
are aspirin, paracetamol and ibuprofen; more
potent, longer-acting drugs (diflunisal,
naproxen, piroxicam) are useful for chronic
pain.
The requirement for narcotic analgesics can be
markedly reduced by NSAIDs in some patients
with bony metastases or postoperative pain.

Clinical uses of the NSAIDs

For anti-inflammatory effects in chronic or
acute inflammatory conditions (e.g. rheumatoid
arthritis and related connective tissue
disorders, gout and soft tissue diseases).
With many NSAIDs, the dosage required for
chronic inflammatory disorders is usually
greater than for simple analgesia and treatment
may need to be continued for long periods;
Treatment could be initiated with an agent
known to have a low incidence of side-effects. If
this proves unsatisfactory, more potent agents
should be used.

Clinical uses of the NSAIDs

To lower temperature. Paracetamol is
preferred because it lacks gastrointestinal
side-effects and, unlike aspirin, has not
been associated with Reyes syndrome in
children.
There is substantial individual variation in
clinical response to NSAIDs and
considerable unpredictable patient
preference for one drug rather than
another.

NSAIDs

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NSAIDs

14

Summary of Nonsteroidal antiinflammatory agents (NSAIDs)

Acetaminophen
(N-Acetyl-P-Aminophenol)
Acetaminophen is not related to

17

Penggunaan

18

Comparison of
antipyretic
analgesics
with a
nonsteroidal
antiinflammatory
drug

 Adverse Effects
Hepatotoxicity
Can occur after the ingestion of a single toxic dose
(20-25 gm) or after long term use of therapeutic
doses.
Children are at high risk for hepatotoxicity because
they are often given doses that are not age- and
weight-appropriate.
Signs and symptoms include nausea, vomiting,
abdominal pain, anorexia.

Nephrotoxicity
It has been associated with long-term use.
Treatment for overdose: Acetylcysteine
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Disease-Modifying Antirheumatic
Agents
Disease-modifying antirheumatic drugs
(DMARDs) are used in the treatment of RA and
have been shown to slow the course of the
disease, induce remission, and prevent further
destruction of the joints and involved tissues
When a patient is diagnosed with RA, the American
College of Rheumatology recommends initiation of
therapy with DMARDs within 3 months of diagnosis
(in addition to NSAIDs, low-dose corticosteroids,
physical therapy, and occupational therapy)
Therapy with DMARDs is initiated rapidly to help
stop the progression of the disease at the earlier
stages

Most experts begin DMARD therapy with one of the traditional drugs, su

ALHAMDULILLAH.