Oleh :

Dimas P.Nugraha
Departemen farmakologi FK UR

Analgetik adalah zat yang pada dosis terapeutik dapat menghilangkan

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

OPIOIDS (MORPHINE-LIKE) ANALGESICS

AND ANTAGONISTS
Opioids
natural or synthetic; produce morphine-like effects.
They act by binding to specific opioid receptors in the CNS
effects mimic the action of endogenous peptide neurotransmitters
(e.g., leu- and met-enkephalins).
They relieve severe pain - essential in treatment of major diseases,
trauma, and surgery.
Danger of the drug abuse.
Although the opioids have a broad range of effects, their primary use
is to relieve intense pain and the anxiety that accompanies it.
Antagonists they can reverse actions of opioids, important
clinically treatment of overdose.

History of Opioids
Opium is extracted from poppy seeds
(Paper somniforum)
Used for thousands of years to
produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression

Opioid Receptors

-receptors are thought to be responsible for most of the analgesic effe

Mu and Kappa Receptor Activation

Response
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence

Mu-1

Mu-2

Kappa

Division (in relation to the activity)

1. Strong agonists (e.g. morphine, meperidine=pethidine,
methadone, fentanyl, sufentanil, alfentanil, remifentanil)
2. Moderate agonists (e.g. propoxyphene, codein, oxycodone)
3. Mixed agonist-antagonists (e.g. pentazocine, buprenorphine,
nalbuphine, butorphanol)
4. Other analgesics ( tramadol)
5. Antagonists (naloxone, naltrexone)

OPIOID ANALGESICS AND ANTAGONISTS

STRONG AGONISTS

Alfentanil
Fentanyl
Heroin
Meperidine
Methadone
Morphine
Remifentanil
Sufentanil
MODERATE/LOW AGONISTS
Codeine
Oxycodone
Propoxyphene
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
ANTAGONISTS
Naloxone
Naltrexone
(according to
OTHER ANALGESICS
Lippincotts
Tramadol
Pharmacology, 2006

Morphine
CNS effects
Respiratory depression and
suppression of cough: reducing the
responsiveness of the respiratory
centers in the brain stem to blood
levels of carbon dioxide and inhibiting
directly the respiratory center.

Morphine
CNS effects
Nausea and vomiting: stimulating the
chemoreceptor trigger zone. In most
cases, after therapeutic dose,
subsequent doses of morphine do not
produce vomiting.
Miosis: pinpoint pupils are indicative
of toxic dosage prior to asphyxia. It
can be block with atropine.

Morphine
Cardiovascular effects:
Orthostatic hypotention can occur
due to vasomotor medullary
depression and histamine release.

Gastrointestinal effect:
Reduces gastrointestinal motility,
causing constipation
Decreases biliary and pancreatic
secretions.
Constriction at the spincter of Oddi
causes an increase in biliary pressure.

Morphine
Other systemic effects:
Increases detrusor muscle tone in the
urinary bladder, producing a feeling
of urinary. Vesical sphincter tone is
also increased, making voiding
Inhibits the cellular immunity and
humoral immunity, which is
significant in withdrawal syndrome
and tolerant in chronic administration.

Farmakokinetik Opioid

Therapeutic uses
Analgesia, such as the relief of pain from myocardial

Adverse effects
Respiratory depression is the most important effect.

Contraindications and
cautions
Use in patients with head injures

Interaksi Obat
Obat yang bekerja secara sentral
seperti barbiturat, fenotiazin,
penghambat MAO, antidepresan
trisiklikefek sedatif dan
depresi pernafasan
Fenotiazinefek menurunkan
tek.darah
Amphetamineanalgesia dari
morphin dan mengurangi efek sedasi
dan depresi pernafasan

Keracunan Akut Morfin

Gejala : coma, miosis, eksterm dari
pernafasan (hingga 2-4 tarikan nafas permenit),
sianosis, suhu tubuh rendah, kehilangan tonus
otot rangka.
Tindakan :
Pembebasan jalan nafas dan pemberian O2
memberikan suatu antagonis morfin untuk
menghilangkan kelumpuhan pernafasan
(naloxone sbg antagonis kompetitif)
Shock ditangani, mungkin perlu pemberian Ab
untuk pencegahan pneumonia

Codeine

Pethidine

It is very similar to morphine (one-seventh to one-tenth potent) in phar

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.

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.
6

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.

Salicylates

Propionic acid derivatives

Ibuprofen, naproxen, ketoprofen, oxaprozin

Acetic acid derivatives

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

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

NSAIDs

13

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 (2025 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.T
Treatment for overdose: Acetylcysteine
19

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.