Farmakologi Obat Nyeri

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi &
Therapeutik
Fak.Kedokteran UHN
MEDAN

Definition of Pain
Pain is an unpleasant sensory and emotional experience.
Pain is whatever the experiencing person says it is, existing
whenever he says it does. (McCaffery & Pasero, 1989).
It is not the responsibility of clients to prove that they are
in pain; it is the nurses responsibility to believe them.
(Crisp & Taylor, 2005).

Chronic pain is difficult to define but understood as

persistent pain that is not amenable to routine pain control
methods

Categorize Type of
Pain

Bone/Soft Tissue (Somatic) Pain

tender, deep, aching
arthritis, myofascial pain, bony mets
Neuropathic Pain
shooting, burning, stabbing,
scalding
trigeminal neuralgia, diabetic
neuropathy, post stroke, reflex
sympathetic dystrophy
Visceral Pain
spasms, cramping
bowel obstruction, adhesions

Types of Pain
Superficial:
- Stimulation of skin & mucous
membranes
- Fast response
Deep:
- Arises from muscles, joints,
tendons, heart ..etc.
- Slow response

Sources of Pain
Nociceptivefree nerve endings
that receive painful stimuli
Neuropathic damaged nerves

Physiology of Pain
Nociceptors
Stimulus
Transmission
Termination
Modulation

Nociception
Transduction

Conduction

Transmission
Modulation

Noxious
stimulus

Ouch Pain

primary sensory neuron

central neuron

Mechanisms of Pain and

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

Mechanisms of Pain and

Nociception
Chemical stimuli acting on PMN to cause
pain include bradykinin, 5-HT, and capsaicin.
PMN are sensitised by prostaglandins,
which explains the analgesic effect of
aspirin-like drugs, particularly in the
presence of inflammation.
Nociceptive fibres terminate in the
superficial layers of the dorsal horn, forming
synaptic connections with transmission
neurons running to the thalamus.

Mechanisms of Pain and

Nociception
Chemical stimuli acting on PMN to cause
pain include bradykinin, 5-HT, and capsaicin.
PMN are sensitised by prostaglandins,
which explains the analgesic effect of
aspirin-like drugs, particularly in the
presence of inflammation.
Nociceptive fibres terminate in the
superficial layers of the dorsal horn, forming
synaptic connections with transmission
neurons running to the thalamus.

Mechanisms of Pain and

Nociception
PMN neurons release glutamate (fast
transmitter) and various peptides
(especially substance P) which act as
slow transmitters. Peptides are also
released peripherally and contribute to
neurogenic inflammation.
Neuropathic pain, associated with
damage to neurons of the nociceptive
pathway rather than an excessive
peripheral stimulus, is frequently a
component of chronic pain states, and
may respond poorly to opioid analgesics.

Modulation of Pain
Transmission
Transmission in the dorsal horn is subject
to various modulatory influences,
constituting the gate control mechanism.
Descending pathways from the midbrain
and brainstem exert a strong inhibitory
effect on dorsal horn transmission.
Electrical stimulation of the midbrain
periaqueductal grey (PAG) causes
analgesia through this mechanism.

Modulation of Pain
Transmission
The descending inhibition is
mediated mainly by enkephalins, 5HT, noradrenaline and adenosine.
Opioids cause analgesia partly by
activating these descending
pathways, partly by inhibiting
transmission in the dorsal horn,
and partly by inhibiting excitation
of sensory nerve terminals in the
periphery.

How is pain measured?

Can use 0-10 scale individually or as
part of your OPQRST
Can use visual aids to measure pain.

Verbal Assessment of
Pain

O Onset
P Palliative/Provocation
Q Quality
R Region/Radiation
S Severity
T Time

Analgesics
Definition
Drugs that selectively inhibit the perception
(sensation) of the pain
Classification
1- Peripheral (miscellaneous):
- Causal
- Non-causal
2- Central:
- Narcotic
- Non-narcotic

Peripheral Analgesics
Causal
-Treat the cause
Example:
Atropine
(antispasmodic
)

Non-causal
- Not treat the cause
Examples:
1- Local anaesthetics
(for superficial
tumor)
2- Counter-irritant
(apply pain that
counteract or mask
the original one e.g.
acupuncture)

Central Analgesics
Narcotics
The class - Opioids (morphine &
morphine like drugs)
Examples 1- Natural (as codeine)
2- Semi synthetic e.g.
di-hydromorphine&
diacetylmorphine (heroin)
3- Synthetic e.g. pethidine
4- Endogenous opiates as
endorphins & encephalins

Central Analgesics
Non-narcotic
- NSAID (Non selective COX inhibitors)
1- Salicylates
: Aspirin ,diflunisal
2- Para-aminophenol:
Acetaminophen,parasetamol
3- Aryl-acetic acid
:Diclofenac
4- Oxicam derivat
:Piroxicam,tenoxicam
5- Propionic acid derivat :Ibuprofen
6-Indole derivat
: Indomethacin
etc.

Where do NSAIDs
Work?
Cell Membrane

Steroids works here:

NSAIDs
Phospholipase A2

Arachidonic Acid

Lipoxygenase

Leukotrienes

Cyclooxygenase

Prostaglandins

Two main forms of Cyclooxygenases (COX)

Cyclooxygenase-1 (COX-1) Cyclooxygenase-2 (COX-2)
Constitutively expressed
Plays an important role in
Gastric mucosa
Kidney
Platelets
Produces prostaglandins
that mediate homeostatic
functions
Vascular endothelium

Produces prostaglandins
that mediate inflammation,
pain, and fever.
Induced mainly in sites of
inflammation by cytokines

Preferential COX2 Inhibitor

- Nimesulide
-Meloxicam
- Nabumatone

Selective COX2 Inhibitors:

- celecoxib
- etoricoxib
- parecoxib

Analgesic-antipyretic with
poor antiinflammatory
action

Para-aminophenol derivat.: Acetaminophen

(parasetamol)
Pyrazolon dervat.

: Metamizol

NSAIDs We Know And Love:

Salicylates
Aspirin

Propionic Acid Derivatives

Ibuprofen, naproxen

Indolacetic Acids
Indomethacin

nd
Lllmann,
Lllmann,Color
ColorAtlas
AtlasofofPharmacology
Pharmacology22ndEd.
Ed.(2000)
(2000)

WHO Ladder
3. Severe
2. Moderate

1. Mild
Aspirin
APAP
NSAIDs
+/Adjuvant
s

Codeine
Hydrocodone
Oxycodone
Dihydroxycodon
e
Tramadol
+/- Adjuvants

Morphine
Hydromorphon
e
Methadone
Levorphanol
Fentanyl
Oxycodone
+/- Adjuvants

OPQRST
Onset: Pain has been present
since she awoke this morning
Palliative: Nothing is making the
pain better
Provocative: It hurts slightly
worse when palpated, but much
worse when pressure on it is
released

OPQRST
Quality: Sharp, stabbing pain
Region: Pain in the lower right
quadrant of her abdomen
Radiation: None
Severity: 10/10
Time: Constant since it began and
it keeps getting worse

Mechanism of action of NSAIDs

1. Antiinflammatory effect
due to the inhibition of the
enzymes that produce
prostaglandin H synthase
(cyclooxygenase, or COX), which
converts arachidonic acid to
prostaglandins, and to TXA2 and
prostacyclin.

Mechanism of action of
NSAIDs
Aspirin irreversibly inactivates COX1 and COX-2 by acetylation of a
specific serine residue.
This distinguishes it from other
NSAIDs, which reversibly inhibit
COX-1 and COX-2.

Mechanism of action of
NSAIDs
2. Analgesic effect
A. The analgesic effect of NSAIDs is
thought to be related to:
the peripheral inhibition of
prostaglandin production
may also be due to the inhibition of
pain stimuli at a subcortical site.
B. NSAIDs prevent the potentiating action
of prostaglandins on endogenous
mediators of peripheral nerve
stimulation (e.g., bradykinin).

Mechanism of action of
NSAIDs
3. Antipyretic effect
The antipyretic effect of NSAIDs is
believed to be related to:
inhibition of production of
prostaglandins induced by
interleukin-1 (IL-1) and interleukin-6
(IL-6) in the hypothalamus
the resetting of the
thermoregulatory system, leading to
vasodilatation and increased heat
loss.

Clinical Pearls on
NSAIDS

pathogens or toxins
(+)
PMNs

pyrogen release
(+)
hypothalamus

PG E2 synthesis and release

(+)
body temperature-regulating center in
hypothalamus

set point for body temperature

heat productionand heat dissipation

body temperature(fever)

Aspirin
Brand Names :
A.S.A., Alka-Seltzer, Entrophen, Novasen
Uses:
Low to moderate pain, RA and
osteoarthritis, reduce risk of TIA and MI
Watch:
Not for use in children with chickenpox
or influenza due to Reyes syndrome
Risk of GI bleed
Take with lots of water

Aspirin(Acetylsalicylic
acid,(ASA)
pharmacokinetics

metabolized in liver by the hydrolyzation

to salicylate and acetic acid by esterases .
in oral small dose metabolized in firstorder kinetics and half life is 3.5 h,
in large dose (1g/time,>4g/day),
metabolized in zero-order kinetics because
hepatic metablic pathway becomes
saturated, which prolong t1/2 of aspirin to
15 h or more to lead to toxication.

 pharmacologic effects
Aspirin is rapidly deacetylated by esterases in body,
producing salicylate which has anti-inflammatory,
analgesic,and antipyretic effects.
Aspirin irreversibly acetylates cyclooxygenase
to inhibit the enzyme activity.
1. antipyretic action: rapid and moderate in potency.
2. analgesic effects: effective for mild, moderate dull
pain.
3. antiinflammatory effects: to treat rheumatoid and
rheumatic arthritis, symptomatic relief.
4.antiplatelet effects: to inhibit platelet aggregation and
secondary release of ADP from activated platelets
by
inhibition of TXA2 production.*

Therapeutic uses
1. hyperpyrexia: middle dose.
2.dull pain: e.g. headache, arthritis, dysmenorrhea
etc. middle dose.
3.rheumatic fever and rheumatoid arthritis (first-line
drugs) in relatively large dose.
4. prevention of thromboembolism, stroke,
myocardial infarction in small dose. decreasing
incidence of transient ischemic attack and
unstable angina as well as that of coronary artery
thrombosis.
5.chronic use of aspirin reduces incidence of
colorectal cancer.*

Adverse effects
1.gastrointestinal reaction: epigastric distress,
nausea, vomiting, gastric ulceration and bleeding.
taking aspirin with meal or with sodium
bicarbonate, taking enteric- coated aspirin.
2. hepatic damage: mild, reversible.
3. prolonging bleeding time due to inhibition of
platelet functions in small dose and reduction of
plasma prothrombin level in large dose.
4.large dose of aspirin uncouples oxidative
phosphorylation. Energy normally used for
production of ATP is dissipated as heat, which
explains hyperthermia caused by salicylates when
taken in toxic quantities.
5.hypersensitivity or allergy.

6.Reyes syndrome:
seen during viral infectionsfatal, especially in
children
manifestations: fulminating hepatitis with
cerebral edema
children should use acetaminophen instead.
7.Salicylate toxication (salicylism):
mild toxication: headache, mental confusion,
drowsiness, difficulty in hearing, vomiting
severe toxication: hyperventilation, severe CNS
disturbulance, respiration depression and
marked alteration in acid-base balance
Medication: discontinuation of salicylates,
gastric lavage, relieving symptoms, intravenous
infusion of NaHCO3 and dialysis.

Aminophenol Derivatives
Acetaminophen=parasetamol
Acetaminophen inhibits prostaglandin
synthesis in CNS,but less effect on peripheral
cyclooxygenase.
antipyretic and analgesic effects are similar to
aspirin in potency
no anti-inflammatory activity.
Use: dull pain and hyperpyrexia., choice for
children with viral infections or chicken pox.
Adverse effects: skin rash and drug fever,
hypoglycemic coma, renal tubular necrosis and
renal failure in long-term administration, acute
hepatic necrosis in large dose.

ADVERSE EFFECTS of
parasetamol
Mainly on liver due to its active
metabolite ( N-acetyl-pbenzoquinone).
At therapeutic doses increases
hepatic enzymes.
At high doses causes hepatic necrosis
& renal necrosis.
Treatment of paracetamol toxicity
with N-acetylcystine (SH donor ) as
life saving

Ibuprofen
Brand Names :
Advil, Motrin, Ibuprin, Medipren
Uses:
Chronic RA, gout
Watch:
Caution with bleeding abnormalities,
renal failure
Can cause hyponatremia
A larger loading dose is often used (400600 mg in adults), followed by 200 mg

Ibuprofen
anti-inflammatory, analgesic and
antipyretic activity.
chronic treatment of rheumatoid and
osteoarthritis.
less intense of gastrointestinal
effects than that of aspirin.

Indomethacin
Brand Names :
Indameth, Indocid, Indocin

Uses:
Also used with rheumatoid, gouty
arthrits
Closes PDAs in premature infants

Clinical Pearls:
Dizziness, hallucinations not
uncommon

Naproxen
Brand Names :
Apo-Naproxen, Naprosyn, Naxen, Walprox
Uses:
Also used with rheumatoid, gouty arthritis
Clinical Pearls:
An OTC drug in Canada, can be purchased
without a script in the US
More sustained duration of action than
ibuprofen

 Other Organic Acids

Indomethacin

Pharmacologic effects
anti-inflammatory, analgesic and antipyretic
effects
more potent than aspirin as an anti-inflammatory
agent
inferior to the salisylates at dose tolerated by
patients with rheumatoid arthritis.
therapeutic uses
rheumatoid and rheumatic arthritis, not routinely
for analgesia and antipyresis because of its toxicity
and side effects.

Adverse effects
35%-50% of patients report some adverse
effects and most adverse effects are doserelated.
1. gastrointestinal complains.
2. CNS effects: frontal headache, dizziness,
vertigo, mental confusion etc.
3. hematologic effects: neutropenia,
thrombocytopenia, inpaired platelet functions,
rare aplastic anemia.
4. contraindication: in pregnancy or nursing
women, patients with psychiatric disorders,
epilepsy, parkinsonism, renal diseases, peptic
ulcers and machine operators.

Other drugs
Sulindac
fenamates (mefenamic acid,
meclofenamate)
tolmetin
propionicacid derivatives (naproxen,
fenoprofen, ketoprofen, flurbiprofen)
piroxicam
nabumetone
etodolac, diclofenac, ketorolac
in single agent or in the compound
preparations.

Summary for this chapter

effects and uses of NSAID
mechanism of action of NSAID
pharmacological basis of small dose
of aspirin for prevention of
thromboembolism
characterastics of aspirin,
acetaminophen, indomethacin and
ibuprofen

COX inhibitors

NSAIDs
NSAIDs

Nonselective
COX-1/COX-2
inhibitors

COX-2
inhibitors

COX-3
inhibitors

Selective (coxibs)

Antipyretic
analgesics

Preferential

Beneficial actions of NSAIDs due

to prostanoid synthesis inhibition
1. Analgesia
prevention of pain nerve ending sensitization
2. Antipyresis
connected with influence of thermoregulatory
centre in the hypothalamus
3. Antiinflammatory action
mainly antiexudative effect
4. Antithrombotic action
in very low daily doses
5. Closure of ductus arteriosus

Shared toxicities of NSAIDs due

to prostanoid synthesis inhibition
1. Gastric mucosal damage
connected with PGE inhibition
2. Bleeding: inhibition of platelet
function (TxA2 synthesis)
3. Limitation of renal blood flow
Na+ and water retention
4. Delay / prolongation of labour
connected with PGF2 inhibition
5. Asthma and anaphylactoid reactions
connected with PGF2 inhibition

Mechanisms by which NSAIDs may induce mucosal injury

nd
Lllmann,
Lllmann,Color
ColorAtlas
AtlasofofPharmacology
Pharmacology22ndEd.
Ed.(2000)
(2000)

Opioid Analgesics
There are three main families of
endogenous opioid peptides; these
have analgesic activity and have
many physiological functions, but
they are not used as drugs.
Opioid drugs include:
Phenanthrene derivatives, structurally
related to morphine
Synthetic compounds with dissimilar
structures but similar pharmacological
effects

Opioid Receptors
-receptors are thought to be responsible for most of
the analgesic effects of opioids, and for some major
unwanted effects (e.g. respiratory depression,
euphoria, sedation and dependence). Most of the
analgesic opioids are -receptor agonists.
-receptors are probably more important in the
periphery, but may also contribute to analgesia.
-receptors contribute to analgesia at the spinal level,
and may elicit sedation and dysphoria, but produce
relatively few unwanted effects, and do not contribute
to dependence. Some analgesics are relatively selective.

Opioid Receptors
-receptors are not true opioid
receptors, but are the site of action of
certain psychotomimetic drugs, with
which some opioids interact.
All opioid receptors are linked through Gproteins to inhibition of adenylate
cyclase. They also facilitate opening of
K+ channels (causing hyperpolarisation),
and inhibit opening of Ca2+ channels
(inhibiting transmitter release). These
membrane effects are linked to the
decrease in cAMP formation.

Morphine
Pharmacological effects and
Mechanisms
CNS effects
Analgesia: increasing tolerance of
pain are the most prominent
effects. Therefore, help patients
to eliminate dysphoria, anxiety.
Consciousness is not lost, and the
patient can usually still locate the
source of pain.

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.

Pharmacokinetics of
Morphine
Is well absorbed from the gastrointestinal
tract. However, the analgesic effect is
greater when drug is administered
intramuscularly or intrvenously. It has a
significant first-pass effect.
Morphine is metabolised to morphine-6glucuronide, which is more potent as an
analgesic.
Ninety percent of a given dose is
excreted in the urine; the remaining 10%
is excreted in the feces.

Contraindications and
cautions
Use in patients with head injures
Use during pregnancy
Use in patients with impaired
pulmonary function
Use in patients with impaired
hepatic or renal function

Therapeutic uses
Analgesia, such as the relief of pain
from myocardial infaction, terminal
illness, surgery, biliary colic and renal
colic (combined with atropine).
Dyspnea due to pulmonary edema
because of sedative, vascular dilataltion
and inhibition of the respiratory centers
responsiveness to CO2 .
Treating severe diarrhea because of
constipating effects.
Treating cough (usually insteaded by
codeine).

Adverse effects
Respiratory depression is the
most important effect.
Nausea and sometimes
dysphoria can occur.
Increase biliary tract pressure.
Allergic reactions.
Bronchoconstrictive action.
Tolerance and Dependence

Tolerance and
Dependence
Tolerance develops rapidly,
accompanied by physical
withdrawal syndrome.
The mechanism of tolerance may
involve adaptive up-regulation of
adenylate cyclase. It is not
pharmacokinetic in origin and
receptor down-regulation is not a
major factor.

Tolerance and
Dependence
Dependence comprises two components:
(a) physical dependence (somewhat
resembling severe influenza, with
yawning, pupillary dilatation, fever,
sweating, piloerection, nausea,
diarrhoea and insomnia), associated
with the withdrawal syndrome, lasting
for a few days;
(b) psychological dependence,
associated with craving, lasting for
months or years.

Tolerance and
Dependence
Weak, long-acting -receptor
agonists, such as methadone,
may be used to relieve
withdrawal symptoms.
Certain opioid analgesics, such as
codeine and pentazocine, are
much less likely to cause physical
or psychological dependence.

Contraindications and
cautions
Use in patients with head injures
Use during pregnancy
Use in patients with impaired
pulmonary function
Use in patients with impaired
hepatic or renal function

Codeine
Although the pharmacologic effects of
codeine are similar to those of
morphine, it has about one-twelfth
the analgesic potency of morphine.
Be used mainly for cough suppressant
and milder pain.
It produces less sedation, respiratory
depression, fewer gastrointestinal
effects, and less addiction and
withdrawal.

Synthetic analgesic:
Pethidine
It is very similar to morphine (one-seventh
to one-tenth potent) in pharmacologic
effects by -receptor agonists.
Therapeutic uses: analgesic, cardiac
asthma, sedation (decrease the dosage of
anesthetic )and artificial hibernation.
It has no gastrointestinal or antitussive
action because of shorter-acting.
Adverse effect: also causes respiratory
depression and possesses addiction
liability, although withdrawal effects are
less severe than with morphine.

Methadone
It is widely used as a means of
treating morphine and diamorphine
addiction because of its chronic and
insignificant addiction.

Opioid receptor mixed

agonists/antagonists
Other drugs, such as nalorphine
and pentazocine, produce a
mixture of agonist and antagonist
effects.

Opioid Antagonists
Pure antagonists include naloxone
(short-acting) and naltrexone (longacting). They block -, - and -
receptors more-or-less equally.
Naloxone does not affect pain
threshold normally, but blocks stressinduced analgesia, and can
exacerbate clinical pain.

Opioid Antagonists
Naloxone rapidly reverses opioidinduced analgesia and respiratory
depression, and is used mainly to
treat opioid overdose or to improve
breathing in newborn babies affected
by opioids given to the mother.
Naloxone precipitates withdrawal
symptoms in morphine-dependent
patients or animals.

Clinical Use of Analgesic

Drugs
The choice and route of
administration of analgesic drugs
depends on the nature and duration
of the pain.
A progressive approach is often used,
starting with nonsteroidal antiinflammatory drugs, supplemented
first by weak opioid analgesics, and
then by strong opioids.

Clinical Use of Analgesic

Drugs
In general, severe acute pain (e.g. trauma,
burns, post-operative pain) is treated with
strong opioid drugs (e.g. morphine, fentanyl)
given by injection.
Mild inflammatory pain (e.g. arthritis) is
treated with non-steroidal anti-inflammatory
drugs (e.g. aspirin) supplemented by weak
opioid drugs (codeine, pentazocine) given
orally if required.
Severe pain (e.g. cancer pain, severe arthritis
or back pain) is treated with strong opioids
given orally, intrathecally, epidurally or by
subcutaneous injection.

Clinical Use of Analgesic

Drugs
Chronic neuropathic pain is often
unresponsive to opioids, and
treated with tricyclic
antidepressants (e.g.
amitriptyline), or other drugs,
such as carbamazepine.

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