analgesics

opioids and NSAIDs

IGM. Surya Trapika; Pharmacology Dept., Faculty of Medicine, Udayana Uni

• Analgesics mrp obat utk site aksi pd SSP
maupun perifer tanpa menyebabkan
hilangnya kesadaran
• Analgesics dibedakan 2 klp utama:
– Opioid/narcotic/morphine like analgesics.
– Nonopioid/nonnarcotic/aspirin like analgesics
• Nyeri ; rasa tdk menyenangkan
• Alasan utama mencari
pengobatan.
• Langkah awal diagnosis: meminta
pasien utk mendeskripsikan
sumber dan tipe nyeri yg dialami
• Mengapa kita harus mengalami dan
merasakan pengalaman yang tidak
menyenangkan ini?
• Rasa nyeri sepertinya tdk memiliki
fungsi apapun kecuali memperburuk
situasi yg tdk menyenangkan seperti
injuri atau infeksi
• congenital analgesia born without
the ability to experience pain
• 2 tipe nyeri :
– nociceptive :
physiological cause such as inflammation
or injury
– neuropathic
neurological dysfunction that results in the
perception of pain
• Kategori lain:
berdasarkan lamanya rasa nyeri
dirasakan
– Akut
– Kronis
Slide Master
The synapse
The body’s own analgesic system

• Prostaglandins mrp mediator penting

pada proses inflamasi
– Prostaglandin E2 (PGE2) mrp
prostaglandin yg utama
• also plays a less-well-defined role in the
transmission of pain signals in the spinal cord
and in the hypothalamus of the brain.
• It can affect the body’s thermostat,resulting in
pyresis (fever).
• maintenance of the gastric mucosa
Slide Master
• Prostaglandin mrp target utama
non-steroidal anti-inflammatory
drugs (NSAIDs).
• Thromboxanes mrp target dari
aspirin dlm pencegahan
pembentukan clotting/bekuan darah
NON OPIOID ANALGESIC
 NSAID

• also known as nonopioid an-algesics.

• They relieve pain
– without interacting with opioid receptors
– do not depress CNS
– have no drug dependence or drug abuse
property
– possess antipyretic activity
Classification of NSAID
Classification of NSAID
Classification of NSAID
Classification of NSAID
SALICYLATES
• mrp esters dari asam salisilat.
• Acetyl salicylic acid (aspirin) scr cepat
dikonversikan dalm tubuh mjd asam
salisilat
• The site of action of central analgesia
seems to be the hypothalamus
• The peripheral analgesic action mll
penghambatan sintesa prostaglandin
dan penghambatan sensitisasi
mekanisme nyeri
SALICYLATES
• Parmakokinetik:
– Diabsorbsi baik stl pemberian oral
– Konsentrasi dlm plasma ditemukan stl
stengah jam pemberian dan mencapai
kadar puncak dalam 2 jam
– 50 persen dieliminasi dlm waktu 24 jam
dan plasma hal life nya 2-8jam
SALICYLATES
• Efek samping:
– nausea, vomiting, gastric irritation and
occult blood in stool.
– Allergic reactions include urticaria,
skinrash, rhinorrhoea, asthmatic attack
and anaphylactic reactions.
– Prolonged administration of salicylates
cause a syndrome called ‘salicylism’
• headache, dizziness, tinnitus, vertigo, difficulty
in hearing, dimness of vision, mental
confusion, drowsiness
 PYRAZOLONE DERIVATIVES

• PHENYLBUTAZONE
– a potent antiinflammatory agent.
– It has poor analgesic and antipyretic action.
– Mechanism of action is similar to other
NSAIDs

• OXYPHENBUTAZONE
– It is a metabolite of phenylbutazone and
having similar pharmacodynamic and phar-
macokinetic properties
 INDOLE DERIVATIVES

• INDOMETHACIN
– It is indole acetic acid derivative possessing
potent antiinflammatory property and having a
good analgesic and antipyretic action also.
– Mechanism of action is same as other
NSAIDs
• SULINDAC
– a fluorinated derivative of indomethacin, has
longer duration of action.
– It is prodrug, converted to active sulfide
metabolite
PROPIONIC ACID DERIVATIVES

• ibuprofen, flurbiprofen,ketoprofen memiliki

efek antiinflammatory yg sama dgn aspirin
tp d toksisitas dan efek samping yg lebih
ringan
• KETOPROFEN
– an inhibitor of cyclooxygenase with analgesic,
antiinflammatory and antipyretic properties.
– Readily absorbed from the GI tract.
– Food slows the rate of absorption but not the
total bioavailability
PROPIONIC ACID DERIVATIVES

• NAPROXEN
– Naproxen is more efficacious and better
tolerated.
– It is also longer acting and has the advantage
of twice daily dosing
ANTHRANILIC ACID DERIVATIVES

• MEFENAMIC ACID
– Mrp penghambat enzim cyclooxygenase
– Memiliki efek analgesic, antiinflammatory dan
antipyretic.
– Diabsorbsi baik pd saluran cerna
– Diekskresikan mll urine dlm bentuk metabolit
 OXICAM DERIVATIVES

• PIROXICAM
– has anti-inflammatory, analgesic and
antipyretic activity.
– It provides effective and long-lasting relief of
pain and stiffness. Its convenient once daily
dosage
– It acts peripherally by inhibiting the synthesis of
prostaglandins by reversible inhibition of
cyclooxygenase.
 OXICAM DERIVATIVES

• PIROXICAM
– Inhibition of the migration of leukocytes to an
inflammatory site
– inhibition of the release of lysosomal enzymes
may also be involved in the antiinflammatory
action
– The rate, but not the extent of absorption is
decreased by food
ARYL ACETIC ACID DERIVATIVES

• DICLOFENAC
– pronounced antirheumatic, antiinflammatory,
analgesic and antipyretic properties.
– Inhibition of prostaglandin biosynthesis is
fundamental mechanism of action.
– In rheumatic diseases, it leads to marked
relief from pain at rest, pain on movement,
morning stiffness and swelling of the joints,
as well as by an improvement in function
ARYL ACETIC ACID DERIVATIVES

• DICLOFENAC
– Due to the enteric coating, onset of
absorption is delayed. However, once the
absorption sets in diclofenac is rapidly
absorbed.
– Diclofenac enters the synovial fluid, where
maximum concentrations are measured two
to four hours after peak plasma values have
been attained
ARYL ACETIC ACID DERIVATIVES

• ACECLOFENAC
– newer COX-2 inhibitor and is a phenylacetic
acid derivative.
– It also inhibits synthesis of IL-1b and TNF-a,
thus inhibiting PGE2 production.
– It is rapidly and completely absorbed after
oral administration,
– It is metabolized to a major metabolite 4'-
hydroxyaceclofenac
PARA-AMINOPHENOL DERIVATIVES

• PARACETAMOL
– acts on CNS to produce analgesia and
antipyretic effect.
– It has negligible antiinflammatory action
peripherally in therapeutic uses.
– It is poor inhibitor of PG synthesis in
peripheral tissues, but more active on
COX in brain.
– It also raises the pain threshold
PARA-AMINOPHENOL DERIVATIVES

• PARACETAMOL
– well absorbed, peak plasma concentration
is reached in 30 to 60 minutes.
– About 1/3rd is bound to plasma proteins
– inactivated in the liver, being conjugated to
give the glucuronide or sulphate which are
excreted in urine
PARA-AMINOPHENOL DERIVATIVES

• PARACETAMOL
– A small proportion of acetaminophen
undergoes CYP-mediated N-hydroxylation to
form NAPQI, a highly reactive intermediate.
– This metabolite normally reacts with
sulfhydryl groups in glutathione (GSH) and
thereby is rendered harmless.
– However, after ingestion of large doses of
acetaminophen, the metabolite is formed in
amounts sufficient to deplete hepatic GSH
and contributes significantly to the toxic
effects of overdose
PARA-AMINOPHENOL DERIVATIVES

• PARACETAMOL INTOXICATION
– >7.5 g of acetaminophen, or repeat use of
supratherapeutic doses, can result in toxicity.
– Activated charcoal, if given within 4 hours of
ingestion, decreases acetaminophen
absorption by 50-90%
– N-acetylcysteine (NAC) is indicated for those
at risk of hepatic injury. NAC functions by
detoxifying NAPQI. It both repletes GSH
stores and may conjugate directly with
NAPQI by serving as a GSH substitute
 NEWER COX-2 INHIBITORS

• KETOROLAC
– chemically related to indomethacin and
tolmetin
– has antiinflammatory and antipyretic action
that, together with its analgesic effects
• NIMESULIDE
– a NSAID of the sulfonanilide class.
– has exhibited potency similar to or greater
than that of indometha-cin, diclofenac,
piroxicam and ibuprofen in standard
animal models of inflammation
 NEWER COX-2 INHIBITORS

• CELECOXIB
– has COX-2 selectivity.
– It is a diaryl substituted pyrazole.
– It exhibits antiinflammatory, analgesic and
antipyretic activities which are believed to be
due to inhibition of COX-2.
– At therapeutic concentrations in humans,
celecoxib does not inhibit COX-1 enzyme
OPIOID ANALGESIC
 OPIOIDS

• Drugs obtained from morphine are known

as opioids or narcotic analgesics
• The opium is obtained from the opium
poppy Papaver somniferum.
• It contains two type of alkaloids.
– phenanthrene derivatives (morphine, codeine
& thebaine)
– benzyl isoquinoline derivatives (papaverine
and noscapine)
CLASSIFICATION of OPIOIDS
 NATURAL COMPOUNDS

A. MORPHINE
– produces analgesia through action in the
brain and spinal cord, that contain peptides
possessing opioid like pharmacological
action.
– These endogenous substances are known as
endogenous opioid peptides (earlier known
as endorphin & now known as β-endorphin)
– Morphine and other opioids exert their
pharmacological actions by acting on diferent
receptors namely mu (µ), kappa (κ) and delta
(δ)
 NATURAL COMPOUNDS

• MORPHINE
– Analgesic, respiratory, depression as well as
euphoria produced by morphine result mainly
from action at mu receptors.
– Most of the currently available narcotic
analgesics act primarily on the mu receptors
– Morphine produces analgesia by elevation of
pain threshold, thereby reducing the
perception of pain.
– It also altered psychic reaction to pain which
may beassociated with feeling of well being
 NATURAL COMPOUNDS

• MORPHINE (p.k)
– Morphine orally is less effective and
absorption is very slow.
– It has variable and high first pass metabolism
when given by subcutaneous route, its
analgesic effect starts within 10 minutes
which persists for 4 to 5 hours and by IV
route, it produces immediate action.
 NATURAL COMPOUNDS

• MORPHINE (a.r)
– CNS side effects include confusion, anxiety,
lethargy, nausea and vomiting.
– GIT related effect is constipation.
– Other side effects are urinary retention, dry
mouth, miosis,dysphoria, hypotension, skin
rash, itching and urticaria.
– Tolerance, drug dependence and drug abuse
are the main drawbacks of morphine
 NATURAL COMPOUNDS

• Acute Overdose/Toxicity (Morphine

Poisoning)
– characterised by respiratory depression, miosis,
cyanosis, reduced body temperature, urinary
retention, hypotension, pulmonary edema and
coma
– can be treated by
• Maintenance of airway and oxygen inhalation.
• Maintenance of BP.
• Specific antagonists: Naloxone 0.4-0.8 mg IV;
alternatively nalorphine (3-5 mgIV) can be given
 NATURAL COMPOUNDS

B. CODEINE
– It is a methyl ester of morphine and less potent
analgesic than morphine.
– It is widely used as antitussive agent.
– Pholcodeine is also used as antitussive agent
and causes less constipation
 SYNTHETIC COMPOUNDS

A. PETHIDINE
– is predominantly a µ agonist and it exerts its
action on the CNS and the neural elements in
the bowel
– The analgesic effects are detectable about 15
minutes after oral administration, reach a
peak in about two hours
– Absorbed by all routes of administration, but
the rate of absorption is erratic after IM
injection.
– Pethidine crosses the placental barrier
 SYNTHETIC COMPOUNDS

B. FENTANYL
– a potent opioid analgesic.
– Chemically it is N-phenyl-N-propanamide.
– It interacts predominantly with opioid µ-recep-
tor in human brain, spinal cord and other
tissues.
– It exerts its principle pharmacologic effects on
the CNS.
– It is 80-100 times more potent than morphine,
both in analgesia and respiratory depression
 SYNTHETIC COMPOUNDS

C. METHADONE
– having same or more analgesic activity than
morphine
D. TRAMADOL
– is not derived from natural sources nor is
chemically related to opiates.
– It acts via opioid receptors in CNS to pro-
duce analgesia and has no abuse potential.
– It also inhibits the reuptake of noradrenaline
and serotonin.
 OPIOID
AGONISTS/ANTAGONISTS
A. PENTAZOCINE
– It is agonist-antagonist of morphine and is
used as an analgesic. It exerts morphine like
action.
– It is a partial agonist at opioid receptors
– It is kappa receptor agonist
– weak mu antagonist or partial antagonist
properties
– Tolerance and dependence develops on
repeated use
 OPIOID
AGONISTS/ANTAGONISTS
B. NALORPHINE
– It is an N-allylnormorphine, semisyn-thetic
congener of morphine
– The agonistic actions are produced by kappa
receptor activation
– antagonistic properties are due to action on
mu receptor which antagonizes all morphine
actions (mainly reverses the analgesia and
respiratory depression).
– It is used mainly in the treatment of acute
morphine poisoning
 OPIOID
AGONISTS/ANTAGONISTS
C. NALOXONE
– It is N-allyl analogue of oxymorphone,
– have a high affinity for mu receptor and lower
affinity at delta and kappa sites.
– It selectively antagonizes the respiratory de-
pression produced by opioids. After intra-
venous administration, it antagonizes all
actions of morphine.
– It also blocks the actions of endogenous opioid
peptides
– It is inactive orally because of high first pass
metabolism in liver
 OPIOID
AGONISTS/ANTAGONISTS
D. NALTREXONE
– It is a pure antagonist and chemically related to
naloxone.
– It is more potent than naloxone and because of
its longer duration of action, it can be used as
maintenance drug for morphine addicts.
– It has no euphoric effect and no physical
dependence liability.
– It is effective orally