2. Presentation outline
Introduction
History
Endogenous opioid peptides
Opioid receptors
Mechanism of action
Uses
Opioid analgesics
Tolerance and dependence
Opioid receptor antagonist
Future direction
3. Introduction
• According to International Association for the Study of Pain, pain is defined as an unpleasant
sensory and emotional experience associated with potential tissue damage od described in terms
of tissue damage.
• Pain can be categorised as Nociceptive, Neuropathic or Nociplastic pain
• Agents which decrease pain are referred as analgesics.
• Narcotic analgesics are the agents which are to relieve acute , chronic and severe pain
• Morphine and its analogue and some synthetic derivatives are called as narcotic analgesics or
( opioid analgesics), they produce analgesia by combining with opioid receptors.
• Opiate is specific term use to describe drugs derived from opium poppy.
4. History
In 1803, German pharmacist, Friedrich Wilhelm
Adam Sertimer isolated major psycoactive
substance form opium and named it as “
morphium” alluding to greek god of dreams
Morpheus.
In 1820 , Heinrich Emmanual Merck commercialize
morphine, and the medical use of morphine was
widespread after discovery of hypodermic needle
5. Endogenous opioid peptides
• An agent found within the brain that acts through an opioid receptor is an endogenous opioid
• They are principally found in spinal cord , hypothalamus, pituitary gland, limbic system, sympathetic
ganglia, skin GIT..
• Analgesia
• Euphoria
• Precursor- pro
opiomelonocortin
ENDORPHINS
• Analgesia
• Sedation
• Precursor- Pro
dynorphine
DYNORPHINES
• Analgesia
• Dysphoria
• Precursor-
proenkaphaline
ENKEPHALINS
7. Mechanism underlying pain
• Tissue injury or local inflammation eg: local
skin burn, toothache etc
• An abnormal pain response ( hyperalgesia) is
evoked
• Pain is due to local release of some active
factors at the injury site.
• There is activation of spinal facilatatory
cascades which gives more output to the
brain from given input, facilate in giving
hyperalgesia state.
8. Role of opioid on various organs system
Mechanism involved in respiratory depression
Mechanism involving mood alteration and
rewarding behavior
9. d
Addiction and physical dependence
• Long term opioid treatment cause behavioral effects like physical dependence and addiction.
• Physical dependence is due to up regulation of cAMP and noradrenergic signaling in the locus
coeruleus neuron of the dorsal pontine tegmentum of brainstem.
• clinical guideline= “START LOW AND GO SLOW” dosage regimen to prevent addiction and physical
dependence, overdosing and abuse.
10. Mechanism of opiate action in producing analgesia
• Opioid binding to mu, kappa and delta receptors act
by Gi protein.
• On presynaptic terminal of primary nociceptive
afferent, inhibition of calcium influx prevents
excitatory neurotransmitter release
• On post synaptic terminal increased potassium
efflux cause hyperpolarisation makes its less
excitable.
• Inhibition of adenyl cyclase decrease alteration of
ion channel.
• Activation of descending inhibition by stimulating the
cells in PAG which relay to raphie nucle iof medulla to
dorsal hornn, reduces the nociceptive input.
11. Natural Semisynthetic Synthetic
1: Morphine
2: Codeine
1: Hydromorphone
2: Hydrocodone
3: Oxycodone
4: Oxymorphone
1: Fentanyl
2: Meperidine
3: Methadone
4: Tramadol
According to the occurrence
Phenanthrene derivatives Benzoisoquinoline derivatives
Morphine
Codeine
Thebaine
Papavarine
Noscapine
According to the basic nucleus
Classification
13. Morphine
• Opium is obtained from the unripe seed capsules of the poppy plant, Papaver
Somniferum.
• Natural alkaloid which is Phenanthrene derivative having Piperidine skeleton.
Pharmacological actions of morphine
Analgesia
Euphoria and sedation
Respiratory depression and supression of cough centre
Nausea and vomitting
Reduce GI motility causing constipation
Bronchoconstriction.
14. Pharmacokinetics of morphine
• Morphine is weak base and is highly ionised in stomach.
• Bioavaliabilty = 15-50%
• Extensively metabolised in liver to morphine-6-
glucoronide and morphine -3- glucoronide.
• t1/2 of morphine is ~2 hours
• Morphine is eliminated by glomerular filtration, primarily
as morphine-3-glucuronide.
15. • Weak agonist and is less potent than morphine.
• Low dependence liability
• Uses= as an antitussive and antidiarrheal
• Disadv= constipation and convulsions( toxic
doses)
Codeine
• More potent analgesic than morphine produce
greater Euphoria
• High dependence liability.
• Also known as diacetylmorphine , diamorphine
Heroin
16. • Fentanyl is synthetic opioid related to phenylpiperidines
• MOR agonist
• 100 times more potent than morphine
• Highly lipid soluble and cross BBB
Fentanyl
• Synthetic congener of codeine
• Weak MOR agonist
• Analgesic effect is produced by inhibition of uptake of
5HT and NE.
• O-demethylated metabolite is 2-4times as potent as
drug.
Tramadol
17. Name Property Dose and Route of
administration
Metabolism and
excretion
Adverse effects Uses
Fentanyl
(Phenylpiperadine)
MOR agonist IV Hepatic
metabolism and
renal excretion
T1/2=4hrs
CVS effects Anesthetic, severe
pain
Methadone
L isomer is 50
times more potent
MOR agonist Oral, IV , IM
(2.5-10mg)
Biliary and urinary
excretion
Sweating,
lymphocytosis, QT
prolongation
Chronic pain
Opioid absistance
syndrome
Meperidine MOR agonist All routes
IV (75-100mg)
Hepatic
metabolism
half life = 3hrs
Nausea vomiting
sedation and
respiratory
depression
Analgesic
levorphanol MOR agonist IV,IM T half= 12 to 14
hours
nausea Preoperative
anxiolytic
Moderate to
severe pain
Propoxyphene
(D-isomer)
(L-isomer
=antitussive)
MOR agonist 90 to 120 mg T half = 6-12hrs CNS and
respiratory
depression
painkillers
18. Opioid receptor partial agonist/weak antagonist
Pentazocine • weak MOR receptor
antagonist or partial
agonist
• Full agonist at KOR
Butorphanol • KOR agonist-MOR
antagonist opioid
Nalbuphine • KOR agonist-MOR
antagonist opioid
• The drugs like Nalbuphine and Butorphanol are
competitive MOR antagonists
• Exert their analgesic actions by acting as
agonists at KOR receptors. or partial agonist
while retaining its KOR agonist activity.
• These drugs show less respiratory depression
and addictive potential.
Buprenorphine
• Partial agonist at MOR receptor
• Highly lipophilic and is derived from thebaine
• 20-50 times more potent than morphine
• Buprenorphine is metabolized to
norbuprenorphine by CYP3A4
• Buprenorphine for the treatment of opioid
addiction is initiated with sublingual drug,
followed by maintenance therapy with a fixed-
dose combination formulation of
buprenorphine and naloxone.
19. agram
Pure Opioid antagonist
Naloxone
• N-allyl derivative of
oxymorphine
• Competitive antagonist
and have 10 fold High
affinity for mu receptors
• Reverse respiratory
depression and analgesia
of opioids and precipitate
withdrawal in addicts.
• Half life= 30=81min
Naltrexone
• Longer acting
• Orally effective due to low
1st pass metabolism
• Used as maintenance
therapy in addicts.
• Half life= 2-8 hours
23. Analgesic tolerance
Clinical management of opioid
tolerance
1. Opioid rotation and combination of
opioid with other adjuvants.
2. Combination of opioid agonist and
antagonist to prevent ant
nociceptive tolerance.
3. Desensitization and receptor
trafficking are known to cause
insufficient analgesia and lead to
opioid tolerance.
