1. Narcotic analgesics – opium
plant – poppy plant - capsule

2. Pain Signaling


These neurons release excitatory
neurotransmitters which relay signals from
one neuron to another.
“The signals are sent to the thalamus, in
which pain perception occurs. From the
thalamus, the signal travels to the
somatosensory cortex in the cerebrum, at
which point the individual becomes fully
aware of the pain (2).”

3. Types of Pain

4. Types of Pain – contd.

5. Opioids
Narcotic analgesics
Prototype: MORPHINE
Major action - CNS/spinal cord
Potent analgesia–Mu receptor agonist
Mu, Kappa, Sigma, Delta
Opioid receptor  decreased calcium 
decreased glutamate  decreased excitation

6. Opioid Analgesics – important
terms



Analgesics: Drugs -selectively relieves painacting in the CNS or on peripheral pain
mechanisms(without significantly altering the
consciousness) – Opioids and NSAIDS
Opioids: drug binds -opioid receptorsantagonized by Naloxone .
– Natural, Synthetic and semi-synthetic
Narcotics: Drugs-opium or opium like
compounds-potent analgesic effects-a/w
significant alteration of mood and behavior-with
the potential for dependence and tolerancerepeated administration.

7. Agonist
Antagonist
Mu
Strong: Morphine, Pethidine,
Methadone, Levorphanol,
fentanyl, alfentanil, sufentanil,
remifentanil
Moderate: Oxycodone, codeine
Weak: Propoxyphene
PA: Buprenorphine- (long)
Naloxone
Naltrexone
Nalmefene
Nalbuphine
Pentazocine
Nalorphine – weak antagonist
Butorphanol – weak
antagonist
kappa
Nalbuphine,Pentazocine
Butorphanol, Nalorphine
Naloxone, Naltrexone
Nalmefene
Delta
Naloxone, Naltrexone ,
Nalmefene
Nalorphine (weak antagonist)
Butorphanol – weak antagonist
Sigma
Naloxone, Naltrexone,
Nalmefene

8. OPIOID/OPIATE RECEPTORS
Mu = µ
Delta = δ
supraspinal analgesia, euphoria, respiratory
depression, physical dependence
µ1 = mainly analgesia
µ2 = mainly respiratory depression
Kappa = κ = spinal analgesia, miosis,
sedation
Sigma = σ = Dysphoria, halluci, respiratory
depr and vasomotor stimulation

9. Where are the receptors ?




Limbic system including amygdaloid nucleus,
hypothalamus
Medial and lateral thalamus, area postrema
(CTZ)
Nucleus of tractus solitarious (cough center)
Substantia nigra, and spinal cord

10. Terminology




Opioid agonist = activates some or all opioid
receptors and do not block any.
Partial agonist = a drug that can activate
opioid receptor, but the response is
submaximal
Mixed agonist-antagonist = a drug that
activates some receptor subtypes and blocks
some other subtypes
Pure antagonist = a drug that blocks all
receptor subtypes

11. OPIOID RECEPTOR TRANSDUCER MECHANISMS

12. Mechanism of action





Opioid drug bind to opioid receptor widely
distributed in CNS & other tissues
A part of family of G-protein complex
receptor
Open K+ channels
Prevent opening of Ca 2+ channels
Inhibit the release of other neurotransmitters

13. Endogenous Opioid Peptides

3 distinct families of peptides
Enkephalins
Endorphins
Dynorphins
Each family -derived - distinct precursor of
polypeptide

14. Acute effects
-Analgesia
-Dose dependent CNS depression
-Respiratory depression– medulla
-Histamine release –
hypotension, peripheral vasodilation
(decreased preload,afterload)
bronchospasm
-Cough suppressant
-Decrease GI motility – constipation

15. Stimulant actions
Euphoria, CTZ – N, V
 Increased ICT
 PINPOINT PUPILS - III N nucleus
 NOTE : Meperidine (Pethidine)
(ATROPINE- LIKE – MYDRIASIS)
 Biliary sphincter contraction
 Increased detrusor, sphincter tone
urgency but retention
 Uterine stimulation


16. Uses
Severe acute shooting visceral pain
 MI
 Terminal stages in malignancy
 Severe crush injuries
 Postoperative pain


17. Contraindications/A/E
Respiratory depression
 -Old, young,COPD, kyphoscoliosis
 Hypovolemia, hypotension
 Increase ICT  HEAD INJURY
 Increased intrabiliary pressure
 UNDIAGNOSED ACUTE ABDOMEN
 Liver disease, renal disease
 Labor: respiratory depression in newborn


18. Acute morphine poisoning
Respiratory depression, hypoxia
 Profound CNS depression, coma
 Hypotension, PINPOINT PUPILS

Use antagonist
 NALOXONE 0.4 mg IV q 2-3 min – pure
anta- competitive – all receptors
 VENTILATORY SUPPORT
 NARROW MARGIN OF SAFETY


19. Chronic effects





Dependence – physical, psychic
Tolerance – Effect goes on decreasing on
chronic use.
Tissue tolerance – means - some tissues do
not get tolerant.
CNS develops tolerance, but GIT (constipation)
and EYE (pinpoint pupils) do not develop
tolerance !!
So, Opiate addict has constipation and
pinpoint pupils

20. How to treat – Morphine dependence

Substitute an agonist !

Which will be less potent than original drug – and which will have long duration of action
This will give similar pleasure and withdrawing this
drug will be easier due to long duration of action






(withdrawal symptoms will be less severe)
So –
1. Methadone (long duration of action)
or
2. Buprenorphine (mild withdrawal)

21. Opiate withdrawal symptoms

Hyperalgesia
muscle cramps, stomach pain
Mydriasis
Diarrhea, Insomnia, Anxiety, Craving,
Sweating, Rhinorrhea,
Tachycardia, increased blood pressure

Treat with –

Methadone or buprenorphine (as replacement)
Clonidine
Beta blockers
Benzodiazepines








22. What is heroin?

23. Heroin, not heroine !!

24. What is heroin?
Synthetic derivative of morphine
 (diacetyl morphine)
 Similar properties
 Treatment of overdose or withdrawal –
same as morphine


25. Heroin’s effects on the body

26. Important opioids








Analgesia (MI, terminal cancer pain, post-op)
-Meperidine(pethidine)- atropine-like
-fentanyl (also as patches)
-methadone, buprenorphine
Others:
-oxycodone, hydrocodone, propoxyphene
Diarrhea – diphenoxylate, loperamide
Cough-codeine, dextromethorphan

27. Pethidine (agonist)
Opioid agonist, but is an atropine substitute
 So, atropine-like effects: Less spasmogenic, less
sphincter contraction
 No urinary retention, produces MYDRIASIS
 Less histamine release, safe in asthma
 PO, IV, IM 50-100 mg. Short duration – 2-3 hours
 Slow tolerance and dependence
 Uses:
 Preanesthetic medication
 Post-operative pain, other severe pains
 For analgesia during labor


28. Fentanyl (agonist)









Congener of pethidine, Rapidly enters brain
Short duration of action: 30-40 min
During anesthesia as analgesic - IV
Post-operative pain - IV
Along with droperidol (neuroleptanalgesia)-IV
Cancer pains – as patch
Chronic pains – as patch
IV: 1-2 mcg/kg
Transdermal patch – 25-50 mcg per hour –
this acts for 2-3 days

29. Methadone (agonist) (long duration)

T1/2 – 24-36 hours, Slow persistent action
Less abuse potential
 Withdrawal gradual, prolonged, less
severe
 1 mg methadone = 4 mg morphine = 2 mg
heroin = 20 mg Pethidine
 Is also Analgesic
 2.5 – 10 mg oral or im


Used as substitute to treat morphine
addiction

30. Mixed agonist-antagonists








Commonly used: Pentazocine
Mu antagonist, K agonist: So, Good analgesic
Oral (50-100 mg),IV IM (30-60 mg) Short duration of action
Post-operative pain
Pain due to burn, trauma, fracture, cancer
Analgesia during anesthesia and other
procedures
Increases heart rate, BP, Remember: Do not use in MI
Remember: such a drug can precipitate
withdrawal in a morphine addict due to Mu
antagonistic effect

31. Diphenoxylate (Lomotil)
 therapeutic
use is as antidiarrheal
drug (treats diarrhea)
 meperidine type drug
 has very little analgesic properties at
therapeutic dose
 no antitussive effect
 at high doses- analgesic problems
 causes respiratory depression and
euphoria at high doses

32. Codeine
 change in the methyl group on 3 position
 one tenth the potency of morphine
 the absorption is more regular than morphine and
more predictable
 metabolized like morphine through glucuronic
acid
 tolerance and physical dependence is protracted
from morphine since potency of codeine is low
 withdrawal from codeine is mild in relation to
morphine
 antitussive drug for cough

33. Structural Activity Relationship
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO
3
11
4
12
O
13
5
HO
CH3O
1
10
15
O
9
14
H
8
6
16
H
N
H
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
N
CH3
HO
Codeine (5X LESS potent than morphine)

34. PURE ANTAGONIST

35. Pure antagonists

Naloxone – for acute morphine
poisoning – 0.4 mg IV q 2-3 min
Naltrexone – tablet 50 mg qd - is of more
benefit to decrease the sensation of
craving during treatment of addiction –
opiates, alcohol, and other drugs of
abuse
 Nalmefene


36. Naloxone







no analgesic activity at all
competitive antagonist at mu, kappa, and
sigma receptor
displaces morphine and other OPIOID from
receptor site
reverses all actions of the OPIOID and does
it rather quickly
it will precipitate withdrawal
increases blood pressure
metabolized same as morphine through
glucuronic acid conjugation and excreted
through kidney

37. Naltrexone








same effect of naloxone except -used orally so
can't be used for person with acute toxicity
long duration of activity
single dose block action of heroin-24 hours
used for emergency treatment
once stabilized, give patient naltrexone
After giving naltrexone patient- no euphoric
effect from heroin so person gets off heroin
(negative reinforcement)
approved for use by the FDA
also used for treatment of alcoholism

38. Pharmacokinetics of opoids
Absorption
 from GI tract, nasal mucosa, lung.

Also through subcutaneous, intramuscular, and
intravenous route
Distribution


Bound/free morphine accumulates- kidney,
lung, liver, and spleen
CNS is primary site of action
(analgesia/sedation)

39. Metabolism/Excretion







metabolic transformation -liver
conjugates with glucuronic acid
excreted by kidney - glomerular filteration
half life -2.5 to 3 hours
morphine 3 glucuronide - main excretion
product
90% is excreted in first day.
duration of 10 mg dose- 3 to 5 hours

40. Drug interactions with
Opioids
 in
general, the
coadministration of CNS
depressants with OPIOID
often produces at least an
additive depression
(potentiation)

41. OPIOID and phenothiazines
produces an additive CNS depression as
well as enhancement of the actions of
OPIOID (respiratory depression)
 this combination - orthostatic hypotension

OPIOID and tricyclic
antidepressants
produce increased hypotension
 meperidine and MAO inhibitors - severe
and immediate reactions that include
excitation, rigidity, hypertension, and
severe respiratory depression


42. OPIOID and barbiturates
 increased clearance
morphine and amphetamine
 enhanced analgesic effect