Mechanism of action, Classification of opioids Morphine, Tramadol, Heroin, Fentanyl... Actions indications side effects contraindication

1. Opioid or Narcotic
Analgesics
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. 1. Classify opioid drugs
2. Identify the molecular mechanism of action of opioids
3. Recognize the pharmacological actions of opioids.
4. Predict the most serious adverse effects and drug interactions
of opioids.
5. Explain the impact of tramadol's dual mechanism of action.
6. Apply the pharmacological basis for proper selection of the
drugs used in the management of intoxication and withdrawal
symptoms of Opioids abuse.

3. Analgesics
• Drugs that relieve pain
due to multiple causes

4. Analgesics
• Paracetamol
• NSAIDs
Non Opioids Opioids
• Morphine
•Synthetic opioids

5. “Invasive & minimally invasive techniques 2020”
WHO analgesic Ladder (2020)
Persistent
pain
(Mild pain)

6. Opioid Analgesics
Used in moderate to sever pain

7. OPIUM POPPEY

8. OPIUM POPPEY
OPIUM
MORPHINE
‫االفيون‬

9. Why Opioid?
• Opium is the dried juice from the unripe seed
capsules of the opium poppy (the plant of joy).
• Morphine (10%) and codeine were isolated from
opium.
Opioids: The class of drugs that includes opiates, opiopeptins, and all synthetic
and semisynthetic drugs that mimic the actions of the opiates
Opiate: drug derived from alkaloids of the opium poppy

10. Why Narcotic?
• Narcotic refers to a drug that induces drowsiness or
stupor (marked impairment but no loss of
consciousness) with analgesia.

11. Sources of opioids
1. Plant: Morphine - Codeine
2. Synthetic: Fentanyl, methadone, tramadol …
3. Semisynthetic: Heroin, Oxycodone
3. Endogenous: (opiopeptins)
endorphins - enkephalins - dynorphins

12. Classification of Opioids
I. Opioid Analgesics
II. Opioid Antitussives
(Less addictive than morphine)
➢ Codeine
➢ Dextromethorphan (See Respiration)
III. Opioid Antidiarrheals
(Less addictive than morphine)
➢ Loperamide
➢ Diphenoxylate (See GIT)

13. Heroin
Classification of Opioid analgesics

14. Partial Agonists:
-Buprenorphine ,
-Pentazocine
-Nalbuphine
Antagonists:
Naloxone,
Naltrexone

15. Opioid receptors
Mu - Delta - Kappa Receptors

16. Mu - Delta - Kappa Receptors
Supraspinal> spinal
Spinal> supraspinal
Spinal> supraspinal

17. Gi-protein coupled receptors
 Ca2+ influx (presynaptic) OR
 K+ efflux (postsynaptic)
Opioid receptors
Hyperpolarization

18. Mechanism of Action
Opioid receptors, Gi protein-R in the CNS & periphery
Opioids (directly or ↑opiopeptides) activate receptors in:
➢ Brain stem, thalamus & cerebral cortex  supraspinal
analgesia.
➢ Spinal cord  spinal analgesia.
➢ Afferent pain-conducting fibers  peripheral analgesia.
➢ Limbic system  euphoria via ↑ DA in the nucleus
accumbens, the center of pleasure & also  emotional
response to pain (feel the pain but the feeling is not unpleasant).

19. Peripheral
analgesia
Spinal
analgesia
Supraspinal
analgesia

21. Classification of Opioid Analgesics
(According to efficacy)
1. Strong
A. Pure Agonists
➢ Morphine
➢ Fentanyl
➢ Pethidine
➢ Heroin
➢ Methadone
B. Partial agonists
Buprenorphine
2. Moderate
Codeine & oxycodone
(Oral)
-Analgesic plus
paracetamol or aspirin
in moderate pain.
-Antitussive.
3. Weak
Propoxyphene
(Oral)
- Analgesic plus
paracetamol or aspirin in
mild to moderate pain.

22. Actions, Uses, Adverse
Effects & Contraindications
(CI) of Morphine

23. Uses Actions Adverse Effects &
CI
1. Analgesic e.g.
• Acute trauma.
• Postoperative
• Cancer pain
2. In Anesthesia
• Pre-anaesthesia
• CVS surgery
I. Main Effects
A. Analgesia
B. Sedation
C. Euphoria
• Masks pain
CI: acute
undiagnosed
abdomen
• Sedation –
Narcosis
• Drug
dependence

24. Reward Pathway: Brain Areas
• The classic anatomical areas of the brain involved in the reward
(pleasure) pathway include: Nucleus accumbens, Ventral tegmental
area and Prefrontal cortex
Pleasure center
(NAc)
Opioids → ↑ Dopamine in NAc → Euphoria

25. Uses Actions Adverse Effects &
CI
3. Anti-tussive
Codeine &
Dextrometho.
(less addictive)
4. Acute Pulmon
edema in LVF
following MI
(↓preload, afterload,
Resp. distress, Anxiety)
II. Inhibitory
Effects
A.  Cough center
B.  Uterine tone
 delayed labor
C. Respiratory center
→ CO2 → Cerebral VD &
↑ (ICT)
D.  VMC → venular
& arterial VD
E. Thermoregulatory
Center
•Delayed labor
•Respiratory
depression
& asphyxia
neonatorum
• ICT
CI: head injury
•Hypotension
•Hypothermia

26. Uses Actions Adverse Effects & CI
4. Antidiarrheal
•Diphenoxylate
(less addictive)
III. Stimulatory
Effects
A.  Oculomotor nucleus
 miosis
B.  CTZ  vomiting
C. Urinary & GIT
 Tone wall & sphin.
(spasmogenic)
but  peristalsis
D. Histamine release
• Miosis
• Nausea - vomiting
• Urine Retention
CI: enlarged prostate
• Constipation
CI: Biliary colic
• ↓BP– itching –
bronchospasm
CI: Asthma
• Hypotension
Tolerance develops to all effects except constipation & miosis

27. Q: 4 types of sever pain in Which Morphine is
Contraindicated?
head
injury
Labor
undiagnosed abdomen

28. Other CI: (opioid metabolism)
Extremes of age –
Hypothyroidism –
Liver dysfunction
Other side effects:
seizures in  doses

29. 1. Morphine (see table).
Given IV - IM - SC - epidurally
- orally (extensive 1st pass metabolism) & bioavailability 20-40%.
- Duration: 4-6 hr

30. 2. Pethidine (Meperidine)
[IM - Oral]
It is less potent but equal efficacy than Morphine
Used in ACUTE moderate & severe pain
e.g. postoperative pain, Biliary or labor pain (??!!)
Meperidine differs from morphine in:
1. Less constipation (Shorter “2-3hr”), Less spasmodic action
2. Less respiratory depressant in neonates & does not delay labor
 preferred during labor (??!!)
3. Atropine-like action: dry mouth, blurred vision, ….....
4.  Risk of convulsions (esp. in high dose or RF) accumulation of toxic
normeperidine. So, Never use > 48 hrs.

31. Can be antagonized by naloxone
Mu receptor

32. 3. Fentanyl
•100-fold potency > morphine
•High lipophilicity, rapid onset (1-5 min.) and short duration (0.5-2 hr).
•Epidural fentanyl is used to induce anesthesia and
analgesia postoperatively & during labor
•Transmucosal & Transdermal patch
are used for cancer patients pain.

33. Fentanyl
High dose→ chest wall rigidity↓ thoracic compliance   ventilation.
Uses (IV, epidural, spinal, T patch)
1. Analgesic in severe pain
e.g. perioperative, labor & cancer pain.
2. In Anesthesia: as preanesthetic medication and
anesthetic in CVS surgery (safer).
3. Conscious sedation - neuroleptanalgesia –
neuroleptanesthesia

34. Conscious Sedation & Neuroleptanalgesia
(Amnesia, sedation & analgesia without complete loss of consciousness)
Uses: minor procedures or diagnostic (e.g. endoscopy).
Conscious Sedation
•IV BZD (e.g .Midazolam) - opioid analgesic (e.g. Fentanyl).
•Easily reversed by flumazenil & naloxone (advantage).
Neuroleptanalgesia
•Neuroleptic (e.g. droperidol) plus opioid (e.g. fentanyl).
•Converted to neuroleptanesthesia by add 65% N2O in O2.

35. Fentanyl subgroup or congeners
✓ Sufentanil is more potent than fentanyl.
✓ Remifentanil (IV infusion): Ultrashort acting
as it is metabolized by blood & tissue esterases
→less ventilatory depression.

37. What is Heroin?
• Heroin is Diacetylmorphine converted to morphine in CNS.
• Rapid onset (greater lipid solubility  crosses BBB more than morphine) &
short duration   risk of abuse (not used clinically in most countries).
Morphine Heroin

38. Opium
‫أألفيون‬
Morphine
2
acetyl
groups
Heroin
Once in the brain, heroin is converted into morphine
>3

39. “black tar” or Hero
Heroin comes from China, Mexico, Iran, Pakistan
and Afghanistan.

40. Injecting:
IV or IM Heroin doesn't dissolve easily, so
users have to dissolve it in a spoon with
water before they can inject it.
Smoking:
heating up the powder on some foil, and then
inhaling the fumes through a small tube.
How do people use Heroin?
Snorting:
sniff the powder up nose, like cocaine, using
$20

41. 4. Methadone
Long duration (24-36 hr)
Uses
2. Analgesic (efficacy equal to morphine).
1. Opioid addicts (detoxification):
Long action → its withdrawal is less severe & smoother

42. Adverse effects of Methadone:
As Morphine
+ (QT interval prolongation) →Torsades de pointes
Normal ECG
Torsades de pointes

43. Tramadol

44. 5. Tramadol
(mixed opioid/nonopioid)
➢ Analgesic acting by inhibiting reuptake of 5- HT & NA.
➢ Weak Mu agonist (partially antagonized by naloxone).
• Less constipation, respiratory depression & addiction than morphine.
• ↑ Risk of convulsions.
Uses (oral, IM, IV)
1. Analgesic (postoperative & chronic pain)
2. Neuropathic pain .

45. Tapentadol
Tramadol is not recommended in liver dysfunc. (prodrug) & in renal dysfunction to avoid accum. Of its
active metabolites (lead to toxicity). While tapentadol is safe in renal dysfunction (no active metabolites)
FDA approved in 2008

46. Buprenorphine
(partial agonist)
Advantages over Pure Agonists (ceiling)
1. Less addiction (less euphoria  less craving).
2. Less respiratory depression
Uses (parenteral, sublingual)
1. Analgesic in severe pain.
2. Opioid addicts (detoxification as Methadone)
Long acting (24hr) & smooth withdrawal ………

47. Heroin Buprenorphine
Blocks euphoric effects (positive
reinforcement)
Very high affinity for opioid
receptors

48. Drug Interactions of Opioids
1. Opioids + CNS depressants (sedatives, alcohol,
antidepress. & antipsychotics)  add CNS depress.
2. Pethidine or tramadol + MAOIs  serotonin syndrome
3. Partial agonist + pure agonist  withdrawal
syndrome &  analgesic effect.

50. Acute Morphine
Toxicity
➢Coma
➢Respiratory depression.
➢ Pin pointed pupil (diagnostic).
Treatment
Support respiration.
Naloxone (IV): opioid antagonist (repeated)

51. Naloxone
• Initial IV naloxone (0.4mg vial) If is no response → 0.8 mg.
• Signs of improvement:
increase in respiratory rate and pupillary dilation

52. In April 2014, FDA approved naloxone pen (Evzio)
Auto-injector (it needs training& has single dose

53. In 2015, FDA approved Narcan nasal spray (easy,
safe, no contaminated needles and has Multi-dosing)

54. Pure Opioid Antagonists
Naloxone
IV & short-acting
Management of acute toxicity
1. Acute opioid toxicity
Repeated since duration of
action is shorter than opioids.
2. Asphyxia neonatorum
Respiratory stimulant in
opioid- induced respiratory
depression in newborns.
Naltrexone
Oral & long-acting
Maintenance therapy in addicts
1. Opioid abuse
Blocks euphoria of opioids →
loss of desire to take drug
(prevents relapse).
2. Alcohol abuse
↓ Craving in chronic
alcoholics.

55. once a month

56. Dependence and Addiction to Morphine or heroin
• Physical dependence
Leading to withdrawal symptoms exaggerated rebound: rhinorrhea,
lacrimation, yawning, hyperventilation, hyperthermia, mydriasis,
muscular aches, vomiting, diarrhea, sympathetic over activity
(hypertension, tachycardia) anxiety, hostility, …………………..
• Psychologic Dependence → compulsive use (Addiction).

57. Sympathetic over activity

58. Treatment of Addiction
1. Symptomatic treatment e.g. NSAIDs for pain, Antiemetic …….
2. Sympatholytic: e.g. Clonidine
3. Detoxification:
Use long acting opioid drugs as Methadone or Buprenorphine
to replace heroin or morphine and then gradual withdrawal
(less severity of withdrawal symptoms).
4.Maintenance
Use opioid receptor blocker, Naltrexone to Block euphoria of
opioids → prevents relapse