Pharmacology of Opioids

1. Opioids
Sanjeev Kumar

2. Introduction
 Drugs which relieve pain by acting on CNS or
peripheral pain mechanism without loss of
consciousness are called analgesics or pain
killers.
 Pain is defined as an unpleasant sensation that
can be either acute or chronic and that is a
consequence of complex neurochemical
processes in the peripheral and central nervous
system (CNS).

3. Introduction
 It is subjective phenomenon and reaction to pain
varies with the situation, individual person
 Pain arising from skin and deep structure like
muscle, bones and joints is termed as somatic
pain
 Pain arising from organ like kidney, heart,
pancreas is called visceral pain.
 According to severety of pain, it can be
 Mild,
 moderate or
 severe pain

4. Introduction
Analgesics can be divided into two groups
(according to their ability to relieve pain):
1. Opioids or narcotic analgesics
2. Non-narcotic or antipyretic- anti-inflammatory
analgesics
Opioid Analgesics:
Any natural, semi-synthetic or synthetic or synthetic
drug that has morphine like Pharmacological
actions is called opioids.
Opiates: products obtained from opium.
Narcotic analgesics: in addition to analgesic effects
they have hypnotic and sedative actions.

5. Opioid Peptides
 Endogeneous opioid system
 Active in small amounts
 Actions blocked by naloxone (Antagonist)
 Bind in high affinity to opioid receptors.
 Normally modulate
 pain perception,
 mood, hedonic (pleasure related) and
 motor behavior,
 emesis,
 pituitary hormone release and
 g.i.t. motility.

6. Opioid Peptides (Contd.)
 Brainstem: Opioid receptors influence respiration,
cough, nausea and vomiting, blood pressure,
pupillary diameter, and control of stomach
secretions.
 Medial thalamus: This area mediates deep pain
that is poorly localized and emotionally influenced.
 Spinal cord: Receptors in the substantia
gelatinosa are involved with the receipt and
integration of incoming sensory information,
leading to the attenuation of painful afferent
stimuli.
 Hypothalamus: Receptors here affect
neuroendocrine secretion.

7. Opioid Peptides
 Limbic system: The greatest concentration of
opiate receptors in the limbic system is located in
the amygdala. These receptors probably do not
exert analgesic action, but they may influence
emotional behavior.
 Periphery: Opioids also bind to peripheral
sensory nerve fibers and their terminals. As in the
CNS, they inhibit Ca2+ - dependent release of
excitatory, proinflammatory substances (for
example, substance P) from these nerve endings.
 Immune cells: Opioid-binding sites have also
been found on immune cells. The role of these
receptors in nociception (response or sensitivity to
painful stimuli) has not been determined.

8. Opioid Peptides
 3 distinct families:
 Each derived from specific precursor polypeptide
 Endorphins:
 Derived from pro-opiomelanocortin (POMC).
 β-Endorphin (most imp)
 Enkaphalins:
 Derived form pro-enkaphalin
 Most imp are
1. Methionine – enkaphalin (met-ENK) [equal affinity for µ &
δ]
2. leucine – enkaphalin (leu-ENK) [prefers δ]

9. Opioid Peptides
 Dynorphins
 Derived from pro-dynorphin
 Most imp are
 Dynorphin A (DYN – A)
 Dynorphin B (DYN – B)

10. Opioid Receptors:
 3 types - µ, κ, δ
 Specific pharmacological profile
 Specific pattern of anatomical distribution in brain, spinal
cord, and peripheral tissues.
 Morphine and other opioids act through specific receptors
µ (mu) κ (Kappa) δ (delta)
Analgesia (supraspinal
+ spinal),
Respiratory depression
Euphoria,
Sedation,
Physical dependence,
Reduced g.i.t. motility
Analgesia (spinal,
supraspinal),
Respiratory depression
Dysphoria,
Sedation,
Physical dependence
---
Analgesia (spinal and
affective component of
supraspinal),
Respiratory depression
Emotional behaviour
---
---
Reduced g.i.t. motility

11. Mechanism of Action
Activation of the opioid
receptor increases K+
efflux and decreases the
responses of the
postsynaptic neuron to
excitatory neuro-
transmitters
Activation of the Opioid
receptor decreases Ca2+
influx in response to
incoming action potential.
This decreases release of
excitatory neuro-
transmitters, such as
glutamate

12. Classification:
1. Natural Opium Alkaloids
i. Phenanthrene
derivatives:
Morphine (10%)
Codeine (0.5%)
Thebaine (0.2%)
ii. Benzisoquinoline
Derivatives:
Papaverine (1%)
Noscapine (6%)
2. Semisynthetic opiates: Heroin (diacetylmorphine)
Pholcodeine
Hydromorphone
Oxymorphone

13. Classification:
3. Synthetic Opioids: Pethidine
Methadone
Dextropropoxyphene
Tramadol
ethoheptazine

14. Natural Alkaloids (Morphine)
 Pharmacological Actions:
1. CNS:
 Interacts with μ receptors.
 Analgesia: Patient
tolerates pains better.
Degree of analgesia
increases with dose.
 Sedation: different from
hypnotics and alcohols (
no motor in-coordination
or no apparent
excitement like alcohol)
No anticonvulsant effect
rather may precipitate fits.
Depresses

15. Natural Alkaloids (Morphine)
 Pharmacological Actions:
1. CNS:
 Mood & Subjective Effects,
Calming effects, loss of
apprehension, Limbs feel
heavy, body warm.
 Rapid i.v. injection gives a
kick in addicts.
 Respiratory centre: Depressed
in dose dependent manner.
 Death in poisoning cases is
due to respiratory failure.
 Cough centre: Depressed
Depresses

16. Natural Alkaloids (Morphine)
 Pharmacological Actions:
1. CNS:
 Temp. Regulatory centre: depressed 
hypothermia in cold surroundings.
 Vasomotor centre: depressed  Fall in B.P.
 CTZ: stimulated Nausea & vomitting
 Vagal Centre: stimulated Produces Bradycardia
 Edinger Wistphal Nucleus of III nerve: stimulated 
miosis (Central Action.) NOT ion topical appln.
 Certain cortical areas & hippocampal cells:
stimulated  Excitement in occassional individuals.
Convulsions in morphine poisoning.
Stimulates
Depresses

17. Natural Alkaloids (Morphine)
 Pharmacological Actions:
2. Neuro-endocrine:
↓es hypothalmic influence on pituitary  ↓ed
levels of FSH, LH, ACTH while prolactin and GH
levels are ↑ed.
 Chronic abusers suffer from infertility.
3. CVS: Vasodilation due to
 Histamine release
 Depression of vasomotor centre.
 Directly ↓ed tone of Blood vessels.
Intra cranial tension tends to rise due to CO2 retention
leading to cerebral vasodilation.

18. Natural Alkaloids (Morphine)
 Pharmacological Actions:
4. G.I.T.: Constipation
5. Smooth muscles:
a) Biliary tract:
Spasm of sphincter of oddi  ↑ed
intrabiliary pressure  biliary colic
b) Bronchi:
Release histamine  bronchoconstriction.
c) Urinary bladder:
tone of detrusor & sphincter ↑ed  urinary urgency
& difficulty in micturation.

19. Natural Alkaloids (Morphine)
 Pharmacokinetics:
 Oral absorption unreliable
 Variable first pass metabolism
 Widely distributed
 Slowly enter brain
 Freely crosses placenta and affects foetus.
 Plasma t½ = 2-3 hrs

20. Natural Alkaloids (Morphine)
 Therapeutic Uses:
Relief of Pain: limited use (due to tolerance and
dependence)
Acute myocardial infarction, fracture of bones, burns,
postoperative pain, visceral pain, pain of terminal
stage of malignancy, and pulmonary embolism.
In combination of atropine also used in renal and
biliary colic.
Cough: Severe case→ Morphine
Mild dry cough → Codeine or Noscapine
Dyspnoea: very useful in dyspnoea of pulmonary edema
due to acute left ventricular failure and CVS shock

21. Natural Alkaloids (Morphine)
 Therapeutic Uses:
Preanaesthetic Medication: for analgesia, preoperative
sedation and to reduce anxiety.
Diahrrhea: Opiades like diphenoxylate and loperamide
Neurolept Analgesia: Fentanyl + droperidol as iv
anaesthesia and neurolept analgesia. Suitable for
endoscopic procedures, burn dressings, and other
minor surgical procedures.
Acute Left Ventricular Failure( Cardiac Asthma):
but contraindicated in bronchial asthma

22. Natural Alkaloids (Morphine)
 Adverse Effects: 1. Side Effects
(i) Lethargy, confusion and anxiety (ii) constipation (iii) nausea
and vomiting (iv) urinary retention especially in old people (v)
postural hypotension (vi) histamine release  itching &
urticaria (vii) respiration depression

23. Natural Alkaloids (Morphine)
 Adverse Effects: 2. Tolerance and Addiction
 Tolerance develops to most effects but NOT to
Constipation and Miotic Effects.
 Tolerance may
 P’kinetic (enhanced rate of metabolism)
 P’dynamic (cellular tolerance)
 Cross tolerance is high
 Produce psychological + physical dependence
 Abuse liability is high (due to orgasm + sense of
orgasm)

24. Natural Alkaloids (Morphine)
 Adverse Effects: 2. Tolerance and Addiction
Withdrawal effects:
 Lacrimation, sweating, yawning, insomnia, mydriasis,
diarrhea, dehydration.
Treatment:
Withdrawal of Morphine and then replacement with
Methodone → withdraw gradually.

26. Natural Alkaloids (Morphine)
 Adverse Effects: 3. Acute Poisoning
May be accidental or attempt to suicide.
60 mg → serious toxicity
250 mg → lethal
Symptoms:
 Slow and depressed respiration, cyanosis, pin point
pupil, hypotension, reduced body temperature, shock
and coma
 Pin point pupil, depressed respiration and coma strongly
suggest opioid poisoning.
 Death usually due to respiratory failure, shock and
pulmonary oedema.

27. Natural Alkaloids (Morphine)
 Adverse Effects: 3. Acute Poisoning
Treatment:
 Respiration assistance
 Gastric lavage (with KMnO4 )[even when injected]
 Antidote: Naloxone (0.4 – 0.8 mg iv repeatedly every 2-
3 minutes till respiration picks up. Repeated again every
1-4 hrs later on.

28. Other morphine derivatives
CODEINE Methyl morphine
Occurs naturally in opium
Similar but less potent actions (than
morphine)
More selective cough suppressant
Active orally
Abuse liability low (than morphine)
USE:
Antitussive
Moderate pain

29. Other morphine derivatives
NOSCAPINE NO analgesic action (like morphine)
USE
Cough suppressant
THEBAINE NO therapeutic use
PAPAVERINE Smooth muscle relaxant (used in
experiments)
HEROIN
(Also known as
brown sugar)
Diacetyl morphine
2-3 times more potent than morphine
Orally effective
NO CLINICAL USE (Potentially
addictive)
PHOLOCODEINE Antitussive
APOMORPHINE CTZ stimulant (Potent EMETIC)

30. Other morphine derivatives
PETHIDINE
(compared with
Morphine)
Syntheitic drug
less potent analgesic
Short duration of action.
Less constipating
NOT antitussive
Less spasmogenic
Does not produce miosis
Safe in asthamatics (does not release
histamine)
ADME:
Absorbed orally, completely
metabolised in liver and metabolite
excreted in urine
USE: Analgesic
For biliary colic
Obstetric analgesia
Preanaesthetic medication

31. Other morphine derivatives
METHADONE
(compared with
Morphine)
Synthetic drug
Produces analgesia, respiratory
depression, miosis, antitussive effect
and hypothermia, increases muscle tone,
produce constipation, and biliary tract
spasm.
ADVANTAGE:
Effective orally, longer duration of
action, NO orgasm like effect,
USE:
oral Analgesic
For de-addiction of Morphine and
Heroin

32. Other morphine derivatives
DIPHENOXYLATE Derivative of pethidine
NO analgesic effect.
USE:
CONSTIPATING effect. Used in
Diarrhea.
LOPERAMIDE Reduces G.I.T. motility
Used in diarrhea.
FENTANYL 80-100 times more potent analgesic and
respiratory depression
Short acting
Used in combination with dorperidol as
an anaesthetic.

33. Other morphine derivatives
DEXTRO-
PROPOXYPHENE
(Dose 32-65 mg)
One-fifth – one tenth as potent as
codeine
Orally effective
Less abuse liability
USE:
analgesic for mild to moderate pain

34. Narcotic Antagonists
Pure Antagonists Naloxone
Naltrexone
Partial agonist or
agonist-antagonist
Nalorphine
Levellorphan
Cyclazocine
Pentazocine
Butorphanol
Nalbuphine
Buprenorphine

35. Pure Narcotic Antagonists
Naloxone Drug of choice for narcotic induced
respiratory depression
Pure antagonist
Competitive antagonist
Blocks μ (mu), κ (kappa), δ (delta)
receptors
NOT orally effective due to first pass
metabolism
On im/sc/iv administration immediately
prevents or inhibits the effects of
opioid drugs in 1-2 minutes.
Naltrexone Pure antagonist
Orally active and long duration.
Blocks euphoric effects of opioids.

36. Pure Narcotic Antagonists

37. Partial Antagonists or Agonist-Antagonists
Nalorphine Partial antagonist
Weak antagonist
NOT orally effective
Pentazocine Partial antagonist
Effect due to action on κ receptors.
Like opioids it produces anlagesia,
sedation, and respiratory depression.
Opioid like action on G.I.T.
Raises BP and heart rate
USE: primarily analgesic
Tramadol Useful for moderate to severe pain
Has no abuse potential
50 – 100 mg orally or parentally.

38. Thank you