Useful for MBBS theory classes

1. OPIOIDS
Dr. Sumitha.A MBBS.,MD
PHARMACOLOGY

2. POPPY PLANT

3. DEFINITIONS
• Opium : a mixture of alkaloids from the poppy
plant - papaver somniferum
• Opioid : any naturally occurring, semi-synthetic or
synthetic compounds that bind specifically
to opioid receptors and share the
properties of one or more of the naturally
occurring endogenous opioids

4. • Endorphins:
Derived from POMC.
• β endorpin -primarily μ agonist and also has δ action.
• Enkephalins:
Derived from Proenkephalin
Met-ENK and leu-ENK
Met-ENK - Primarily μ and δ agonist and leu-ENK –
δ agonist.
 Dynorphin:
Derived from pro-dynorphin –Dyn-A and Dyn –B.
Potent κ agonist and also have μ and δ action
ENDOGENOUS OPIOID PEPTIDE

5. • Novel opioid peptide Nociceptin/orphanin FQ isolated from
mammalian brain.
• N/OFQ –play a role in stress response,reward and reinforcing
actions,learning and memory.
• N/OFQ receptor – now called nociceptin opioid peptide
receptor.

6. OPIOID RECEPTOR
• Mainly 3 (three) types of receptors – μ (mu), κ (kappa) and δ
• Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2
• Location: Peripheral Nerve endings, SG in spinal cord,
• Periaqueductal gray (PAG) in midbrain and Brain stem.

7. • μ receptor-high affinity for Morphine.
Endogenous ligand for μ receptor are peptides called
endomorphins1 and 2.
K receptor-high affinity for dynorphin.
δ receptor – high affinity for leu/met enkephalins.
Limbic areas rich in δ receptors –role in affective component of
supraspinal analgesia,reinforcing actions and analgesia.
Naltrindole-selective δ antagonist.

8. OPIOID RECEPTORS

9. Mechanism of action

10. Mechanism of action
• Opioid receptors are coupled with inhibitory G-proteins &
their activation has a number of actions:
•
- closing of voltage sensitive calcium channels,
- stimulation of potassium efflux leading to hyperpolarization
& reduced cyclic adenosine monophosphate (cAMP)
production.
• Effect : reduction in neuronal cell excitability - reduced
transmission of nociceptive impulses.

12. MORPHINE ACTIONS
CNS:
• Analgesia:Dull,visceral pain relieved better.
Mechanism: acts in substantia gelatinosa of dorsal horn –inhibit
release of excitatory transmitters(glutamate,substance P) from
primary afferent carrying pain impulses.
• Sedation
• Subjective effects and Euphoria

13. • Respiratory Cough Hypothalamic vasomotor
centre centre thermostatic centre
Resp.rate depressed depressed fall in BP
Decreased Hypothermia
DEPRESSANT ACTIONS

14. • STIMULANT CENTRAL ACTIONS:
CTZ Edinger-westphal vagal centre cortical areas
nucleus
Vomiting Miosis Bradycardia
• CVS: vasodilatation
Histamine release
Depression of vasomotor center
direct action decreasing tone of blood vessels.

15. • Morphine –spasm of sphincter of oddi-biliary colic
:increased intrabiliary pressure.
• Tone of bladder sphincter is increased –urinary
urgency.
• Bronchoconstriction-releasing histamine(due to its
bulky basic molecule)

16. • GIT:
• Enteric plexus neuron and g.i.mucosa rich in opioid receptors.
• Constipation -how
• Morphine tone and segmentation .,decreases propulsive
movements.
• Spasm of pyloric,ileocaecal and anal sphincter.
• Decrease in all gastrointestinal secretions-peripheral action
through opioid receptors.
• Neuro-endocrine actions:
Hypothalamic activation by afferent collaterals is dampened.
FSH,LH,ACTH levels are lowered.Prolactin and GH levels are
raised.

17. Pharmacokinetics
• Oral absorption unreliable.
• Freely crosses Placenta.Metabolised in liver.
• Morphine 6-glucoronide-analgesia.
• Morphine 3 –glucoronide-neuroexcitatory effects.
• 10-15 mg oral.,im.s.c.
• 2-3 mg intrathecal.,i.v.

18. USES OF MORPHINE
• Analgesic
• Pre anaesthetic medication
• Relief of anxiety and apprehension
• Acute left ventricular failure
• Balanced anaesthesia and surgical analgesia-
Fentanyl,Morphine,Remifentanil used

19. Adverse effects of Morphine
• Idiosynracy and allergy.
• Sedation,vomiting,constipation,mental
clouding.Respiratory depression,urinary
retention,blurring of vision.
• Apnoea of newborn:
BBB of foetus is undeveloped.Higher conc in foetal
brain.
Naloxone-10 μg/kg injected in umbilical cord.

20. • Acute Morphine poisoning:
Lethal dose:250 mg
Flaccidity,shallow breathing,cyanosis,pinpoint pupil,fall in B.P.
shock,convulsions,coma.
Treatment: Respiratory support,maintenance of B.P.,Naloxone 0.4-
0.8 mg i.v. repeated every 2-3 min till respiration picks up.
Tolerance and dependance:
WITHDRAWAL symptoms
Pneumonic -WITHDRAWAL
Insomnia,tremor,hypertension,Diarrhoea,dehydration,Rhinorrhoea,
anxiety,abdominal colic,mydriasis,aggression,lacrimation

21. CONTRAINDICATIONS
• 1. Infants and the elderly : more susceptible
to the respiratory depressant action of morphine.
• 2. It is dangerous in patients with respiratoryinsufficiency
(emphysema,
cor pulmonale)
3. Bronchial asthma: Morphine can precipitate
an attack
• 4.Hypotensive states and hypovolaemia exaggerate
fall in BP due to morphine.by its histamine releasing action.

22. • Elderly male: chances of urinary retention
are high.
Hypothyroidism, liver and kidney disease
patients are more sensitive to morphine.
• Head injury:
By retaining CO2, it increases intracranial
tension which will add to that caused by head
injury itself.
• Undiagnosed acute abdominal pain: morphine
aggravate conditions like diverticulitis,
biliary colic, pancreatitis.

23. PETHIDINE
• 1/10th as potent as Morphine, but Efficacy is similar.
• Less spasmodic action in smooth muscles – less miosis,
• constipation and urinary retention.
• Rapid but short duration of action (2-3 Hrs)
• Vagolytic effect – Tachycardia
• Devoid of antitussive action
• Less histamine release – safer in asthmatics

24. Pharmacokinetics
• Oral absorption unreliable,bioavailability 50%
• Effects appear in 10-15 min. after oral
• Absorption.
• Metabolized in liver – hydrolysed to meperidinic
acid
• Small fraction demethylated to Norpethidine.
• Norpethidine has excitant effects.
• Dose: 50 mg tab.,50 mg/ml inj.

25. • Adverse effects:
• Pethidine synthesised as atropine substitute.
• Atropine like effects – dry mouth, blurred vision,
tachycardia.
• Overdose – tremors, mydriasis, delirium and
convulsion,hyperreflexia due
to norpethidine accumulation.
Nonselective MAO inhibitors interfere with hydrolysis but not with
demethylation of pethidine :norpethidine produced in excess –excitement
occurs.
Pethidine in SSRI receiving patients produce “SEROTONIN SYNDROME”
by enhancing 5-HT release.

26.  Fentanyl:
more potent than morphine-analgesia and respiratory depression.
High lipid solubility.
Transdermal fentanyl- for pain relief.(Durogesic)
Used in anaesthesia-as injection.
 Remifentanil: Faster acting congener.(10-15 min)
Duration of action after i.v.injection.
 Tramadol:Inhibits reuptake of NA and 5HT release,activates
monoaminonergic spinal inhibition of pain

27. • Tramadol: oral bioavailability-good 75 mg tab
• Serotonin syndrome –with SSRI therapy
 Tapentadol:Similar to tramadol in mechanism.
It can also trigger SSRI syndrome.
50 mg tab
 Methadone:Pharmacologically similar to Morphine.
Substitution therapy for opioid dependance.
1 mg methadone-substituted for 4 mg morphine,2 mg heroine.
Methadone maintenance for opioid addicts.40-80 mg/day orally
over long term-high degree of tolerance – pleasurable effects
of heroin not perceived.

28.  Pure antagonists: Naloxone, Naltrexone and Nalmefene
 Mixed Agonist-antagonists: Nalorphine, Pentazocine,
Butorphanol and Nalbuphine
Pentazocine- μ antagonist, κ agonist
 Partial/weak μ agonist and κ antagonist:
Buprenorphine

29. Pentazocine
• μ antagonist . κ agonist actions.
• κ – spinal analgesia.
• Tachycardia,rise in B.P. – sympathetic stimulation.Better
avoided in coronary ischaemia and MI
• Biliary spasm and constipation –less marked.
• Vomiting less frequent
• Tolerance ,dependance – on repeated use.

30. • Oral dose:50-100 mg
• FORTWIN- 25 mg tab,30 mg/ml inj
• Use: used for postoperative severe pain in
burns,trauma,fracture.
• Side effects:dysphoric/psychotomimetic effects.
 Buprenorphine: μ analgesic.25 times more potent than
morphine.Sedation,miosis,vomiting,cardiovascular effects
similar to morphine.
 Good effect by sublingual route-0.2 mg.
 Use:long lasting painful conditions,premedication,treatment of
morphine dependance as alternative to methadone.

31. OPIOID ANTAGONIST
Naloxone:
Competitive antagonist on all opioid receptors.
0.4-0.8 mg i.v. Antagonises all actions of morphine.
Uses:DOC for morphine poisoning.
Reversing neonatal asphyxia due to opioid use during labour.
Diagnosis of opioid dependance.
Naltrexone: orally active .long duration of action.
Reduce alcohol craving.50 mg/day used in opioid blockade therapy
of post addicts.Hepatotoxicity –with high dose.
Nalmefene:long acting.lack hepatotoxicity.

32. THANK YOU