Opioid analgesic

Undergraduate MBBS level theory class power point presentation

1. Opioid Analgesics
Dr. D. K. Brahma
Department of Pharmacology, NEIGRIHMS
Shillong, Meghalaya, Imdia

2. Opioid Analgesics (against
algesia) – some important
terms
•Analgesics: Are the Drugs which selectively relieves pain by
acting in the CNS or on peripheral pain mechanisms, without
significantly altering the consciousness – Opioids and
NSAIDS
•Opioids: Any drug which binds to the opioid receptors
(Pharmacologically related) in the CNS and antagonized by
Naloxone . They may be – Natural, Synthetic and semi-
synthetic
•Opiates: Drugs derived from opium – Natural or semi-
synthetic
•Narcotics: Drugs derived from opium or opium like
compounds, with potent analgesic effects associated with
significant alteration of mood and behavior, and with the
potential for dependence and tolerance following repeated
administration.

3. Types of Pain

4. Types of Pain – contd.

5. Types of Pain – contd.

6. Opioids - Opium
•A dark brown, resinous material
obtained from poppy (Papaver
somniferum) Capsules.
OPIUM
PHENANTHRENE
•Morphine 9-14%
•Codeine 0.5-2%
•Thebaine 0.2-1%
BENZYLISOQUINOLINE
•Papaverine 0.8-1%
•Noscapine 3-10%
•Narcine 0.2-0.4%

7. Poppy Plant - image

8. Poppy to Opioids

9. Opium - History
•Friedrich Wilhelm Serturner
–A German Pharmacist
–Isolated Morphine in 1803 and named it
after the Greek god of Dreams
“MORPHEUS”

10. MORPHINE (Pharmacological
actions) - CNS
•Analgesia:
•Strong analgesic
•Visceral pain is relieved better than somatic
pain
•Degree of analgesia increases with dose
•Nociceptive pain is better relieved than
Neuretic pain
•Associated reactions to pain are also relieved
– apprehension, fear and autonomic effects
•Tolerance to pain is better

11. MORPHINE – Analgesia
action
•Two components – spinal and supraspinal
•Inhibits release of excitatory transmitters
from primary afferents – at Substantia
gelatinosa of dorsal horn
•Exerted through Interneurones – gating of
pain
•At supraspinal level in cortex, meidbrain and
medulla - alter processing and interpretation
and send inhibitory impulses through
descending pthway

12. D
E

13. Morphine - The Gate
Theory

14. Pharmacological actions of
Morphine (CNS) – contd.
•Sedation:
–Drowsiness and indifference to surroundings
–Inability to concentrate and extravagant imagination –
colorful day dream
–Apparent excitement
–Larger doses produce sleep – EEG resembles normal
sleep
•Mood effects:
–In Normal persons calming effect, mental clouding,
feeling of detachment, lack of initiative etc. -
unpleasant in absence of pain
–Sometimes DYSHORIA
–But in persons with pain & addicts sense of wellbeing,
pleasurable floating feelings – kick
–EUPHORIA

15. Pharmacological actions of
Morphine (CNS) – contd.
•Depression:
1.Respiratory centre
depression – Both rate
and depth of respiration
are diminished
•Dangerous in Head
injury and asthmatics
1.Cough Centre –
Depressed
2.Temperature regulating
centre – depressed
3.Vasomotor centre – high
doses cause fall in BP
•Stimulation:
1.CTZ – sensitize CTZ
to vestibular and
other impulses
2.Edinger Westphal
Nucleus – miosis
3.Vagal centre –
Bradycardia
4.Hippocampal cells –
convulsions (inhibition
of GABA release)

16. Morphine - Effects

17. Pharmacological actions
of Morphine – contd.
•Neuro-endocrine:
•GnRH and CRH are inhibited – FSH, LH and ACTH levels
are lowered – only short term – tolerance develops
•Decrease in levels of Sex hormone and corticosteroids, but
no infertility
•Increases ADH release – oliguria
•CVS: NO DIRECT EFFECT ON HEART
•Vasodilatation – histamine release, depression of vasomotor
centre and directly on blood vessels decreasing the tone
•Cardiac work reduction due to consistent vasodilatation

18. Pharmacological actions
of Morphine – contd.
•GIT: CONSTIPATION
•Due to direct action on intestine reducing
propulsive movement, spasm of sphincters,
decrease in all GIT secretions
•Smooth Muscles:
•Billiary Tract: Billiary colic – closure of sph.
Of Oddi
•Bladder: Urinary urgency but difficulty
•Bronchi - Bronchospasm

19. Morphine -
Pharmacokinetics
•Absorption and Distribution:
•Variable orally (usually not given orally – 1
st
pass metabolism,
given IM or IV)
•Widely distributed – liver, spleen, kidney etc.
•Enters Brain slowly
•Readily crosses placental barrier – dependence in fetus
•Metaboloism:
•In Liver by glucoronidation – water soluble metabolites
•Morphine-6- Glucoronide – analgesic – in renal failure
prolong analgesia
•Morphine-3-glucoronide – No analgesia – neuroexcitatory
•Excretion:
•Via Urine, Plasma t1/2 = 2-3 Hrs
•Action lasts for 4-6 Hrs
•Completely eliminated in 24 Hrs
•Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)

20. Morphine -
Pharmacokinetics

21. Morphine – Adverse
Effects
1.Respiratory Depression: Infant and Old
2.Vomiting
3.Sedation, Mental Clouding – sometimes dysphoria
4.Hypotensive effect
5.Rise in Intracranial Pressure
6.Apnoea: Newborn
7.Urinary retention
8.Idiosyncrasy and allergy
9.Acute Morphine Poisoning: occurs if >50 mg (Lethal dose –
250 mg), Gastric lavage with KMNO4, Specific antidote:
Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till
respiration picks up
10.Tolerance and dependence

22. Morphine – Therapeutic
uses
•Analgesic:
1.Long Bone Fracture
2.Myocardial Infarction
3.Terminal stages of cancer
4.Burn patients
5.Postoperative patients
6.Visceral pains – pulmonary embolism, pleurisy, acute
pericarditis
7.Biliary colic and renal colic
8.Obstetric analgesia
9.Segmental analgesia

23. Morphine – Other
Therapeutic uses
•Preanaesthetic Medication
•Balanced anaesthesia and surgical analgesia
•Acute Left ventricular failure – Cardiac
asthma
•Cough – not used but Codeine is used
•Diarrhoea – colostomy - Loperamide,
Diphenoxylate

24. Morphine -
Contraindications
1.Two Extremes of Age
2.Bronchial asthma
3.Respiratory insufficiency - empysema
4.Head Injury
5.Shock – Hypotension
6.Undiagnosed acute abdomen
7.BHP
8.Renal Failure, Liver diseases and hypothyrodism
9.Unstable personalities

25. Opioids - Classification
1.Natural Opium Alkaloids: Morphine and Codeine
2.Semi-synthetic: Diacetylmorphine (Heroin) and
Pholcodeine
3.Synthetic Opioids:
•Phenylpiperidines:
•Pethidine (Mepiridine) and its congeners – Diphenoxylate
and Loperamide
•Fentanyl and its congeners – sufentanil, remifentanil and
alfentanil
•Phenyl-heptylmines: Methadone and congeners like
Propoxyphene and Dextropropoxyphene
•Benzomorphans: Pentazocine
•Morphinan compounds and congeners: Levorphanol and
Butorphanol

26. Pethidine
•Morphine Vs Pethidine:
–1/10th as potent as Morphine, but Efficacy is similar
–Produces as much sedation, euphoria and respiratory
depression in equianalgesic dose and similar abuse
potential
–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
–Better oral absorption

27. Pethidine – contd.
•Pharmacokinetics
–Well absorbed orally, bioavailability 50%
–Effects appear in 10-15 min. after oral
absorption
–On parenteral administration action lasts for
2-3 Hrs
–Metabolized in liver – mepiridinic acid and
norpethidine
–Norpethidine accumulates on chronic use
–Excreted in urine

28. Pethidine – contd.
•Adverse Effects:
•Similar to Morphine
•Atropine like effects – dry mouth, blurred vision,
tachycardia
•Overdose – tremors, mydriasis, delirium and convulsion due
to norpethidine accumulation
•Uses:
•Analgesic as substitute of Morphine
•Ptreanaesthetic medication
•As analgesic during labour – less fetal respiratory
depression
•Dose 50-100 mg IM/SC, oral – 50-100 mg tabs.

29. Methadone
•Chemically dissimilar but similar in most of pharmacological
actions – analgesic, respiratory depression etc.
•High action orally as well as parenterally
•Single dose effect is – same with Morphine including
duration of action
•Cumulation – on repeated administration (t1/2 24-36 Hrs)
•Highly bound to plasma protein 80 to 90%
•Metabolized in liver by – demethylation and cyclization
•Excreted in urine
•Slow action and less subjective effect – abuse potential is
low
•Used as substitution therapy as opioid dependence: 1:4mg
and 1:20 mg of Morphine and Pethidine respectively
•Codeine is used as substitution in Methadone addiction

30. Tramadol
•Centrally acting analgesic
•Very low action on opioid receptors (
•Other mechanisms involved in analgesic action – 5-HT and
NA reuptake inhibition – spinal inhibition of pain
•Effective both orally and IV (100mg = 10 mg Morphine)
•Side effects are similar to Morphine but less prominent
•Well tolerated and low abuse potential
•Only Partially reversed by Naloxone
•Used in chronic neuropathic pain and short diagnostic
procedures
•Dose: 50-100 mg IM/IV/Oral
(Contramol)

31. Opioid Receptors
•Mainly 3 (three) types of receptors – μ (mu), κ (kappa) and δ
(delta)
•Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2
•Location: Peripheral Nerve endings, SG in spinal chord,
Periaqueductal gray (PAG) in midbrain and Brain stem
(medulla, hypothalumus and also amygdala
•Opioids are – agonists, partial agonist or competitive
antagonists of these receptors
•Overall effect depends on nature of interaction and affinity
to these
•Morphine is agonist of all but affinity is higher for mu

32. μ receptor κ receptor δ receptor
Location μ1 – supraspinal
μ2 - spinal
κ1 – spinal
κ3 -supraspinal
Spinal
supraspinal
Effects Analgesia
Respiratory
depression
Sedation
Euphoria
Miosis
Physical dependence
Loss of GI motility
Spinal analgesia
Dysphoria
Sedation
Psychomimetic
Physical
dependence
(nalorphine
type)
Spinal analgesia
Affective
behaviour
(Supraspinal)
Respiratory
depression
Reduced GI
motility
Agonists Morphine, Codeine,
Fentanyl and
pentazocine weakly
Pentazocine
Effects of Different Opioid Receptor Stimulation:

33. Effects of Opioid
Receptor Stimulation

34. Effects of Opioid Receptor
Stimulation – contd.

35. Opioid Receptors –
Intracellular mechanism
•All are G-protein coupled receptors
•Located on prejunctional neurones
•Inhibits release of transmitters – NA, DA, 5-HT,
GABA and Glutamate
•Activation reduces intracellular cAMP formation -
Opening of K+ channel via μ and δ. and supression
of N type of Ca++ channels
•Ultimately Hyperpolarization and reduced
intracellular Ca++ Reduced Neurotransmitter
release

37. Endogenous Opioid
Peptides
•Endorphins:
•Derived from POMC
•ß-endorphins: 2 Types - ß-endorphin1 and ß-endorphin-2
•Primarilty μ agonist and also has δ action
•Enkephalins:
•Derive from Proenkephalin
•Met-ENK and leu-ENK
•Met-ENK - Primarily μ and δ agonist and leu-ENK – δ
agonist
•Dynorphins:
•Derive from Prodynorphin: DYN-A and DYN-B
•Potent κ agonist and also have μ and δ action

38. Opioid Antagonists
1.Pure antagonists: Naloxone, Naltrexone and
Nalmefene
•Affinity for all receptors (μ, δ and κ)
•Can displace opioids bound to α-receptors
•No action on Normal person but reverses poisoning and
withdrawal symptoms in addicts
1.Mixed Agonist-antagonists: Nalorphine, Pentazocine,
Butorphanol and Nalbuphine
2.Partial/weak μ agonist and κ antagonist:
Buprenorphine

39. Nalorphine
•Not used anymore
•Previously used as Opioid antagonist
•But, antagonism is restricted to μ-
receptor only and agonist of κ-
receptor
•Drawbacks - dysphoria and
psychomimetic effects

40. Pentazocine
•Weak α-receptor antagonist, but agonist of κ-receptor
•One of the commonly used agents, given orally and IM
•Low abuse liability
•Pharmacokinetics:
–High 1
st
pass metabolism but effective orally
–Half life = 3-4 Hrs
–Metabolized in liver by glucoronide conjugation
–Dose: orally 50-100 mg and parenterally 30-60 mg IM
•Uses:Moderately severe pain in Injury, Burns, Fracture
Trauma, Cancer and Orthopaedic manuevers
(Fortwin, Fortagesic)

41. Pentazocine Vs Morphine
•Spinal analgesia via kappa receptor
•Dose is 30 mg Vs 10 mg and low ceiling effect
•Sedation and Respiratory depression at lower doses
•Tachycardia and rise in BP – dangerous in MI
•Lesser smooth muscle spasms
•Vomiting and other side effects are less
•Subjective effects – lower ceiling (psycomimetic effects)
•Tolerance develops on repeated use, but lesser than
Morphine
•Withdrawal symptoms – both Morphine and Nalorphine like
•Good analgesic in subjects not exposed to Morphine
•Precipitate withdrawal – in Morphine addicts

42. Buprenorphine
•Synthetic thebaine congener and highly lipid soluble
•Given Sublingually or parenterally but not oral – high 1
st
pass
metabolism
•Selective μ-agonist analgesic
•20-30 times more potent than Morphine
•Slow but longer duration of action upto 24 Hrs
•Pharmacological effects are similar to Morphine
•Has ceiling effect in analgesic and respiratory depression
•Good analgesic for naive patients but addicts – precipitates
withdrawal syndrome
•Lower tolerance and physical dependence than Morphine and abuse
liability
•Withdrawal syndromes are similar to Morphine

43. Buprenorphine – contd.
•Adverse Effects:
–Hypotension (Postural)
–Respiratory depression (fatal in neonates) and cannot be
reversed by Naloxone
•Uses:
–Long lasting painful conditions – cancer
–Postoperative pain
–Myocardial infarction
•Preparations: Norphine, Tidigesic
•0.3 mg/ml injections and 0.2 mg sublingual tablets

44. Naloxone
•Competitive antagonist of all types of opioid
receptors
•But, blocks μ-receptors at much lower dose
•Always injected IV (0.4 t0 0.8 mg) - All symptoms
of Morphine action are antagonized – respiratory
stimulation
•At higher doses 4-10 mg: antagonizes actions of
Nalorphine and Pentazocine – dysmorphic and
psychomimetic effects are not suppressed (δ)
•Withdrawal symptoms: 0.4 mg doses – Morphine
and 4-5 mg doses – Nalorphine and Pentazocine

45. Naloxone – contd.
•Buprenorphine actions are prevented but not
reversed fully – tight bond with receptors
•Also acts on endogenous opioids
•Antagonizes respiratory depression of Diazepam
and N2O
•Uses:
•Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min,
maximum 10 mg.
•New Born – opioid poisoning
•Reverse respiratory depression intr-aoperatively
•Diagnosis of Morphine addiction
•Alcohol intoxication

48. SAR - Opioids
(Phenolic)
(Alcoholic)
Morphine
Codeine
Heroin
Naloxone