Opioids and Morphine pharmacology presentation

Opioids pharmacology

1. OPIOIDS

2. THANK- YOU

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ic conditions for which cures were unknown,

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6. Opioids - Opium
+ A dark brown, resinous material
obtained from poppy (Papaver
somniferum) Capsules.
OPIUM 6 à

8 1
OR.
— 2 PHENANTHRENE BENZYLISOQUINOLIN
*Morphine 9-14% *Papaverine 0.8-1%

6 5 4 3

*Codeine 0.5-2% *Noscapine 3-10%
A "Thebaine DU *Narcine 0.2-0.4% -
SE

7. 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

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8. Morphine - The Gate
Theory

Tiber Projection

neuron

세

Inhibitory
interneuron

Strong
- €
activation

AB fibers

fiber
C fibe Projection

neuron

+
K Reduced

— or weak
activation

Inhibitory
interneuron

9. Opioid Receptors

(dele) 3 (three) types of receptors - y (mu), k (kappa) and 5
elta

Subtypes: ul, u2, 1, k2, k3, 51 and 02

Location: Peripheral Nerve er SG in spinal chord,
Periaqueductal gray (PAG) in midbrain and Brain stem
(medulla, hypothallemes 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

=

10. Location

Effects

Agonists

f=

H receptor
ul - supraspinal
H2 - spinal

Analgesia
Respiratory
depression

Sedation

Euphoria

Miosis

Physical dependence
IpfifreTd6eBy
Fentanyl and
pentazocine weakly

K receptor
kl - spinal
k3 -supraspinal

Spinal analgesia
Dysphoria
Sedation
Psychomimetic
Physical
dependence
(nalorphine

PS) zocine

Effects of Different Opioid Receptor Stimulation:

5 receptor

Spinal
supraspinal

Spinal analgesia
Affective
behaviour
(Supraspinal)
Respiratory
depression
Reduced GI
motility

11. Opioid Receptors -
Intracellular mechanism

ㆍ 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 and 3. and supression
of N type of Ca++ channels

・ Ultimately Hyperpolarization and reduced
ee ar Ca++ ——+ Reduced Neurotransmitter
relea

AA

12. Endogenous Opioid
Peptides

・ Endorphins:
・ Derived from POMC
ㆍ B-endorphins: 2 Types - B-endorphini and B-endorphin-2
・ Primarilty agonist and also has à action
・ Enkephalins:
ㆍ Derive from Proenkephalin
・ Met-ENK and leu-ENK
ㆍ Met-ENK - Primarily y and 6 agonist and leu-ENK - 3
agonist
・ Dynorphins:
・ Derive from Prodynorphin: DYN-A and DYN-B
ㆍ Potent k agonist and also have H and à action

=

13. MORPHINE (Pharmacological
actions) - CNS E 1

Analgesia:
ㆍ STrong analgesic Ta
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

{=

14. 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

WP

1.

Stimulation:

CTZ - sensitize CTZ
to vestibular and
other impulses
Edinger Westphal
Nucleus - miosis
Vagal centre -
Bradycardia
Hippocampal cells -
convulsions 니이
of GABA release)

15. MORPHINE - Analgesia
action

ㆍ 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

A=

16. Pharmacological actions of
Morphine (CNS) - contd.

Sedation:

- Drowsiness and indifference to surroundings

- Inability to concentrate and extravagant imagination -
colorful day dream

- Apparent excitement

u 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,

leasurable floating feelings - kick
EUPHORIA
II |

17. Pharmacological actions
of Morphine - contd.

・ Neuro-endocrine:

・ 6nRH 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

ㆍ 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

A=

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

ㆍ Smooth Muscles:

* Billiary Tract: Billiary colic - closure of sph.
Of Oddi

+ Bladder: Urinary urgency but difficulty

= Bronchi - Bronchospasm
DS

19. Morphine - Effects

20. Morphine -
Pharmacokinetics

Abaorpfion and Distribution:

・ Variable onaty{usually not given orally - 1" pass metabolism,
given IM or I

・ 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:
ㆍ Via Urine, Plasma t12= 2-3 Hrs
・ Action lasts for 4-6 Hrs
Completely eliminated in 24 Hrs
eparation: 10, 15, and 20 mg. (IV: 2 - 10 mg)

21. Morphine -
Pharmacokinetics

22. Morphine - Therapeutic
uses

ㆍ — Analgesic:

Long Bone Fracture
Myocardial Infarction
Terminal stages of cancer
Burn patients
Postoperative patients

Visceral pains - pulmonary embolism, pleurisy, acute
pericarditis

Biliary colic and renal colic
Obstetric analgesia
Segmental analgesia

=

von DALIA

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. 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
ㆍ Phenyl-heptylmines: Methadone and congeners like
Propoxyphene and Dextropropoxyphene
Benzomorphans: Pentazocine
> Morphinan compounds and congeners: Levorphanol and
Butorphanol

25. DONSO SUN

Morphine - Advers
Effects

Respiratory Depression: Infant and Old 는
Vomiting
Sedation, Mental Clouding - sometimes dysphoria
Hypotensive effect

Rise in Intracranial Pressure
Apnoea: Newborn

Urinary retention
Idiosyncrasy and allergy

Acute Morphine Poisoning: occurs if >50 mg (Lethal dose -
250 mg), Gastric lavage with KANO4, Specific antidote:
Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till
respiration picks up
Tolerance and dependence

26. Morpnine -
Contraindications

Two Extremes of Age

Bronchial asthma

Respiratory insufficiency - empysema

Head Injury

Shock - Hypotension

Undiagnosed acute abdomen

BHP

Renal Failure, Liver diseases and hypothyrodism
Unstable personalities

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27. 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

mon action and less subjective effect - abuse potential is
ow

Used as substitution therapy as opioid dependence: 1:4mg
and 1:20 mg of Morphine and Pethidine respectively

is used as substitution in Methadone addiction

28. Pentazocine

Weak a-receptor antagonist, but agonist of k-receptor
・ One of the commonly used agents, given orally and IM
Low abuse liability
・ Pharmacokinetics:
- High 1° 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)

AF

29. 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

5

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)
At

31. Nalorphine

・ Not used anymore

* Previously used as Opioid antagonist

ㆍ But, antagonism is restricted to y-
receptor only and agonist of k-
receptor

ㆍ Drawbacks - dysphoria and
psychomimetic effects

=

32. Buprenorphine

Synthetic thebaine congener and highly lipid soluble

Given Sublingually or parenterally but not oral - high 1* pass
metabolism

Selective u-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

awe and physical dependence than Morphine and abuse
tadill

Withdrawal syndromes are similar to Morphine

33. 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

=

34. 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

=

35. 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

=

36. Pethidine - contd.

・ Pharmacokinetics
- Well absorbed orally, bioavailability 50%

- Effects appear in 10-15 min. after oral
absorption

ー on parenteral administration action lasts for

-3 Hrs

- Metabolized in liver - mepiridinic acid and
norpethidine

- Norpethidine accumulates on chronic use

- Excreted in urine

ia

37. 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.

Me

38. Effects of Opioid
Receptor Stimulation

f pain-promoting

neurotransmitters (Le., substance P, bradykinin)

2. -1eceptors in spinothalmic tract, inhibitory
st-synaptic potenti | aTVI pall

inhibitory pain ions

39. Effects of Opioid Receptor
Stimulation - contd.

limited to perception of nociceptive stimuli

no ceiling effect

+ development

dependence

40. Opioid Antagonists

1. Pure antagonists: Naloxone, Naltrexone and
Nalmefene
Affinity for all receptors (u, 5 and k)
Can displace opioids bound to a-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 agonist and k antagonist:
Buprenorphine

=

41. Naloxone

・ Competitive antagonist of all types of opioid
receptors

・ But, blocks y-receptors at much lower dose

・ Always injected IV (0.4 +0 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 (3)

・ Withdrawal symptoms: 0.4 mg doses - Morphine
and 4-5 mg doses - Nalorphine and Pentazocine

Ae

42. Naloxone - contd.

・ Buprenorphine actions are prevented but not
reversed fully - tight bond with receptors

・ Also acts on endogenous opioids

+ 100 respiratory depression of Diazepam
and NzO

・ Uses:
・ Acute Merida 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

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45. SAR - Opioids

Morphine

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46. THANK- YOU