opioid drugs, and narcotic analgesices and its antagonists

1. Opioid Analgesics
Mr. RVS Chaitanya Koppala
Lovely professional university, Punjab

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. 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%

4. Poppy Plant - image

5. 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

6. 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

7. 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

8. 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)

9. 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

10. 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

11. Morphine -
Pharmacokinetics
• Absorption and Distribution:
• Variable orally (usually not given orally – 1st
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)

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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.

20. 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

21. 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:

22. 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

23. 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

24. 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

25. 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 1st
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)

26. 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