The document discusses opioid analgesics and their mechanisms of action, receptors, endogenous opioids, and examples like morphine, codeine, pethidine. It summarizes their pharmacokinetics, pharmacodynamics, uses, adverse effects, interactions, and contraindications. The three major classes of opioid receptors are mu, kappa, and delta, which are G-protein coupled receptors located in the CNS and peripheral nerves. Opioids can act as agonists, antagonists, or mixed agonist-antagonists at these receptors. Tolerance and dependence develop with repeated use of opioids.

1. (Narcotic analgesics)
ANALGESICS
NON-
ANALGESICS
Opioid Analgesics

2. Relevant terminology
 Analgesic:-drugs that relieve pain without significantly
altering consciousness.
 Algesia (pain):- is an unpleasant bodily sensation perceived
as suffering, usually evoked by an external or internal
noxious stimulus
 Hyperalgesia- excessive ↑sensitivity to pain (barbiturate)
 Opium-a mixture of alkaloids from poppy seed
 Opiate- drug derived from opium
 Opioids- All compounds that work at opioid receptors
 Narcotic Analgesic(opioid analgesics):- drug relieves pain
together with drowsiness,sleep.e.g.-morphine
 Non-Opioids- relieves pain without sedation.e.g.-NSAID’s

3. Opioid receptors
3 major classes of opioid receptors have been found in the CNS(Spinal &
supra-spinal): μ, κ and δ receptors.
μ κ δ
μ1 μ2
Gi-GPCR
Morphine opioid receptor(MOR)
 High affinity for
Morphine
 Endogenous
ligands-
Endorphins &
enkephalins binds
here
OP-3 OP-2 Op-1
Delta opioid receptor
Kappa opioid receptor
κ1 κ2 κ3
 Dynorphins act here mainly  Enkephalins act
here mainly
δ1 δ2

4. Mu Kappa Delta
μ1-Analgesia
μ2-
Sedation,
vomiting,
Respiratory depression,
pruritis,
euphoria,
anorexia,
urinary retention,
Physical dependence
 Analgesia
 Dysphoria
 Miosis
 Psychomimetic effect
 Dependence
 Respiratory depression
• Analgesia
• Respiratory depression
• Feeding
• Inhibition of Dopamine
release
Response Mediated on stimulation of different opioid receptor
• The drugs acting at these receptors are called as “opioids”
• These opioids can act as: Agonists or Antagonists or Mixed agonist-
antagonist (agonist at one receptor & antagonist at the other).

5. Endogenous opioids
 These are morphine like endogenous substances normally present in
the body (mainly CNS) acts on opioid receptor
 These endogenous opioids are peptide chains present as precursor
molecules
 Mainly 3 precursors have been isolated:
– Prepro-opio-melanocortin→ β-Endorphin+MSH+ACTH
– Preproenkephalin→ Enkephalins (Met- & Leu-)
– Preprodynorphin→ Dynorphins (A & B)
 The endorphins, enkephalins & dynorphins are the endogenous opioid
peptides
 These are released during the stress like pain and act on the opioid
receptors
 These peptides appear to be involved in placebo and acupuncture-
induced analgesia

6. OPIOIDS
Agonists Opioid agonist-antagonist
Natural
•Morphine
•Codeine
•Thebaine
•Papaverine
•Noscapine
Semi-synthetic
•Heroin
•Pholcodine
•Hydromorphone
•Oxymorphone
Partial agonist
•Buprenorphine
Synthetic
•Pethidine
•Tramadol
•Methadone
•Dextropropoxyphene
•Fentanyl
•Alfentanil
•Sufentanil
•Remifentanil
 Pentazocine
 Butorphanol
Antagonists
•Naloxone
•Naltrexone
•Nalmefene

7. Morphine
Prototype- the principal alkaloid in opium
white, crystalline powder
Source:- Morphine is a naturally occurring substance
extracted from the seedpod of the poppy plant, Papavar
somniferum
Name derived from “Morphius” the god of dreams
Mechanism of Action:-
Morphine & other opioids acts on various opioids receptor (μ,κ,δ) which
are Gi types of GPCR located in located at spinal and supraspinal levels
(medulla, midbrain, limbic system and cortical areas) and peripheral
nerves.
Presynaptic neurons- acts via ↓intracellular cyclic AMP due to
inhibition of Adenylate cyclase & block voltage gated N-type Ca++
channel

8. Also inhibit-Glutamate release from nociceptive nerver
terminal In spinal cord
In post synaptic neurons-(μ)-receptor hyperpolarization
by opening K+ channel

9. Opioids:Pharmacokinetics
 Absorption:-
– oral absorption is rapid BA is much lesser because of the high first pass
metabolism
– To avoid first pass metabolism, can be given by SC, IM, slow diluted iv
 Distribution:-
– Rapidly concentrated in the organs of high blood supply like brain, lungs, liver,
kidney & spleen
– In organs of less blood supply like skeletal muscles & fatty tissues, the drug is
slowly accumulated → Act as drug reservoir
– Cross placenta → Neonatal respiratory depression
 Metabolism:- liver
– In liver mostly by glucuronide conjugation
– Morphine-6-glucuronide is also an active metabolite
 Excretion:-
– In urine mainly as metabolites
– In renal failure → Accumulation of active metabolites → Toxicity
– Morphine may affect suckling infants-contraindicated in lactating female

10. Pharmacological effect
 Miosis
 Analgesia
 Respiratory depression
 Physical and psychological dependence
 Histamine release, hypotension, hypothermia
 Itching
 Nausea and vomiting
 Euphoria
 Cough suppression, constipation
 Vagal stimulation (bradycardia)
 Sedation and hypnosis
MARPHINE CVS

11. Opioids: Pharmacodynamics
 Analgesia:-
–  Perception of pain,  threshold &  reaction to pain
(Patient is aware of the pain but is more comfortable with it)
 Euphoria:- A sense of well being & contentment (physical/psychological
dependence) by μ-receptor action
 Sedation:-More with morphine & codeine; Less with synthetic agents
 Respiratory depression:- Respiratory centre sensitivity to CO2→Respiratory
depression
 Cough suppression:-Causes suppression of the cough centre in brain(Central
Anti-tussive action)
 Miosis (Pinpoint pupil):-
– This is due to the stimulation of Edinger-Westphal nucleus which causes
contraction of the constrictor pupillae muscle of the iris
– No development of tolerance to miosis & constipation
 Nausea & vomiting:-Due to the stimulation of CTZ; vomiting  by movement
 Hypothermia:-high dose suppress Temperature regulating center
I. ACTIONS ON CNS:

12. Pharmacodynamics:-
 On GIT:-
–  g.i. motility &  tone of anal sphincter,delay gastric emptying →
Constipation, cramping
– Constriction of biliary sphincter of oddi→  Biliary pressure (C/I-
in biliary colic)
– Alvimopan is a peripheral opioids blocker use for paralytic ileus
 On CVS:- (minimal effect on Heart)
– Only large doses cause hypotension (because of histamine release
& ↓sympathetic tone)
– bradycardia-(except-pethidine, pentazocine , butorphanol which
casuse tachycardia)
– Sifting of blood from pulmonary to systemic circulation (i.e. why
use in pulmonary edema )
II. PERIPHERAL EFFECTS:

13.  On muscle:-
SM- longitudinal muscle- relaxation
Circular muscle- constriction
 Sk.M-Muscle rigidity-maximum by alfentanil
 Rigidity in thoracic muscle- causes wooden chest
syndrome
 On Endocrine system:-
–  LH, FSH, ACTH →  Testosterone & Cortisol levels
–  prolactin & GH secretion
 On Urinary system:-
–  Renal blood flow &  ADH secretion →  Urine formation
(Oligurea)
–  Bladder tone &  Sphincter tone → Difficulty in urination
 On Uterus:-
–  Uterus tone → May prolong labor
 Histamine release:-
– Bronchoconstriction, urticaria, vasodilatation & sweating

14. Tolerance:- (repeated expose)
1.occur due to inhibition of release of endogenous
opio-pepties
2.Due to down regulation of opiate receptors(change
in no. of receptors)
High cross tolerance is seen with all actions
Except- 3C
Constipation,
Convulsion,
Constriction of pupil(miosis)
There is Cross tolerance among opioids.

15.  Dependence:- by µ-receptor due to euphoric action
1.Physical dependence 2.Psychological dependence
1.Physical dependence- abrupt withdrawal symptoms
(abstinence syndrome)-due to rebound ↑NA
lacrymation, sweating, anxiety, insomnia, raise in BP,
palpitation, loss of weight, irritability ,dehydration
(symptoms are just opposite to morphine action)
2.Psychological dependence:- Associate with instance
craving for the drug

16.  Treatment:-
1.Hospitalization of pt. & psychotherapy
2.If addiction is short duration & small doses sudden stoppage
of drug can be done & mild withdrawal symptoms can be
treated by ß-blockers & clonidine
3.Gradual withdrawal of morphine
3.Substitute therapy with- Methadone
Advantage:-
-longer duration of action than morphine
-same potency as morphine
-slow acting &Long duration of action
-Less withdrawal symptoms
-less liable to tolerance & addiction

17. [1mg Methadone-substitute 4mg Morphine]
4.Complete withdrawal of morphine followed by
withdrawal of methadone. This is known as
“detoxification”
5.Clonidine is given to control withdrawal
symptoms
6.Acupuncture to stimulate release of endorphins
7.After detoxification:- opioid antagonist as
naltrexone are given orally to maintain the opioid
free state to prevent relapse

18. Opioids: Clinical Uses
 To relieve sever visceral pain:-
– Very effective in relieving severe deep visceral pains
e.g. of Acute. M.I.
– Terminal illness:-Cancer pain(o)
– Post operative-pain -IM,S.C route (except-after
cholecystectomy & eye operation)
– Bone fracture-(except- heard injury)
– Morphine i.v is indicated in prevention of neurogenic
shock due to excruciating pain
– Surgical analgesia: in abdominal lower limb and
pelvic
– Burns

19.  Acute LVF (Acute pulmonary edema):-
Morphine-IV-route
Advantage:-
1.↓Anxiety and fear
2.↓Sympathetic discharge resulted in reduction of
both pre & after load on heart by vasodilatation
of systemic vessels more than pulmonary vessels
so sifting of blood from pulmonary to systemic
circulation
3.Relieves pulmonary congestion & edema & also
depress respiratory center

20.  Pre-anaesthetic medication:-
opioids are used about half an hour before anaesthesia
because of their sedative,analgesic and euphoric effects
–  the dose of anaesthetic needed
– “Neurolept anaesthesia”-fentanyl & its analogue
– Fentanyl (I.V. or epidural)-provide anaesthesia during
coronary bypass grafting because of no cardiovascular toxicity
 Cough:- (Anti-tussive)
– Morphine acts by suppressing the cough centre in medulla in
sub-analgesic dose
– Codeine is preferred because of its more specific action on
cough centre
Drugs:- codeine,pholcodeine,dextromethorphan centrally acting
anti-tussive

21.  Diarrhoea:
– Opioids act by inhibiting the g.i. motility and
secretions
– Synthetic derivatives like Diphenoxylate, Difenoxin
& Loperamide are preferred in non infectious acute
diarrhoea because of their more specific action on
GIT

22. Opioids: Adverse effects
 Apnoea: Due to respiratory depression
 Allergy: Can cause urticaria & itching around the
nose(due to histamine release)
 B.P. falls: Postural hypotension,  by hypovolemia
 Blurring of vision
 Constipation
 Chronic use leads to tolerance & dependence
 Dysphoria: Feeling not well and restlessness
 Dysuria: Difficulty in urination & urinary retention

23. Acute morphine poisoning
 Accidental , suicidal or seen in drug abuser
 Manifestation:- (extension of pharmacological actions)
- Respiratory failure (central respiratory failure due to
inhibition of RC )
- coma,
- hypotension, pulmonary edema
- bradycrdia,
- Miosis- pinpoint pupils
 Diagnosis:-
– Pin-point pupil and signs of CNS depression
– May be history of addiction and needle marks

24.  Treatment:-
– Gastric lavage by KMno4, followed by purgative as
MgS04
– Respiratory support by ventilator is most important as
the death is always due to respiratory failure
– Specific antidote:-Naloxone-(IV)-DOC
 Rapidly reverses all signs and symptoms of toxicity
 It is given 0.4-0.8 mg IV and repeated every 2-3 min till
respiration picks up.

25. Contraindications:-
 Head injury:- Opioids should never be used, the reason is
1. Opioids cause respiratory depression
CO2 retention
Cerebral vasodilatation
Intracranial tension
Dangerous alteration of brain functions
2.Vomitig miosis and altered mentation produced by
morphine interfere with assessment of progress in head
injury cases(interference of prognosis )

26.  Hypothyroidism
 Respiratory disease as Bronchial asthma & COPD-
precipitate due to histamine release (fentanyl-safe)
 Pregnancy, labor, lactation
 Lever & kidney impairment
 Extremes of age (very old pt due to deficient urinary
retention)
 Acute abdominal pain- before diagnosis of the cause
because morphine will mask pain which is the diagnostic
symptom
 After cholecystectomy
 Alone in renal & biliary colic's
 History of addiction to opiates
 Allergy to morphine

27. Interaction:-
Phenothiazines ,
TCA,
MAO-I ↓Absorption
Amphetamine
Neostigmine
2. Morphine retards- absorption of many orally
administered drug by delaying gastric empting
Morphine

28. Codeine:-
 Codeine has analgesic and cough-suppressant effects.
 It is administered orally.
 Advantage over morphine:-
a. It is less potent as an analgesic.
b. It has less respiratory depressant effect.
c. It is less constipating.
d. It has low addiction liability.
 It has selective cough suppressant effect (antitussive); hence it is
used to suppress dry cough.
 4. It potentiates analgesic effect of aspirin and paracetamol.
 Use:-moderate pain.
 SE:-constipation and sedation

29. Pethidine
 Synthetic opioid- Atropine like action
 Effect of pethidine in comparison with Morphine
 Less potent-less addictive
 rapid onset & shorter(3hr) duration of action
 Less sedation, Less Anti-tussive action, less tendency of nausea &
vomiting
 Less constipation-less spasm of smooth muscle
 Less likely to cause retention of urine
 Doesn’t delay labour & less respiratory depression in neonates
 Additional LA action(corneal anaesthesia on systemic use)
 Tachycardia-iv administration

30. Pharmacokinetics:-
 Absorption:- orally BA-50% (high first pass)
 T1/2-3hr
 Distribution-Plasma protein bindig-60%
 Metabolism-glucuronide conjugation(toxic metabolites)
 Excretion-urine (↑excretion-acidifying urine)
 SE:- similar to morphine like tremors, hallucinations, muscle twitches
and rarely convulsions, tolerance & dependence can also occur
USE:-
 Obstetric analgesia-
Advantage-
 don’t block oxytocin action,
 no delay in labour,
 no PPH
 Less neonatal respiratory depression

31.  Post operative anti-shivering agents
 Deep visceral pain
 Pre-anaesthetic medication
 Effective-diarrhoea & cough but not use due to toxicity &
availability of better drug(congeners)
 Diphenoxylate:-
 pethidine congener and is used in the treatment of diarrhea
 Well absorbed orally-higher dose produce CNS side effect
 Produce abuse or addiction
 For deaddiction-FDC use (0.025mg Atropine+2.5mg diphenoxylate)
 It is rarely used at present because of its dangerous side effect—
paralytic ileus
Congeners

32.  Loperamide:-
 Loperamide is a pethidine congener.
 ↓GI motility and secretions but ↑ tone of the anal sphincter-effective
for pt.with anal incontinence
 CNS-penetration-negligible(no abuse liability)
 It is used in the symptomatic treatment of diarrhea.
 Common side effects are constipation and abdominal cramps
 Heroin (Diacetyl morphine):-
 Fast acting & highly potent analgesic
 Banned in most countries because of addiction liability
 Fentanyl:-
 A strong analgesic-μ-agonist
 Combination-neuroleptics(droperidol) in short painful operation
 Called As “Neurolept-analgesia”
 Midazolam+ Fentanyl- produce conscious sedation
 Also used for-labour pain,cancer pain,po-pain

33. Tramadol:-
 It is a synthetic codeine derivative with weak agonistic
activity at μ-receptors.
 Central analgesic-
 It also inhibits the reuptake of noradrenaline and 5-HT-
atypical opioids(non opioid mechanism)
 It ↓seizure threshold
 Tramadol+ SSRI,MAO inhibitors-produce serotonin
syndrome
 Effective for mild-moderate pain(post op pain)

34.  Methadone:-
 Long acting μ receptor agonist
 It Also block-NMDA recptor & reupake of monoamines
 Use for neuropathic & cancer pain that are not cotrolled
with morphine
 Preferred for de-addiction of heroin & morphine addicts, by
substitution treatment, because it is:
– As potent as morphine
– Orally used and is longer acting
– Tolerance & dependence develops slowly
– Withdrawal symptoms are less –as t1/2 in longer

35.  Sufentanil:-
– 5-7 times more potent than fentanyl
 Alfentanil:-
– Less potent than fentanyl but acts more rapidly and is shorter
acting
 Remifentanil:-
– Very short acting because of rapid metabolism by cholinesterases
in blood and tissues
 Propxyphene:-
– Has lower analgesic efficacy
– Analgesic effect is additive with NSAIDs
– Usually used in combination with aspirin or paracetamol in mild to
moderate pain
– Has lower potential of abuse

36. Mixed agonist-antagonists
 They include- pentazocine, butorphanol
MOA:-
 Pentazocine-effective orally/parentally
 Cause-hallucination-higher dose
 ↑BP=due to anti-cholinergic nature –contraindicated in MI
 Use-diagnosis of opioid addiction because they precipitate
withdrawal symptoms by blocking μ-receptor
Pentazocine,
butorphanol μ-receptor Antagonist
κ- Agonist
 Butorphanol:- Produces analgesia similar to others but is more sedative

37.  Buprenorphine:-
 25 times more potent than morphine as analgesic.
 Pharmacological actions: They are qualitatively similar to
morphine but has a delayed onset and
 prolonged duration of action.
 Antagonized the fentanyl induced respiratory depression
 USE:-
 Post op pain,Cancer pain,Acute MI,Pre-Anasthetic
medication
 Biliary colic-no increase in intrabiliary pressure
Buprenorphine μ-receptor Agonist
κ- Antagonist

38. Opioid Antagonists
 These are pure antagonists at all opioid receptors
 They do not completely reverse buprenorphine induced
respiratory depression.
 Used as antidotes to reverse the effects in cases of opioid
poisoning and opioid adverse effects
 Actions depends on the pt. Receiving these drug-
 In Normal individual(absence of opioids)- no analgesic
effect
 In case of acute opioid toxicity- they reverse the action of
opioids as morphine (respiratory depression, constipation)
 In opioid addiction-they induce withdrawal symptoms
 There are 3 pure opioid antagonists available:-

39. 1. Naloxone:-
– given IV, 0.1-0.4 mg(high first pass)-not effective orally
– Half-life only 1-2 hours, so to be repeated as needed(short acting)
– also blocks analgesic effect of placebo and acupuncture, and
effects of endogenous opioid peptides
2. Naltrexone:-
– Orally effective,Long acting
– More potent
– Higher dose-hepatotoxicity
– Also now found useful in alcohol addiction
3. Nalmefene:
– Orally & iv effective
– Given IV like naloxone but has  half-life of 8-10 hours
– Long acting without hepatotoxicity
– Can be use in long acting opioid poisoning like methadone

40. Therapeutic use
1.Opioid toxicity- adult & neonates
 Acute toxicity-Naloxone (i.v.)
 Treatment of neonatal asphyxia(i.m. naloxone to the mother before
delivery or intra-umbilical after delivery )
2.Severe opioid induced constipation- Analogue of naloxone
(alvimopan)-peripheral μ-blocked without withdrawal syndrome
3.Morphine induced paralytic ileus
4.Opioid dependence- Naltrexone-orally effective &long acting
 To maintain opioid-free state after treatment of addiction
 Alcohol deaddiction-↓craving
5.Diagnosis of morphine & heroin addiction (i.v. naloxone)

41. Thank You