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.
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
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
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
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)