opioid analgesics

1. Opioid analgesics &
antagonists

2. OPIOID ANALGESICS
Pain is an illdefined, disabling accompaniment of
many medical conditions. Evoked by external or
internal noxious stimuli.
Analgesics are drugs which possess significant
pain relieving properties by acting on CNS or
PNS without significantly affecting
consciousness.
Types of analgesics;
1.Narcotic/Opioid/Morphine like analgesics
2.Non-Norcotic /Non-steroidal anti-inflammatory-
analgesic-antipyretic agents.

3. PATHOPHYSIOLOGY OF PAIN
Pain has 2 components
1.Nociceptive –disabling unpleasant sensation.
2.Affective component -Psychological response
associated with pain.
The synaptic responses of dorsal horn neurons
display a wind up phenomenon. NMDA, subP,
NO, NGF all contribute to facilitation of
nociceptive transmission-hyperalgesia.

4. Nonmyelinated C-fibres are the main types
of peripheral sensory neurons that
respond to noxious thermal, chemical or
mechanical stimuli.
Few chemical stimuli are sub-P, neurokinin-
A&B, bradykinin,5-HT,histamine, Pg, H+,
ATP and vanilliods.

5. DESCENDING PATHWAYS
Control impulse transmission in the dorsal horn
through PAG of midbrain-rostro ventral medulla-
nucleus raphy magnus -substantia gelatinosa –
inhibition.
NRM itself receives input from ST neurons via
NRPG.
Also NA pathway from LC has inhibitory effect.
All descending pathways from midbrain and brain
stem exert inhibitory effect on transmission.

6. ENDOGENOUS OPIOID
PEPTIDES
Β –Endorphins –have greater affinity for μ opiod
receptor
Encephalins have more affinity for δ type of
receptors. Present both in CNS and PNS. Found
mainly in shorter interneurons in main brain
areas.
Dynorphins-have affinity for ĸ receptors. Found in
spinal cord. Sensitize nociceptive transmission.

11. Opioid receptor types
parameters mu kappa Delta
distribution PAG,NTS,
Thalamus,
Area postrema,
dorsal horn
Cortex, midbrain,
striatum,hippocam
pus, Dorsal horn,
medulla.
Trigeminal
nucleus, myentric
plexus +kappa
sites.
Analgesia
Supra spinal
Spinal
Peripheral
+++( )
++( )
++
+
+
++
-
++
-
Resp. depresion +++ +/- ++
Euphoria +++ - -
Dysphoria - +++ -

12. OPR contn
mu kappa Delta
Miosis ++ + -
Constipation ++ + ++
Sedation ++ ++ _
Physical
dependence
+++ + -
Agonist Methadone
Endomorphin1
&2.
dynorphin Encephalins.
Antagonist. NALOXONE

13. OPR are GPCR. Act by
1. ↓ intracellular cAMP.
2.Activate K+ channels
3. ↓Ca2+
Decrease neurotransmitter release .
Opiod analgesic are opium like analgesics
Opium is an extract from P.somniferum.
The milky exudate from unripe seeds contains two groups
of alkaloids.
1.Benzyl-isoquinolines
2.Phenanthrene group.

14. MORPHINE
Protoype opioid analgesic
From capsule of papaver somniferum
Isolated by SERTURNER
Named after Greek God of dreams-
MORPHEUS

18. MORPHINE
It is a pure agonist. Used for pain control
A.CENTRAL PHARMACOLOGICAL ACTIONS
1.Analgesia;
Increases pain threshold in supra spinal (μ1 ),spinal(μ2),
peripheral and limbic system.
Has sensory and affective components.
Sensory;
concerned with the source and localisation of pain.
Emotional;
concerned with motivational and emotional aspects like
one’s reaction towards pain.
Opioids are generally more effective against dull,
continous pain such as deep seated visceral pain .

19. 2.EUPHORIA,DYSPHORIA AND CONVULSIONS.
Causes an appreciable sense of well being (μ).
In Depressed patient’s euphoria is pronounced. Some
complaint of dysphoria( ĸ)- ch -restlessness and malaise.
Generally opioids depress polysynaptic responses but in
high doses increase the monosynaptic responses
through supraspinal stimulation leading to convulsions.
3.SEDATION
Disrupt normal REM sleep,
Produces Drowsiness ,clouding of judgement and sleep –
more in the elderly.

20. 4.RESPIRATORY DEPRESSION
Analgesia (μ1, μ2) and respiratory depression (μ1) .Analgesia is
directly proportional to respiratory depression in a dose related
manner. (at the level of medulla).
a.Depression of respiratory centre -increase PCO2.
b. ↓ Sensitivity of medulla to increased PCO2.
c.produce indifference towards breathing.
But respiratory depression occurs in therapeutic doses itself & is the
commenest cause of death in acute opiod poisoning.
Tolerance to respiratory depression develops slowly than to analgesic
and euphoric response.

21. 5.COUGH SUPPRESSION
Are effective antitussives.
Cough suppression occurs at opioid doses
lower than that required to produce
analgesia or respiratory depression.
Tolerance develops later.

22. 6.MIOSIS
Due to centrally mediated effects-- μ and ĸ
receptor induced III cr nerve nucleus –
(EDINGER WESTPHAL )stimulation. Has
no local action.
Pin point pupil is an important diagnostic
sign in opioid toxicity.
7.NAUSEA AND VOMITING
Directly stimulates CTZ, later depress it.

23. B.PERIPHERAL
PHARMACOLOGICAL ACTIONS
1.PERIPHERAL ANALGESIA
Opioid receptors are located both
centrally and peripherally.During inflammation o
are up-regulated .opioid peptides in the
inflammatory cells are attracted and released to
combat pain associated with injury.
So exogenously administered opoid agonist
directly to the site of inflammation can provide
an effective peripheral analgesia
Ex.intra-articular injection of morphine in knee
joints.

24. 2.GASTROINTESTINAL TRACT
Produce uncomfortable constipation.
Increase the sphincter tone, reduce the
motility and delay gastric emptying-retard
the absorption of various drugs. Decrease
the awareness for the necessity to
defaecate.

25. 3.BILIARY TRACT
Increases the pressure in the biliary tract
-contraction of gall bladder and
constriction of sphincter of oddi. So
contraindicated in biliary colic.
Holds back pancreatic juice and increases
Sr amylase conc. So avoided in
pancreatitis.

26. 4.OTHER SMOOTH MUSCLES
Broncho constriction—in part from histamine
release esp in br.asth.
Increase uterine tone-increase neonatal morbidity.
5.CARDIOVASCULAR EFFECTS
Vascular tone unaffected at analgesic doses.
Histamine release—bradycardia, hypotension.
↑PCO2—cerebral vasodilatation, increase in blood
flow and ↑ ICT.

27. 6.Tolerance
Develops to depressant effects –
Analgesia, euphoria,sedation and respiratory
depression. Not to miosis, constipation and
convulsions.
Cross tolerance devolops to opiods acting on
same receptors.
Tolerance may be due to long term
desensitization or down regulation of receptor-
effector coupling mechanisms / compensatory
increase in ca2+, increase in cAMP, efflux of K
etc.

28. 7.Dependence
Physical dependence. Abstinance cause life
threatening withdrawl syndrome—pain,
hyperventilation, coughing, mydriasis,
hypertension, diarrhoea, dysphoria, agitation
and piloerection (cold turkey).
Psychological dependence. More of drug seeking
behavior. Facilitates DA in mesocortical and
mesolimbic pathways—activates endogenous
reward pathways.
Abrupt withdrawl - nonadrenergic storm due to
locus ceruleus rapid firing.

29. PHARMACOKINETICS
Subjects to extensive first pass metabolism-
glucuronide conjugation.80%.Metabolites
are usually inactive-- exception –morphine
6-glucuronide a potent analgesic..
Excretion requires adequate renal function.
also via biliary route-deconjugated and
hydrolysed. Enterohepatic circulation +.
Crosses BBB less readily/ placental barrier
more easily.

30. USES
1.As Analgesic,
2.Acute left ventricular failure
3.Cough suppressant
4.In anesthetic practice
5.Diarrhoea
6.Relief from anxiety and apprehension.

31. ADVERSE EFFECTS
with 15 MG ADR occurs. Are extension of
ph effects.
Respiratory depression, constipation,
bronchospasm, postural hypotension,
urinary retention, nausea and vomiting,
tolerance and dependence.

32. CONTRAINDICATIONS AND
DRUG INTERACTIONS
CONTRAINDICATIONS
1.Hypotention
2.Hepatic damage
3.Hypertrophy of prostate
4.Head injury
5.Hypothyroidism
6.Bronchial asthma
7.Biliary colic
8.Babies
DRUG INTERACTIONS
1.OPIOIDS AND STEROIDS
2.OPIOID PARTIAL AGONIST AND AGONIST
3.MAO INHIBITORS AND MORPHINE
4.MORPHINE AND SEDATIVES.

33. ACUTE MORPHINE POISONING
May be accidental or suicidal.
Symptoms-Coma,severe respiratory
depression,pin point pupil, jerks,convulsions,
cyanosis,pulmonary edema.
TREATMENT:
A.Supportive care
B.Gastric lavage
C.Specific antidote- NALOXONE-0.4-0.8 mg IV rep
every 5 mts till respiration recovers and
repeated every 1-3 hrs till morphine is cleared
from the body.

34. CLASSIFICATION
Morphine analogues;
Agonists- Morphine, codeine.
Partial agonist- Nalorphine
Antagonist-Naloxone, Naltrexone, Nalmefene.
Synthetic derivatives
Agonists- Pethidine, Fentanyl, Methadone.
Partial agonist- Pentazocine, Buprenorphine,
Tramadol.,dextropropoxyphene ,ethoheptazine
Without analgesic action- Loperamide,
Dextramethorphan.

35. 1.PENTAZOCINE
Weak antagonist –μ; moderate agonist - ĸ ,
Weak agonist – δ.
Potency and efficacy – less than morphine
30 mg pentazocine = 10 mg of morphine
Produces spinal analgesia.
High doses =nightmares and hallucinations
Sympathetic
stimulation….CVS=tachycardia, rise in BP.

36. Pentazocine…
Tolerance
Psychological and physical dependance –
on rptd use
Less abuse liability
Dose:
50 to 100 mg orally/ 30 to 60 mg im

37. Pentazocine:
Effective orally, has high first pass
metabolism. Metabolised by liver & glucuronide
metabolites are excreted through kidney.
USES:
1.Post operative pain,
2. pain in burns and trauma.
CONTRAINDICATIONS;
1.Pt’s of MI.
2.Epileptic Pt’s.
3.Psychosis,
4.Head injury

38. 2.NALBUPHINE
Moderate antagonist- μ ,moderate partial agonist-
ĸ ,no action - δ.
Pentazocine analog,= to morphine, 5 times potent
to pentazocine (parenteral).
Produce less dysphoria and few psychotomimetic
effects.
Less CVS effects, less abuse potential.
PPT withdrawal in addicts.
USES:
1.Moderate to severe pain
2.obstetrical analgesia.

39. 3.BUPRENORPHINE
Strong partial agonist- μ, moderate
antagonist- ĸ , no action - δ.
25 times more potent than morphine.
More resp dep , analgesia, least dysphoria.
Resp dep not reversed with naloxone.
due to tight binding to opioid
receptors.
Less abuse potential.
Used for moderate to severe pain.

40. Buprenorphine…
Given sublingually
T1/2- 4 hrs
Dose:
0.2 to 0.4 mg
tolerance, physical dependance ,
psychological dependance +
Withdrawal symptoms

41. Pethidine ( meperidine)
Atropine substitute
Chemically unrelated to morphine but
interacts with opioid receptors
Differences from morphine:
1/ 10 times analgesic potency
Efficacy similar to morphine
Duration of action – shorter – 3 to 4 hrs
No suppression of cough

42. Pethidine..
Sedation, euphoria, respiratory
depression= morphine
Less histamine release – safe in BA
Side effects:
Similar to morphine
Atropine side effects+

43. pethidine
Pethidine hydrolysis meperidinic
acid
demethylation
norpethidine – conjugated with glucoronic
acid- excreted in urine
Overdose: excitatory effects- tremor ,
mydriasis, convulsions – due to
norpethidine

44. Pethidine..
Tolerance
Physical dependance
Uses:
Analgesic
Preanaesthetic medication
Preferred during labour
Less neonatal respiratory depression
Dose: 50 to 100 mg im

45. codeine
Methyl morphine
Converted to morphine in the body
1/10 potency & efficacy as morphine
Selective cough suppressant
ADR:
Constipation
USES:
Diarrhea

46. pholcodeine
Codeine like
Antitussive
Less constipating
HEROIN:
Diacetyl morphine
X 3 times more potent than morphine
More euphoriant, highly addicting

47. Methadone
Similar to morphine in actions
Cumulates on rptd administration
T1/2 – 4 to 6hrs
Chronic use – 24 to 36 hrs
Metabolized by demethylation& cyclization
Slow action – does not produce “kick”
Uses :
Substitution therapy for morphine
dependance

48. Methadone…
1 mg of morphine- substitutes for
4 mg morphine
2 mg heroin
20 mg of pethidine
In opioid addicts – methadone
maintenance therapy
Given orally to produce high degree of
tolerance- so that effect of morphine is not
perceived

49. dextropropoxyphene
Related to methadone
Metabolite – propoxyphene- cardiotoxic
Uses:
Mild oral analgesic
60 to 120 mg

50. tramadol
relieves pain by combining with µ receptor
Also  reuptake of NA & 5HT-
activates spinal inhibition of pain
100 mg = 10 mg of morphine
Less respiratory depression
,constipation
Well tolerated drug

51. Tramadol …
Uses –
short lasting pain, medium intensity
Diagnostic procedure
Chronic pain
Not used for severe pain

52. Fentanyl
100 times more potent than morphine
Highly lipid soluble
Enters brain rapidly
Peak effect within 5 min of IV injection
Weans off within 30 to 40 min
Uses:
Transdermal patch – chronic cancer pain

53. Fentanyl…
Duragesic TD patch – delivers 25µg /hr
Changed every 2 to 3 days
Patient controlled anlgesia of IV
fentanyl inusion
Also used in anaesthesia

54. OPIOID ANTAGONISTS
Naloxone, Naltrexone, Nalmefene
These have high affinity for μ receptor and low affinity for δ
and ĸ receptors.
Block all effects of opioids except psychotomimetic and
hallucinogenic effects which are mediated by sigma
receptors.
Naloxone---- has poor oral efficacy.
Fast and short duration of action.
First pass metabolism +
metabolised by glucuronide
conjugation .

55. Op . Antagonists
Naltrexone---5 times as potent as naloxone.
good oral absorption.
has rapid first pass metabolism.
long half life=10 hrs. can block heroin for 48 hrs.
is a good maintenance drug for treating
addicts. But opioid free interval of 10 days is
needed.
HIGH DOSES ARE HEPATOTOXIC.
Nalmefene--- Newest derivative of naltrexone.
available only for IV use. Fast onset of
action 1-2 mts & has long half life-10hrs.
Can be used in Tt of opiod overdose. Lacks
hepatotoxicity.

56. USES
1.Acute opiod overdose.
0.1-0.4 mg IV –resp dep and CNS dep.
0.4-0.8 mg IV , repeated whenever
needed.
2.Opioid depressed new born.
5-10 μg / kg and upto 25 μg if needed.
3.Tt of ADR with the use of IV or EPIDURAL opioid.---0.04
mg.
4.Oral non absorbable naloxone analog .
In the treatment of opioid induced ileus or
constipation.
5.Deaddiction
Long acting –NALTREXONE is used. (REDUCES
CRAVING IN ALCLHOL ADDICTS ALSO)

57. Thankyou…