1. Opioids analgesics and antagonistsBy
S.Bohlooli PhD

2. Narcotics
Those drugs which possess both an analgesic (pain relieving) and sedative properties. (Not Correct term)
Opioid
refer to drugs in a generic sense, natural or synthetic, with morphine- like actions

3. Classification of OPIOIDS
Natural
phenanthrene
morphine 10%
codeine 0.5%
thebaine 0.2%
semisynthetic
heroin
oxymorphone
Hydromorphone
synthetic
Phenylpiperidines (meperidine –fenatnyl)
Phenylheptylamines (methadone – levomethadyl )
morphinians (Levorphanol)
benzamorphans (pentazocine – dezocine)

4. Classification of OPIOIDS
Strong agonist:
Phenanthrenes: morphine, hydromorphone, oxymorphone, heroin
Phenylheptylamines: methadone, levomethadyl
Phenylpiperidines: meperidine, fentanyl, sufentanyl, alfentanyl, remifetanyl
Morphinans: levorphanol
Mild to moderate agonists:
Phenanthrenes: codeine, oxycodone, dihydrocodeine, hydrocodone
Phenylheptylamines: propexyphene
Phenylpiperidines: diphenoxylate, difenoxine, loperamide
Mixed receptor action:
Phenanthrenes: nalbuphine, bupronorphine
Morphinans: butorphanol
Benzomorphanes: pentazocine, dezocine
Miscellaneous:
tramadol
Opioids antagonists:
naloxone, naltrexone, nalmefene

5. Chemistry Morphine pentacyclic alkaloid (five ring structure)
phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6
modifications at those positions changes pharmacokinetics and potency of drug
nitrogen at 16 position (n16)
changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist)

6. Morphine related opioids

7. Mepridine related opioids

8. OPIOID receptors CNS distribution is not uniform 1. cerebral cortex
they are at areas concerned with pain
receptor locations beginning with highest concentration areas
1. cerebral cortex
2. amygdala
3. septum
4. thalamus
5. hypothalamus
6. midbrain
7. spinal cord

9. Receptor Stimulation mu Physical dependence Euphoria
Analgesia (supraspinal)
Respiratory depression

10. delta sigma kappa Sedation Analgesia (spinal) Miosis
analgesia (spinal & supraspinal)
release of growth hormone   
sigma
dysphoria (opposite of euphoria)
hallucination (both visual & auditory)
respiratory and vasomotor stimulation
mydriasis

11. Opioids’ mechanism of action

14. Endogenous Opioid Peptides
Three distinct families of peptides have been identified:
enkephalins
endorphins
dynorphins
the precursors are now designated as:
proenkephalin (also proenkephalin A)
proopiomelanocortin (POMC)
prodynorphin (also proenkephalin B)

15. Pharmacokinetics of morphine
absorption
readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route
distribution
Bound & free morphine accumulates in kidney, lung, liver, and spleen
CNS is primary site of action (analgesia/sedation)

16. Pharmacokinetics of morphine
metabolism/excretion
metabolic transformation in liver
conjugation with glucuronic acid
excreted by kidney
half life is 2.5 to 3 hours (does not persist in body tissue)
morphine -3 -glucuronide in main excretion product
lose 90% in first day
duration of 10 mg dose is 3 to 5 hours

17. Pharmacokinetics of morphine

18. Pharmacokinetics of morphine
Morphine administration
oral morphine not given due to erratic oral availability
significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day)
IV morphine acts promptly and its main effect is at the CNS

19. Pharmacodynamics of Morphine
CNS is primary site of action of morphine
analgesia
sedation
euphoria
mood change
mental cloudiness

20. Pharmacodynamics of Morphine
Morphine analgesia
**Changes our reaction and our perception of pain
severe cancer pain is tolerated more when person is given morphine
relieves all types of pain, but most effective against continuous dull aching pain
sharp, stabbing, shooting pain also relieved by morphine

21. Pharmacodynamics of Morphine
Morphine sedation - morphine causes sedation effect, but no loss of consciousness
Morphine euphoria
sense of well being
reason why morphine is abused

22. Effects of morphine on respiration
There is a primary and continuous depression of respiration related to dose
decrease rate
decrease volume
decrease tidal exchange

23. Pharmacodynamics of Morphine
mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression
CNS becomes less responsive to pCO2 thereby causing a build up of CO2
rhythm and responsiveness causes irregular breathing patterns; one will see periods of apnea

24. Pharmacodynamics of Morphine
nausea and vomiting – Stimulation of CTZ, in brain stem
stimulation by stretch receptors causes nausea and vomiting
has afferents from gut and ear
involved in motion sickness

25. Pharmacodynamics of Morphine
pupil size
morphine causes miosis (pinpoint pupils)
kappa receptor effect
pinpoint pupils still responsive to bright light
oculomotor nerve (CN3) is stimulated by kappa receptor site
if kappa receptor is blocked, mydriasis from sigma effect will result
atropine partially blocks effect indicating parasympathetic system involved

26. Pharmacodynamics of Morphine
Acute overdose
High doses (overdose situation) of morphine
excitatory and spinal reflexes
high doses of many OPIOIDs cause convulsions
due to stimulation at sigma receptor

27. Pharmacodynamics of Morphine
Cardiovascular effects
Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure
morphine causes the release of histamine and
suppression of central adrenergic tone and
suppression of reflex vasoconstriction

28. Pharmacodynamics of Morphine
Morphine effects on the gastrointestinal system increase in tone and decrease in mobility leads to constipation
decreased concentration of HCl secretion
increased tone in stomach, small intestine, and large intestine
delay of passage of food (gastric contents) so more reabsorption of water
**tolerance does not develop (i.e. same amount of effect each time) to this constipation effect

29. Pharmacodynamics of Morphine
Morphine effects on various smooth muscles
biliary tract
marked increase in the pressure in the biliary tract
10 fold increase over normal (normal is 20 mm H20 pressure)
increase due to contraction of Sphincter of Oddi
urinary bladder
tone of detrusor muscle increased
feel urinary urgency
have urinary retention due to increased muscle tone where sphincter closed off
bronchial muscle
bronchoconstriction can result
**contraindicated in asthmatics, particularly before surgery
uterus
relaxation of uterus can prolong labor

30. Pharmacodynamics of Morphine
Neuroendocrine Effects: inhibit the release of:
gonadotropin-releasing hormone (GnRH)
corticotropin-releasing factor (CRF),
luteinizing hormone (LH)
follicle-stimulating hormone (FSH)
ACTH, and - endorphin;
testosterone
cortisol.
Secretion of thyrotropin is relatively unaffected.

31. Tolerance to morphine nausea analgesia sedation respiratory depression
cardiovascular
euphoric
not to:
miosis
Constipation
Convulsive effect

32. Toxicity of morphine Acute overdose respiratory depression
pinpoint pupils (miosis)
coma
Treatment
1. establish adequate ventilation
2. give OPIOID antagonist (naloxone)

33. Toxicity of morphine Naloxone it has no agonist activity
it displaces morphine from all receptors, reverses all of the effects of morphine
its effects are immediate (3-5 min)
duration is minutes must be reinjected often

34. Therapeutic uses of morphine
relief of pain
terminal illness
preoperative medications
postoperative medications
acute pulmonary edema
constipating effect
cough
obstetrical analgesia ?

35. Drug interactions with Opioids
**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

36. Drug interactions with Opioids
OPIOID and phenothiazines
produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression)
this combination may also produce a greater incidence of orthostatic hypotension
OPIOID and tricyclics antidepressants
can produce increased hypotension
meperidine and MOA inhibitors
results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression
OPIOID and barbiturates
increased clearance
morphine and amphetamine
enhanced analgesic effect

37. Codeine
change in the methyl group on 3 position of morphine (substituted for the hydroxyl group)
one tenth the potency (analgesic properties) of morphine
absorbed readily from GI tract
the absorption is more regular than morphine and more predictable
given orally
metabolized like morphine through glucuronic acid
physical dependence is necessity of drug so you don't go through withdrawal
tolerance and physical dependence is protracted from morphine since potency of codeine is low
withdrawal from codeine is mild in relation to morphine
antitussive drug for cough

38. Heroin (diacetylmorphine)
at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups
it is anywhere from 3 to 4 times the analgesic potency of morphine
heroin is the most lipophilic of all the OPIOIDs
morphine is the least lipophilic of all the OPIOID
OPIOID withdrawal is NOT fatal

39. Heroin (diacetylmorphine)
When heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent
withdrawal symptoms of heroin similar to morphine, but more intense (rebound effect)
mydriasis
diarrhea
vasoconstriction
dysphoria
etc.

40. Hydromorphone Hydromorphone
have ketone at 6 hydroxyl position of morphine
also strong agonist
9 times more potent than morphine
more sedation than morphine so less euphoric feeling so not abused much
less constipation
does not produce miosis
tolerance and physical dependence is more intense than morphine because of its high potency
respiratory depression same as morphine

41. Fentanyl synthetic drug different structure than morphine
80 to 100 times more potent than morphine
rapidly acting drug
used as preoperative medication
short acting (30-45 min)
onset of action is 5 minutes
very high potency
highly abused

42. Meperidine produced in 1940's same CNS actions as morphine
wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine
same CNS actions as morphine
sedation, analgesia, respiratory depression
potency same as morphine
unlike morphine:
more respiratory depression
more bronchoconstriction activity
less constipation
no antitussive activity
**it causes mydriasis (not miosis)
toxic effects similar to atropine
drug absorbed orally
drug most abused by health care professionals due to its availability
withdrawal similar to morphine
Less sedative ( preferred to morphine in obstetrics)

43. Methadone
pharmacological activity similar to morphine, same potency as morphine
long duration of activity
absorbed well orally
16 to 20 hour duration of action
powerful pain reliever
used in maintenance program for narcotic treatment

44. Diphenoxylate (Lomotil)
can be OTC drug now
**therapeutic use is antidiarrhea drug
meperidine type drug
has very little analgesic properties at therapeutic dose
no antitussive effect
at high doses it has analgesic effects
causes respiratory depression and euphoria at high doses

45. Tramadol Tramadol (ULTRAM) is a synthetic codeine analog that is
a weak m-opioid receptor agonist.
Part of its analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin.
In the treatment of mild-to-moderate pain, tramadol is as effective as morphine or meperidine.
However, for the treatment of severe or chronic pain, tramadol is less effective.
Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression.

46. Tramadol
Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly.
Tramadol is supplied as a racemic mixture, which is more effective than either enantiomer alone.
The (+)-enantiomer binds to the m receptor and inhibits serotonin uptake.
The (-)-enantiomer inhibits norepinephrine uptake and stimulates a2 adrenergic receptors.
Analgesia begins within an hour of oral dosing and peaks within 2 to 3 hours. The duration of analgesia is about 6 hours. The maximum recommended daily dose is 400 mg.

47. Tramadol Common side effects of tramadol include:
nausea, vomiting, dizziness, dry mouth, sedation, and headache.
Respiratory depression appears to be less than with equianalgesic doses of morphine, and the degree of constipation is less than that seen after equivalent doses of codeine
Tramadol can cause seizures
However, the use of naloxone increases the risk of seizure.
Physical dependence on and abuse of tramadol have been reported.
Because of its inhibitory effect on serotonin uptake, tramadol should not be used in patients taking monoamine oxidase (MAO) inhibitors

48. Antagonism of Morphine
three drugs: naloxone, nalmefene and naltrexone (pure antagonist)

49. Naloxone no analgesic activity at all
competitive antagonist at mu, kappa, and sigma receptor
displaces morphine and other OPIOID from receptor site
reverses all actions of the OPIOID and does it rather quickly
it will precipitate withdrawal
person on heroin, then naloxone will precipitate withdrawal, but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes:
increased blood pressure
metabolized same as morphine through glucuronic acid and excreted through kidney

50. Naltrexone
same effect of naloxone except it is used orally so can't use it if for person with acute toxicity
long duration of activity
single dose block action of heroin effects for 24 hours
once stabilized, give patient naltrexone
patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement)
approved for use by the FDA
also used for treatment of alcoholism