toxicology of opiates

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Toxicology of Opiates
Dr. George Braitberg
Austin and Repatriation
Medical Centre
Heidelberg Victoria
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Opiates and Opioids
•
Opiate refers to a substance that originates
from opium, and is gained out of the latex of
the capsule of the opium plant, Papaver
somniferous
•
Opioid is the term used for substances with an
analogue effect to morphine. Opioids are
ligands on opioid-receptors and they possess
an intrinsic activity.
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Opiates and Opioids

Not all opiates bond to opioid-
receptors: not all opiates are
opioids
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Opiates
Opiates are the
approximately 20 natural

substances
from the opium-juice of
poppy seed capsule
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Opiates

Morphine

Codeine (3-ortho-methyl-
morphine)

Papaverine

Noscapine
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Opioids
Opioids are substances with
effects similar to morphine:
•
Natural opioids, opioid opiates
•
Semi -synthetic opioids
•
Synthetic opioids
•
Active metabolic products from
Heroin and Morphine
•

Endogenic, opioid peptides
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Opioids with morphine like action

Phenanthrenes: are opium alkaloids that have
an effect analogue to that of morphine. They
are opioid effective opiates.

Morphine (Morphium): raw opium contains 10-
17% morphine

Codeine: is used mainly as an antitussive.
Raw opium contains 1-4% codeine.
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Opioids with no morphine like
action

Thebaine:starting substance for synthesis of
naloxone, naltrexone and buprenorphine; has
only a very slight effect on it’s own.

Benzylisochinoline: are opium alkaloids which
have no effect analogue to that of morphine.

Papaverine: Phosphodiesterase inhibitor:
works mainly spasmolytic.

Noscapine: antitussive without addiction

potential. Raw opium contains 2-9% noscapine.

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Semisynthetic Opioids

Heroin (DAM, Diamorphine
3,6-O-Diacetylmorphine)

Hydromorphone

Nicomorphine

Dihydrocodeine

Hydrocodone (Dihydrocodeinone)

Buprenorphine
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Synthetic Opioids

Methadone

Dextromoramide

Tilidine

Pethidine


Pentazocine
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Endogenous opioids

Beta-endorphin is a peptide-opioid
substance found in the body
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Morphine - opioid and opiate

Morphine
–
Analgesic, natural opioid
–
Duration of effect:
4-5 hours; in retard form 6-12
hours
–
Elimination half-life:
3 hours (also in retard form)
–
Minimal deadly dose:
•
25 mg i.v./ 50 mg po.
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Codeine - opioid and opiate

Codeine

•
Antitussive
•
(Analgesic)
•
Duration of effect:
4-6 hours
•
Elimination half-life
3-4 hours

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Semisynthetic Opioids

Heroin

Hydromorphone
•
Analgesic
•
Duration of effect: 4-5 hours
•
Elimination half-life: 0.5 hours
•
Minimal deadly dose: 25 mg i.v.
•
from morphine through acetylation by acetic acid
anhydride
•

Analgesic
•
Duration of effect: 4-5 hours
•
Elimination half-life: 2.5 hours
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Semisynthetic Opioids

Nicomorphine

Dihydrocodeine

Analgesic

Duration of effect: 4-5 hours

Elimination half-life: 2-3 hours

Antitussive, (Analgesic)

Duration of effect: 4-5 hours

Elimination half-life: 4 hours
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Semisynthetic Opioids

Hydrocodone


Buprenorphine

antitussive

Duration of effect: 8-10 hours

Elimination half-life: 4 hours

Analgesic

Duration of analgetic effect: 6-8 hours

Duration of withdrawal prevention effect in
high doses up to 48 hours

Elimination half-life: 5 hours

Agonist/Antagonist; synthetised out of Thebain
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Synthetic Opioids

Methadone
•
Analgesic
•
Duration of analgetic effect: 8-48 hours
•
Duration of withdrawal prevention effect in
high doses: rarely less than 24 hours

•
Elimination half-life: 15-22 hours
•
Minimal deadly dose : 25 mg i.v.;
•
50 mg p.o.; (25 mg L-Methadone p.o)
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Synthetic Opioids

Dextromoramide

Tilidine

Pentazocine
•
Analgesic

•
Analgesic
–
Duration of effect: 4-6 hours
–
Elimination half-life: 3-5 hours
•
Analgesic
–
Duration of effect: 3 hours
–
Elimination half-life: 2-3 hours

–
Takes effect on κ -Receptoren agonistically
and on the µ -Receptoren antagonistially
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Pethidine
•
Analgesic
–
Duration of effect: 2-4 hours
–
Elimination half-life: 2.5-3 hours
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Heroin Addiction

Heroin is an opioid that is
biotransformed in the body ultimately to
morphine (Heroin -> 6-
monoacetylmorphine (6MAM) ->
morphine).

Heroin and morphine produce analgesia
by acting on the mu (µ)-type opioid
receptors in the brain. action of heroin
vs. morphine are clearly separable.
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Heroin Addiction
In mice (Swiss Webster, SW), heroin

acts on delta-type opioid receptors.
By using specific antagonists, the
action of heroin and morphine are
clearly separable.
These studies may provide the basis
for relating genetic factors to
differences in response between
heroin and morphine
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Heroin Addiction
The analgesic action of µ opioid
agonists such as morphine occurs in
the brain but activates neurons in the
spinal cord which release
norepinephrine and serotonin. When
heroin acts on delta receptors in the
brain a different set of neurons are
activated which release a different
neurotransmitter, GABA, to produce
analgesia.
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Opiate Withdrawal Syndrome

Eye watering, runny nose, yawning, sweating

Occurs within 8-12 hours of last heroin

Followed by restlessness, piloerection,

mydirasis, tremor, anorexia, bone and joint
pain, muscle cramps.

Symptoms peak at 48-72h

Symptoms disappear at 7-10 days

General malaise and craving lasts months

Rarely life threatening
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Naltrexone
Naltrexone is a long acting potent pure
narcotic antagonist. Clinical pharmacology
studies demonstrated that oral naltrexone
at 50, 100 and 150mg effectively blocks
the physiological and subjective effects of
parenterally administered heroin,
hydromorphone or morphine for 24, 48
and 72 hours respectively.
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Naltrexone
The lowest effective plasma
naltrexone concentration of 2ng/ml
provided an average of 86.5%
blockade of 25mg IV heroin effects.
In sustain released therapy for
opiate antagonist activity, plasma

level of naltrexone should be kept
above 2ng/ml