A vast range of semi-synthetic or totally synthetic morphine like derivatives. These are collectively referred to as opioids. Many have similar narcotic and pain relieving properties as morphine. Other possess the cough relieving properties or both activities. Some semi-synthetic derivatives of morphine More than 90% of the morphine extracted from opium or poppy straw is currently processed to give other derivatives 1- Codeine 2- Dihydrocodeine 3-Pholcodine 4- Hydromorphone 5-nalorphine 6-apomorphine 7- Diamorphine (Heroin) Synthetic drugs modelled on morphine 1-Alfentanil 2-Fentanyl 3- levomethorphan 4- dextromethorphan 5- Tramadol 6- Pentazocine 7- Dextropropoxyphene 8- Methadone

1. Opium Alkaloids
By
Dr. Mostafa Mahmoud Hegazy ( PH.D.)

2. Opium Alkaloids
 Opium is the air-dried milky exudate, or latex, obtained by incising the unripe
capsules of the opium poppy Papaver somniferum (Papaveraceae).
 For opium production, the ripening capsules, which are just changing color from blue-
green to yellow, are carefully incised with a knife to open the latex tubes.
 Although the ripe poppy capsule can contain up to 0.5% total alkaloids, opium represents
a much concentrated form and up to 25% of its mass is composed of alkaloids ( more than
40 alkaloids were identified).

3. Importance: source economically valuable chemicals as
 1- treating medicines as a- pain killer analgesics ex. Morphine.
 b- cough suppressants ex. codeine and Noscapine.
 c- smooth muscle relaxant ex. Papaverine
 2- leading compounds for modelling of semi-synthetic and totally synthetic
 a-analgesics
 b- cough suppressants
 3- abused drugs.
Historical overview
 1- Poppy in ancient Egypt.
 2- Opium wars.
 3- Poppy in Art.

4. 1- Opium in ancient Egypt : The plant was known in Europe at least 4000 years
ago, as evidenced by fossil remains of poppy seed cake and poppy pods found
in the Swiss lake dwellings of the Neolithic Age. Opium was probably consumed
by the ancient Egyptians and was known to the Greeks as well.

5.  2- Opium wars:
The continuing illegal export of opium to China by the British triggered a
two-phase war, aptly called the Opium Wars, between 1839 and 1842.
They concluded with China being forced to accept opium and endure a
growing addiction rate.

6. 3- Poppy in Art.
Poppy Flowers (also known as Vase And Flowers ) is a painting by Vincent
van Gogh with an estimated value of $50 million to $55 million; it was
stolen from Cairo's Mohamed Mahmoud Khalil Museum in August 2010
is yet to be found.

7. Opium addiction:
 def. physical dependence.

8. Opium addiction:
 drug abuse testing using Multi-panel drugs of abuse urine test:
test based on ENZYME MULTIPLIED IMMUNOASSAY TECHNIQUE (EMIT)

10. ENZYME MULTIPLIED IMMUNOASSAY TECHNIQUE
(EMIT)

11. ■ Opium alkaloids usually occur naturally combined with
a specific acid: (Meconic acid).
■ Meconic acid present only in Opium with morphine.
■ Meconic acid gives a deep purplish red-colored complex
with FeCl3
O
OH
COOHHOOC
O

12. Classification of OpiumAlkaloids
1) Benz ylisoquinoline Alk a loids
Benzylisoquinoline
N
Narcotine
e.g. Papaverine.
2) Phenyl et hyl a mine Al ka l oids
e.g. Narceine.
3) Phena nt hr ene Al ka l oids
4) Pr ot opine
Phenylethylamine
H2N
e.g. Morphine Codeine Thebaine
Phenanthrene
e.g. Cryptopine

13. OpiumAlkaloid of the Benzylisoquinoline gruop
◘ Papaverine and Narcotine are very different from the morphine, codeine, thebaine group of
alkaloids (Morphinans).
◘ Papaverine and Narcotine (Noscapine) are very weak bases, their solutions are neutral to litmus
paper.
◘ The free bases can be extracted from their acid solution [unstable salts] with CHCl3.
◘ They are derived biosynthetically from Tyrosine amino acid.
N
O
O
H
OCH3
OCH3
O
H
CH3
O
OCH3
Narcotine (Noscapine)
N
OCH3
OCH3
H3CO
H3CO
Papaverine

14. NarcotinePapaverine
Tetrahydro
Benzylisoquinoline
Fully aromatic
Benzylisoquinoline
Optically active.Optically inactive
Soluble in hot alkali
solution and CHCl3.
Soluble in alcohol,
CHCl3, insoluble in
water.
Contain lactone ring that
is opened upon
addition of alkali.
No lactone ring.
Papaverine and Narcotine
Does not possess narcotic effect.

15. Isolation of the major opium alkaloids Principle:
1- Morphine (phenolic), codeine (water soluble) and narceine (-COOH) are soluble in
NaOH.
2- In presence of NaOH, only, codeine can be extracted by CHCl3.
3- Narceine dissolved in NH4OH (-COOH) leaving morphine insoluble in NH4OH.
4- Papaverine, narcotine and thebaine are insoluble in NaOH.
5- Thebaine acetate is water soluble salt while papverine and narcotine acetate
salts are insoluble in water.
6- Narcotine oxalate salt is water soluble while papaverine oxalate salt is
insoluble in water.

16. Opium - Addition of CaCl2
- Maceration with H2O for 24 hours
- Filtration
Residue
Calcium meconate,
lactate & resinate
Filtrate (Alkaloidal HCl)
- Alkalinization with NaOH
- Filtration
Morphine, Codeine & Narceine
Precipitate
Papaverine, narcotine & Thebaine
- Extraction with CHCl3 - Solubilization in dilute alcohol
- Acidification with acetic acid
- Addition of boiling H2O
- Filtration
Filtrate Precipitate
- Concentration
- Alkalinization
with NH4OH
- Addition of boiling H2O +
0.3% oxalic acid
- Filtration
Thebaine Precipitate Filtrate
Papaverine Narcotine
Codeine
- Acidification
- Alkalinization with NH4OH
Filtrate
Narceine Morphine
Morphine (as phenate)
& Narceine (as Na salt)
Aqueous Layer
Precipitate
Chloroform Layer
Isolation of
Opium Alkaloids
Filtrate

17. Tests for identification:
Papaverine
1- Warren’s test
Papaverine + crystal of KMnO4 + Marqui’s reagent (HCHO/ H2SO4)  Green
color  Blue
2- Papaverine + Conc H2SO4  Violet color on heating
Narcotine
1- Alkaloid + conc. H2SO4  violet. (This test is –ve with Morphine)
2- Alkaloid + sucrose + conc. H2SO4  green-yellow  blue- violet

18. Uses of Papaverine
▀ It has little or no analgesic or hypnotic properties put possesses
spasmolytic and vasodilator activity. (antispasmodic for GIT spasms and in
bronchial asthma).
▀ Effective for treatment of male impotence, being administered by direct
injection to achieve erection of the penis.
Uses of Narcotine (Noscapine)
◘ Anti-tussive and cough suppressant activity comparable to that of codeine,
but no analgesic or narcotic action.
◘ Its original name ‘narcotine’ was changed to reflect this lack of narcotic
action.

19. Opium Alkaloids of the
Phenylethylamine group
Narceine
It is not used
medicinally
NMe2
O
MeO
OMe
COOH
O
O
OMe
Narceine

20. Properties
◘ Narceine occurs as white silky crystals.
◘ Very hygroscopic, Optically inactive.
◘ It is slightly soluble in water, soluble in
ethanol, insoluble in CHCl3 and ether.
◘ It is a weak monoacidic tertiary base. Can be
extracted from aqueous solution of its salts
with CHCl3.
◘ Contain C=O and COOH groups, thus it forms:
Oxime Salt with NaHCO3 Ester with alcohol

21. Tests for identification
2) Narceine + Wagner`s solution
1) Narceine
dil. H2SO4
Violet color long heating
Blue-violet
2) Narceine + Iodine solution Blue color
3) Narceine + chlorine water + ammonia Blood red color
Color tests
Crystal tests
1) Narceine + lead iodide solution Thread-like needle crystals
Needle crystals

22. Opium Alkaloid of the Phenanthrene Group
O
HO
HO
N
CH3
O
H3CO
HO
N
CH3
O
H3CO
H3CO
N
CH3
H H H
H H
Morphine Codeine Thebaine
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16
* Thebaine is Tetrahydro-Phenanthrene type differs
structurally from morphine/codeine mainly by its
possession of a conjugated diene ring system.
* Morphine and Codeine are Hexahydro-Phenanthrene
type

23. ThebaineCodeineMorphine
Insoluble in H2O, but soluble
ether, benzene, and CHCl3
Soluble in H2O, ether, benzene,
ethanol and CHCl3
Insoluble in H2O, ether, benzene, ethanol and
CHCl3
No phenolic or alcoholic OH
groups.
It contains one alcoholic OH group
at C-6
It contains two OH groups, one is phenolic at
C-3 and the other is alcoholic at C-6
It dissolve in NH4OH due to
formation of Codeine NH4OH
complex.
It can be precipitated from its acid solutions
by addition of NH4Cl, or NH4OH
Has basic N-CH3 groupHas basic N-CH3 group and an acidic OH
group
Dissolve in both acids and bases
(Amphoteric alkaoid)
It prepared from Morphine by
methylation of the phenolic OH
group
Methylation of the phenolic OH group 
Codeine
is the 3-O-methyl ether of
morphine.
Heating in a sealed tube with conc HCl 
Apomorphine (Dehydration)
Acetylation of both OH groups 
Diacetylmorphine (Heroin)

24. 5. Salicylate salt is H2O
soluble.
Morphine Thebaine
4- Salicylate salt is soluble
in water.
5) Salicylate salt is
H2O insoluble.
Codeine
1- Phenolic.
2- Solid, crystalline.
3- Insoluble in ether,
benzene, CHCl3,water
and ammonia.
1. Non-phenolic
2. Solid crystalline.
3. Soluble in ether, benzene,
CHCl3 and water.
4. Soluble in ammonia as
Complex.
1) Non-phenolic.
2) Solid crystalline.
3) Soluble in
benzene, CHCl3.
4) Insoluble in ammonia.

25. O
HO
HO
N
CH3
H
H
Morphine
Py
O
O
O
N
CH3
H
H
Heroin
O
H3C
O
H3C
HO
Apomorphine
N
H
CH3
H
Ac2O
HO

26. Chemical Tests:
A) Tests due to Phenolic properties
1) Morphine
FeCl3
Blue color
2) Nitrous acid test:
Morphine solution in HCl + NaNO2 + NaOH Red color
B) Tests due to Reducing properties
1) Iodic acid test
Morphine solution in H2SO4 reduces iodic acid or KIO3 (K-iodate) to Iodine,
upon shaking with CHCl3 Violet color in the CHCl3 layer
2) Morphine + Sucrose + Conc. H2SO4 Purple red color
Morphine

27. Codeine
Codeine + Conc. H2SO4 + FeCl3
on Water bath
Blue color
HNO3
Red color
Thebaine
Thebaine + Conc. H2SO4 Blood red color Orange color

28. Uses of crude opium :
1- as an analgesic.
2- sleep-inducer (narcotic).
‫النوم‬ ‫ابو‬ ‫بإسم‬ ‫النبات‬ ‫تسمية‬ ‫تمت‬ ‫هنا‬ ‫ومن‬
Morphine named after Morpheus the god of dreams (Greek Mythology).
3- for the treatment of coughs.

29. Morphine is a powerful analgesic and narcotic,
* It also induces a state of euphoria and mental detachment, together with nausea,
vomiting, constipation, tolerance, and addiction.
Codeine
* Its action is dependent on partial demethylation in the liver to produce morphine, so
it produces morphine like analgesic effects.
• Codeine is always taken orally and is a component of many compound analgesic
preparations.
* Codeine is a relatively safe non-addictive medium analgesic.
* Codeine also has valuable anti-tussive action, helping to relieve and prevent
coughing.
Thebaine
* It is almost devoid of analgesic activity.
* Its main value is as substrate for the semi-synthesis of other drugs

30. Structure Activity Relationship
of Morphine

31. Analgesic activity of morphine
can Increase by:
1) Catalytic Reduction, methylation, oxidation or even
elimination of the C-6-OH (alcoholic OH group).
2) Introduction of an OH group at C-14.
3) Introduction of a CH3 group at C-5
4) Replacement of N-CH3 group by other groups e.g.
phenylethyl "N-CH2-CH2-ph" group.
5) Acetylation  diacetylmorphine (heroin), that is
more potent than morphine.
O
HO
HO
N
CH3
HH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16

32. Analgesic activity of
morphine can decrease by:
1) Methylation of the phenolic OH group e.g.
codeine.
2) Opening of the N-containing ring.
3) Opening of 4,5-oxygen bridge.
4) Dehydration by heating with HCl 
apomorphine.
5) Demethylation, N-CH3  N-H (Nor-morphine).
6) Quaternization of the tertiary nitrogen.
O
HO
HO
N
CH3
HH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 16

33. opioid drugs as leading drugs for other
semisynthetic and totally synthetic analogues
 A vast range of semi-synthetic or totally synthetic morphine like derivatives. These are collectively referred to
as opioids.
 Many have similar narcotic and pain relieving properties as morphine. Other possess the cough relieving
properties or both activities.
 Some semi-synthetic derivatives of morphine
 More than 90% of the morphine extracted from opium or poppy straw is currently processed to give other
derivatives
 1- Codeine 2- Dihydrocodeine 3-Pholcodine 4- Hydromorphone 5-nalorphine
 6-apomorphine 7- Diamorphine (Heroin)
 Synthetic drugs modelled on morphine
 1-Alfentanil 2-Fentanyl 3- levomethorphan 4- dextromethorphan
 5- Tramadol 6- Pentazocine 7- Dextropropoxyphene 8- Methadone

34. Mixed agonist-antagonists, such as pentazocine, nalorphine, levallorphan, buprenorphine,
nalbuphine and butorphanol, have characteristics which enable them to displace a pure agonist at
the receptor site (antagonistic effect). When administered by themselves, they induce opioid related
effects such as analgesia and respiratory depression (agonistic effect)! The latter is mediated by their
intrinsic activity.

35. Some semi-synthetic derivatives of morphine
Codeine: Mono-O-methylation occurring at the acidic phenolic hydroxyl (C-3).
Dihydrocodeine: a reduced form of Codeine.
Antitussive and analgesic, codeine or dihydrocodeine are often used as combinations
with paracetamol.
Codeine: Egyptian and Global markets Dihydrocodeine: Global market
Pholcodine: Effective and reliable antitussive. Egyptian and Global markets.
Hydromorphone: Sever pain associated with cancer and also has antitussive activity.
Egyptian and Global markets.
Nalorphine: mixed agonist-antagonist

37. Apomorphine
 Apomorphine has no analgesic activity.
 Apomorphine is a powerful emetic, and can be injected for emergency
treatment of poisoning
( mostly veterinary).
 apomorphine, which is structurally related to dopamine and acts as a
potent dopamine agonist(dopamine D1- and D2-receptor agonist), but
must be given parenterally and with an antiemetic.
 It is also used in the differential diagnosis and management of
parkinsonism.
 It has also been used in the management of erectile dysfunction.
 Global market

38. From cough to addiction
Diamorphine (Heroin)
 Heroin was synthesized originally as a cough suppressant.
 It is merely the diacetate of morphine, and is a highly addictive analgesic and
hypnotic.
 The increased lipophilic characters result in better transport (passing BBB) and
absorption, though the active agent is probably the 6-acetate, the 3-acetate group
being hydrolysed by esterases in the brain.

39. Synthetic drugs modelled on morphine
Alfentanil : is a short-acting opioid analgesic related to fentanyl.
uses
1- surgical procedures as an analgesic and adjunct to general anaesthetics
2-respiratory depressant in the management of mechanically ventilated patients
under intensive care.
Cause Dependence and given intravenously. present in Global market.
Fentanyl : It is 50 times more potent than morphine due to more lipid soluble than
morphine ( in micrograms).
Uses: as Alfentanil
Cause Dependence and administrated by intravenous and transdermal routs .
present in Egyptian and Global market.

41. Synthetic drugs modelled on morphine
Levomethorphan:
Narcotic analgesic 5-10 times potent as morphine and antitussive.
Limit test in dextromethorphan preparation not more than 0.1%.
In fact, it is so powerful that it is no longer commercially available just like its cousin,
Heroine.
Dextromethorphan:
Antitussive with no analgesic activity.
used for the relief of non-productive cough; it has a central action on the cough
centre in the medulla.
Egyptian and Global markets

42. Synthetic drugs modelled on morphine
Tramadol: A drug claimed to produce analgesia by two mechanisms, an opioid
mechanisms and also by enhancement of serotoninergic and adrenergic pathways. It
produces few typical opioid side effects. Egyptian and Global markets
Pentazocine: Both agonist and antagonist properties, and although it is a good
analgesic. Global market
Dextropropoxyphene: Low analgesic activity, about half that of codeine, and finds
application as a combination with aspirin or paracetamol. Global market
Methadone: Treatment and rehabilitation of heroin addicts. Global market

43. Some semi-synthetic derivatives of Thebaine
 Thebaine, for many years regarded as an unwanted by-product
 1- no medicinal use.
 2- even conversion of thebaine into morphine and heroin is much more difficult and
low yielding.
 Thebiane, in now the raw material for semi-synthetic several useful drugs which may
help in the battle to eliminate illicit morphine production and subsequent conversion
into heroin.

44. Some semi-synthetic derivatives of Thebaine
Naloxone: Potent antagonist at all receptors for all opioids that possess agonist or mixed
agonist antagonist activity and is used to treat opiate poisoning (known or suspected opioid
overdosage) to reverse central depression (Respiratory depression), including that in children born to
heroin addict mothers. Available in Egyptian and Global markets
Naltrexone: similar to naloxone however, it is more potent than naloxone and has a longer
duration of action.
Naltrexone is used as the hydrochloride as an aid to maintaining abstinence after opioid withdrawal in
detoxified, formerly opioid-dependent patients. Naltrexone treatment should not be started until the
patient has been detoxified and abstinent from opioids for at least 7 to 10 days because of the risk of
acute withdrawal; abstinence should be verified by analysis of the patient’s urine. A naloxone
challenge test should then be performed to confirm the absence of opioid dependence. Available in
Egyptian and Global markets

45. Some semi-synthetic derivatives of Thebaine
Nalbuphine: Mixed agonist antagonist.
Potent analgesic. Available in Egyptian and Global markets
Oxycodone: Potent analgesic. Available in Global markets
Etorphine: 5000 times more potent than morphine.
In veterinary practice to sedate large animals (elephants, rhinos) as tranquillizer darts

46. Remember
The cause of death due to opioids overdose is
primarily from respiratory depression