COMPOUNDS AFFECTING CENTRAL NERVOUS SYSTEM
Activity of CNS is a result of two-way exciting or inhibiting affection
of its single parts.
Compounds affecting CNS are known from prehistoric times – today
ones of the most utilized therapeutics
(misuse to increase the feeling of wellness – euphoria, ecstasy).
Therapeutics affecting mostly on specific receptors, which modulate
synaptic transmission.
COMPOUNDS AFFECTING CENTRAL NERVOUS SYSTEM
ANALGETICS
• Analgesics – anodynes
• Analgesics - antipyretics
• SEDATIVES
• PSYCHOPHARMACS
• Neuroleptics
• Psychostimulants
• Psychodysleptics
• ANTIPARKINSONICS
• CENTRAL ANALEPTICS
ANALGESIGS – ANODYNES (NARCOTIC ANALGESICS)
Opiate alkaloids, especially morphine and its semisynthetic
derivatives
• Huge analgesic effect
• Risk of euphoria and addiction
• Narcotic effect of higher doses
• Suppression of respiratory center and center for cough
(antitussic)
Analgesic effect show also polypeptides of animal origin
• Encephalins
• Endorphins
§§ OPIUM
§§ OPIUM CRUDUM (ČL 2002) – RAW OPIUM
Contains at least 10,0 % of morphine counted for drug
and at least 2,0 % of codeine dried at 100-105 0C
Raw opium is used only as material for galenic preparation. It is
not used independently!
Year overall production cca 8.000 tons
For medicinal purposes used approx. 400 tons/year.
§§ OPIUM
§§ OPII PULVIS NORMATUS (ČL 2009) –
OPIUM POWDERED STANDARDIZED
It is raw powdered opium dried at temperature no more than 70 0C
Yellow-green to dark brown colored powder
Containing:
• morphine (C17H19NO3): 9,8 % to 10,2 % drug dried 4 h
• codeine (C18H21NO3): at least 1,0 % at 100 to 105 0C
If necessary, the contain is modified by addition of suitable additive at raw
powdered opium.
Material for preparation of galenic preparations.
§§ OPIUM
Source: Papaver somniferum L.,
poppy (Papaveraceae)
• Annual cultivated plant
• Whole plant (especially fruit) is
rich in lactiferous ducts
• Lots of variants – differ in color
of flowers, seeds, shape and
size of fruits, in content of
alkaloids and in their spectrum
• UN – permission for opium
production: India, Turkey
(formerly also Yugoslavia,
Greece, Bulgaria, some parts of
USSR)
§§ OPIUM
OPIUM – air dried milky latex,
rapidly getting brown,
distributed in pieces of darkbrown
color with
characteristic odor
• Obtained by cutting of unripen
fruits 1-2 weeks after
falling of corolla leaves
• From one capsule can be
obtained 20-30 mg of opium
Dried opium is hard, fragile, on
the section grainy. At 37 0C
becomes plastic and sticky
MORPHINANE TYPE OF OPIUM ALKALOIDS
• morphine
• codeine
• thebaine
• 10-hydroxycodeine
• 6-methylcodeine
• neopine
• pseudomorphine
• salutaridine
O
N CH3
H
1
3
2
4
5
6
7
8
9
10
11
12
13
14
15
16
A
B
C D
BENZYLISOQUINOLINE TYPE OF OPIUM ALKALOIDS
N
• papaverine
• laudanine
• codamine
• laudanosine
• reticuline
• somnipherine
PHTALIDE-TETRAHYDROIQUINOLINE TYPE OF OPIUM
ALKALOIDS
O
N
CH3
O
• noscapine (= narcotine)
• narcotoline
• narceine
PROTOPINE TYPE OF OPIUM ALKALOIDS
N
H
O
• protopine
• cryptopine
• α-allocryptopine
TETRAHYDROISOQUINOLINE TYPE OF OPIUM
ALKALOIDS
NH
• hydrocotarnine
RHOEADINE TYPE OF OPIUM ALKALOIDS
N
O
• rhoeadine
• papaverrubine
SPECIFIC MECONIC ACID
O
O
OH
COOHHOOC
OPIUM
CONTAIN COMPOUNDS
• more than 40 alkaloids, total content oscillates from 15 to
25 %
• alkaloids in form of meconates, fumarates, lactates and
sulphates
• meconic acid 3 to 8 %
• mucilages, pectins, sugars
• resins, proteins
• cautchuc
• mineral compounds
IMPORTANT OPIUM ALKALOIDS
N CH3
OH
R
H
H
HO O
R
N
OH H
CH3
O
N CH3
MeO
MeO
N
MeO
MeO
OMe
OMe
O
N
O
O
CH3
OMe
OMe
MeO
O
1
3
2
4
5
6
7
8
9
10
11
12
13 14
15
16
A
B
C
D
5
6
7
8
9
14
15
16
3
=
morphine R=OH
codeine R=OCH3
thebaine
papaverine noscapine
PERCENTUAL CONTENT OF IMPORTANT ALKALOIDS IN
OPIUM %
MORPHINE 3 to 23 in average 13
CODEINE 0,2 3 1,3
THEBAINE 0,2 1,3 0,5
PAPAVERINE 0,5 1,3 1
NOSCAPINE 2 10 5
OTHER SOURCES OF OPIUM ALKALOIDS
Matured dried fruits without seeds (empty poppy heads)
1823 – pharmacist Tiloy from Dijon – poppy is a source of morphine
1934 – Hungarian pharmacist János Kabay applied a patent of industrial
procedure
Drug is formed from matured dried capsules of Papaver somniferum deseeded
(Papaveris fructus maturi sine semine), or more often poppy
hay (Papaveris stramentum), formed from capsules without seeds
and maximal 10 cm long residue of stem.
Capsules contain alkaloids, with spectrum similar to opium, prevalent is
morphine. Its contain fluctuates between 0,1 to 1 %. Present time:
isolation from poppy hay represents approx. ¼ of world morphine
consumption.
PAPAVERIS FRUCTUS MATURI SINE SEMINE
OPIUM ALKALOIDS - UTILIZATION
Morphine was the first described alkaloid, discovered by pharmacist
Sertürner in 1806. Absolute structure resolved after 164 years.
It is prepared via isolation from opium or poppy hay only.
It is used as strong analgesic – anodyne / high risk of addiction
• to suppress pain of malignant tumors, post-surgery, after serious injury,
heart attack and pulmonary embolism
• sometimes surgery pre-medication.
• In combination with atropine (spasmolytics) is used for suppression of
pain in kidney and gallbladder colics.
Morphine is approx. from 90 % used for preparation of semi synthetic
derivatives
• methylmorphine (CODEINE), ethylmorphine (DIOLAN),
morpholinoethylmorphine = folcodine (NEOCODIN)
• antagonists of morphine, for example NALORFINE.
Heroine – diacetylmorphine – strong analgesic, rapidly penetrates into CNS,
where is hydrolyzed to morphine. In therapy it is not used, triggers
strong addiction. It is misused as narcotic substance.
OPIUM ALKALOIDS - UTILIZATION
Codeine – central affecting antitusic, lowers bronchial secretion. A part of
analgesic mixtures. Natural occurrence in opium does not cover the
requirement, therefore it is prepared from morphine via semisynthetic route
(less from thebaine). In organism is from 10-15 % demethylated to
morphine and can trigger the addiction when used repeatedly.
Thebaine is starting reagent for preparation of CODEINE, hydrocodon
(VICODIN), non-addictive analgesic butorphanol, addictive oxycodon
(DINARKON, OXYCONTIN), which is in mixture with scopolamine and
ephedrine part of BENARCOS injections – premedication before anesthesia.
From thebaine is derived allyloxycodon = NALOXON, antagonist of
morphine
Papaverine belongs to spasmolytics, lowers tonus of smooth muscles by direct
action on cells. Opium isolations do not cover utilization, therefore it is
prepared via synthesis. Spasmolytic effect of papaverine is predominantly
demonstrated on gastrointestinal tract, it lowers tonus of smooth muscles of
cardiovascular system and respiratory and urinary tract.
Noscapine (formerly narcotine) – long time waste product of opium processing.
Nowadays central antitusic with parallel papaverine relaxation effect. It does
not trigger addiction and therefore is used instead of codeine in antitusics
and analgesics.
OPIUM ALKALOIDS IN PHARMACOPEA
§§ OPIUM CRUDUM
§§ OPII PULVIS NORMATUS
§§ MORPHINI HYDROCHLORIDUM TRIHYDRICUM
§§ MORPHINI SULFAS PENTAHYDRICUS
§§† CODEINI PHOSPHAS HEMIHYDRICUS
§§† CODEINI PHOSPHAS SESQUIHYDRICUS
§§† CODEINUM MONOHYDRICUM
† PAPAVERINI HYDROCHLORIDUM
NOSCAPINUM
NOSCAPINI HYDROCHLORIDUM MONOHYDRICUM
Law n. 167/1998 Sb., about addictive
compounds and about changes of some other
corresponding laws
Narcotics and psychotropic substances are according to this law
compounds listed in supplement n. 1 to 7 of this law
Law 167/1998 Sb. Changes also the handling with precursors (supplement
n. 9) and adjuvants (supplement 10 or 11)
Table I: Narcotic and psychotropic substances
Supplement n. 1 – narcotics listed in pharmacopeia 1 (selection) „§§“
• Cocaini hydrochloridum
• Morphini hydrochloridum trihydricum
• Morphini sulfas pentahydricus
• Opium crudum
Supplement n. 2 - narcotics listed in pharmacopeia 2 (selection) „§§†“
• Codeinum in all forms (phosphas, hydrochloridum, monohydricum)
• Ethylmorphini hydrochloridum dihydricum
Law n. 167/1998 Sb., about addictive
compounds and about changes of some other
corresponding laws
Supplement n. 9 – Precursors from pharmacopeia listed in table I (selection) „(§)†“ or „(§)††“
• Ephedrini hydrochloridum and other forms
• Ergometrini maleas
• Ergotamini tartras
• Pseudoephedrini hydrochloridum
Table II: Venena (poisons)
Contains therapeutics strongly active (especially danger poisons), assigned in pharmacopeia
with „††“ (selection)
Atropini sulfas monohydricus
Digitoxinum
Table III: Separanda
Contains strongly active substances and corrosives assigned in pharmacopeia with „†“
(selection)
Belladonnae folium
Papaverini hydrochloridum
ANALGESICS OF PEPTIDE CHARACTER
ENDOGENOUS OPIATES / OPIOID PEPTIDS
1973 – S. Snyder and C. Pert – isolation of opioid receptor
1975 – H. Kosterlitz aj. Hughes – isolation of first encephalin
Propiomelanocortine – β-lipotropic hormon – fragmentation –
High-molecular endorphins, low-molecular encephalins
β-endorphine (aminoacids 61-91); 48× more effective than
morphine
α-endorphin (61-76)
γ-endorphin (61-77)
Met-encephalin Tyr-Gly-Gly-Phe-Met (61-65)
Leu-encephalin Tyr-Gly-Gly-Phe-Leu
ANALGESICS OF PEPTIDE CHARACTER
ENDOGENOUS OPIATES / OPIOID PEPTIDES
Rtg structural analysis
N
H
Gly
O
O
NH2
OH
Phe Met
Leu
N
O
OH
OH
H
H
CH3
morphine
ANALGESICS OF PEPTIDE CHARACTER
ENDOGENOUS OPIATES / OPIOID PEPTIDES
KYOTORPHIN – Tyr-Arg – acting indirectly, increases secretion of opioid
peptides
CASOMORPHINS (EXORPHINS) – tetra-, penta-, hexa- and heptapeptides
from milk; fragments of β-kaseine and α-lactalbumine
ENDORPHINS
• in brain, hypophysis, circulate in blood, excreted in urine
• trigger morphine effects – analgesia, euphoria, respiratory suppression,
spasms of smooth muscles
• strong short-termed effect, strongly triggering euphoria
• produce psychic and somatic addiction
• Similarity of effect to neuroleptics – γ-endorphin „specific
antischizophrenic neuroleptic
ANALGESICS – ANTIPYRETICS
CHARACTERISTICS:
• effect mild analgesic
• effect antipyretic
• effect antiphlogistic
Derivatives of salicylic acid
Quinine
Preparation from Aconitum napellus
Snake products
Potentiating of effect – caffeine in dosage up to 50 mg
DERIVATIVES OF SALICYLIC ACID – HISTORY
• 400 BC Hippokrates prescribed leaves and bark of willow to
combat fever and pain
• 1763 Journal of Royal Society in London – E. Stone –
experiments confirmed hundred years of folk observation
• 1828 Johann Büchner (Germany) isolated salicin from willow
bark
• 1853 Ch.F. Gerhardt (France) synthesized raw acetylsalicylic
acid (ASA), effects were not studied
• 1897 Felix Hoffmann (Germany) prepared pure ASA
• 1899 Bayer trades ASA as ASPIRIN
• 1950 L. Craven (USA) – ASA „dilutes blood“, recommends
preventively against heart attack
• 1971 Joh R. Vane (GB) – ASA inhibits COX (enzyme limiting
production of prostaglandins – mechanism of antiphlogistic
effect
SALICIS CORTEX – WILLOW BARK (ČL 2009)
Source: Salix species - willow
(Salicaceae); S. purpurea, S.
fragilis, S. daphnoides
Dioecious shrubs or trees, in
mild and subarctic areas
Drug is formed by dried bark of
young branches or its
fragments, harvested in the
spring. It possesses strong
bitter taste.
SALICIS CORTEX – WILLOW BARK
CONTENT COMPOUNDS
• At least 1,5 % of salicylic acid
derivatives, counted as salicin
• Catechine tannins
• Hydroxyderivatives of cinnamic
acid
• Flavonoids (isosalipurposide,
isoquercitrine, naringenine)
SALICIS CORTEX – CONTENT COMPOUNDS
CH2
OH
O Glc
CH2
OH
OH
Glc
OH
COOH
CH2
O
O C6H10O5
OH
OC
CH2OH
O Glc
OH
O
OH
OH
OOGlc
CH2OH
O C6
H10
O5
OH
OC
R
OH
C
O
R
R
+hydrolysis oxid.
salicin saligenin salicylic acid
salireposid
isosalipurposid
salicortin
= salicylpopulin
= H = populin
=
SALICIS CORTEX – WILLOW BARK
INTERNAL USAGE
Maceration (1,5 g/200 ml of water)
• diseases from cold
• Inflammatory diseases
• Rheumatic disorders
Problems of GIT triggered by tannins
EXTERNALLY (9 g/200 ml of water)
• astringent
Individual intoleration on salicylates (urtica, spasms of bronchi)
SPIRAEAE FLOS – FLOWER OF MEADOWSWEET
Filipendula ulmaria L., Spiraea
ulmaria L. – meadowsweet
(Rosaceae)
• perennial plant of moist places
• harvest in VI – VII
Drug – dried white-yellow flowers
• Smells like oranges
• Bitter acrid taste
Usage
• antiphlogistic, diuretic, folk
medicine
SPIRAEAE FLOS – FLOWER OF MEADOWSWEET
OH
COOCH3
OH
CHO
O
O
OH
OH
OH
OH
O-Glc
CHO
O
O
methylester of
salicylic acid
salicylaldehyde piperonal
(= heliotropin)
spiraeosid
quercetin - 4'-O-glucosid
DERIVATIVES OF SALICYLIC ACID
Gaultheria procumbens –
wintergreen
Monotropa hypopitis – Dutchmen's
pipe
Betula lenta – sweet birch
O - Glc - Xyl
COOMe
OH
COOMe
monotropitosid
= gaultherin
primverose
H+
+ Glc + Xyl
methylester of salicylic acid
DERIVATIVES OF SALICYLIC ACID
OH
COOMe
O - Glc - Ara
COOMe
O - Glc - Xyl
COOMe
MeO
O - Glc - Xyl
COOMe
OMe
methylester of salicylic acid
Senegae radix
vicianose
violutosid
Violae tricoloris herba
primverose primverose
primulaverosid primverosid
Primulae radix
QUININE
Sources: species of Cinchona;
C. Succirubra
C. calissaya (Rubiaceae)
Drug: Chinae cortex – cinchona
tree bark, contains at least
6,5 % of alkaloids quinine
type (quinine, quinidine)
QUININI HYDROCHLORIDUM DIHYDRICUM (ČL 2005)
QUININI SULFAS DIHYDRICUS (ČL 2005)
Prepared only by isolation from cinchona tree bark
Effect analgesic
• Effect antipyretic
• Effect antiinflammatory
• Prolongs and stimulates
effect of other antipyretics
• In combination (Harburn,
Harbureta) for acute
diseases of upper respiratory
trackt of viral etiology with
fever
• Antimalaric
N
H
OH
H
H
N
OH3C -
1 2
3
4
5
6
7
8
9
1'
2'
3'
4'5'
6'
7'
8'
8S, 9R
ACONITINE
Source: Aconitum napellus L. –
Aconite Ranunculaceae
Perennial plant, turnip-shaped
tubers.
Drug: tuber of dark-brown color,
for pharm. Purposes is cultivated,
harvest in autumn, when is
content of aconitine the highest.
Content compounds: 0,6 – 2 %
diterpene ester alkaloids
(aconitine, napeline), starch,
tannins
ACONITINE
Usage: Narrow therapeutic width,
The most potent alkaloid poison,
LD 2-5 mg!!
Externally
• Inflammation of n. trigeminus
• Chronic joint inflammations
• arthritis uratica
Internally
• anestetic dolorosum (obsolete)
Products of hydrolysis less active
benzoylaconine 1/400, aconine
1/4000
O
CH3
N
OH
O
OH
OMe
OMe
OH
OMe
O COCH3
C
O
1
3 5
6
8
13
14
15
16
17
18
19
aconitine
SNAKE POISONS
Mixtures of compounds with different composition. Common
characteristic – presence of hyaluronidase (fast penetration and
absorption of poison into tissues)
Naja tripudians – cobra (COBRATOXIN)
Sterile lyophilized poison – ophiotoxin. Partially hydrolyses lecithine
to lysocithine, which suppresses pain without disruption of neural
transmission.
Strictly subcutaneous injection (for tumores).
Vipera ammodytes – horned viper (VIPERALGIN)
Sterile lyophilized toxin, injections, component of external remedy
with camphora and essential oils – analgesic, hyperemic for
symptomatic treatment of rheumatism and neuralgias.
ANTIMIGRAINICS
Migraine – seizures of reversible pain mostly often one half of head
(hemicrania), accompanied by vertigo, vision disorders, nausea
Caused – increased release of neuromediator serotonin
Antimigrainics – compounds inhibiting serotonin
Ergotamini tartras (ČL 2005) (Secale cornutum)
In combination with caffeine
In prodromal state benefiting effect of caffeine vasodilatation