CARDIOVASCULAR DISEASES
Diseases of cardiovascular system (CVS) belong to most serious worldwide health
problems.
Ischemic heart disease (IHD) is in prevalence caused by atherosclerosis of coronary
arteries (ischemia is local disorder of blood supply, atherosclerosis is a form of
hardening of coronary arteries) ischó – hold; haima – blood
Chronic cardiac insufficiency
Hypertension (high blood pressure) is most often occurring CVS disease of adult persons (≥
20 % of inhabitants)
• accelerates development of atherosclerosis
• accelerates IHD
• induces brain vascular disorders
Diseases of blood vessels – most often, varicose veins at cca 15 % of population above 18
years, mainly women
• Venous inflammations approx. 2 % of population (complications – streptococcal
and fungal infections)
CARDIOVASCULAR DISEASES
Activity of Health Care
PREVENTION
THERAPY
CARDIOVASCULAR DISEASES
PREVENTION
Affection of risk factors
• Change of lifestyle
• High level of blood cholesterol
• High blood pressure
• Addiction to cigarettes smoking („paper tube filled with weed, which possesses from
one side fire and from opposite lunatic“)
• Sedentary way of life („kinetic crises“)
• Overeating
• Diabetes
• Excessive stress
CARDIOVASCULAR DISEASES
THERAPY
To hit the certain level of disease which shows very complex character – therefore
in maximal rate to use complex approach to therapy
• Drugs affecting heart
- cardiotonics
- antidysrytmics (antiarhytmics)
• Drugs affecting blood vessels
- vasodilatants
- vasoconstringents
• Antihypertensives
• Venopharmacs
• Drugs affecting hyperlipoproteinemia
• Sedatives
DRUGS AFFECTING HEART
Heart action is possible therapeutically affect by drugs targeting:
• directly heart muscle
• cardiac conduction system
• coronary arteries
• CNS
• VNS
Traditional division
• Cardiotonics
• Antidysrytmics (antiarhytmics)
DRUGS AFFECTING HEART
CARDIOTONICS
• Increase tonus of decompenzed myocardium
• Increase the force of contraction
• Improve energetic balance
• Show indirect diuretic effect
• In therapeutic doses do not affect healthy heart
DRUGS AFFECTING HEART
cardiotonics
Cardioactive glycosides
• Native biogenic compounds
• Products of their hydrolysis
• Semisyntethic analogues
Present especially in plants of family
• Scrophulariaceae – Digitalis spp.
• Apocynaceae – Strophantus spp., Nerium oleander, Thevetia spp.
• Liliaceae – Convallaria majalis, Urginea maritima
• Ranunculaceae – Adonis vernalis, Helleborus niger
• Brassicaceae – Erysimum spp., Cheiranthus spp.
CLASSIFICATION OF CARDIOACTIVE GLYCOSIDES
O
O
CH3
OH
H
H
CH3
H
H
OH
O
CH3
OH
H
CH3
OH
O
A B
C D1
2
3
4
5
6
7
8
9
10
11
12
13
14 15
16
17
cyklopentanoperhydrophenanthrene
18
19
20
21
22
23
24
20 21
22
23
C23 cardenolide C24 bufadienolide
Relationship with sterols, sex hormons, hormons of
adrenal gland, with bile acids and steroidal saponins
CARDENOLIDES
O
O
OH
O
O
OH
A
B
C
A
B
C
anelation C/D-cis (active) C/D-trans (non-active)
D D
CARDENOLIDES
C23 type; Digitalis, Strophanthus
O
O
CH3
OH
H
H
CH3
H
H
OH
18
19
20
21
22
23
card-20(22)-enolide
17
14
Structure activity conditions
1. at C17 α,β-unsatturated γ-lactone
(butenolide) ring β-oriented
2. hydroxyl group at C3 β-oriented
3. hydroxyl group at C14 β-oriented
4. anelation of rings A,B – cis
5. anelation of rings C,D - cis
BUFADIENOLIDY
C24 typ Scilla, Buffo
Structure activity conditions
1. at C17 α-pyrone lactone
(cumaline) ring β-oriented
2. hydroxyl group at C3 β-oriented
3. hydroxyl group at C14 β-oriented
4. anelation of rings A,B – cis
5. anelation of rings C,D - cis
O
CH3
OH
H
CH3
OH
O
24
20 21
22
23
bufa-20,22-dienolide
Cardiotonics
OH
O O
O
O
O
H
O
H
OH
O
OH
OH
O
OH
OH
OH
O
O
OH
OH
O
Pregnolone Progesterone 5ß-pregnandione
5ß-pregnanolone
5ß-hydroxypregnanolone
C2
C3
digitoxigenine
hellebrigenine
SUGAR COMPONENTS OF CARDIOACTIVNE GLYCOSIDES
CH2OH
CHO
CH3
CHO
CH3
CHO
CH2
CH3
CHO
CH3
CHO
MeO
CH2
CH3
CHO
OMe
CH3
CHO
OMe
CH2
CH3
CHO
MeO
CH2
CH3
CHO
OMe
CH2
CH3
CHO
OMe
D-glucose L-rhamnose D-fucose D-digitalose D-digitoxose
D-diginose D-sarmentose L-oleandrose D-cymarose L-thevetose
L-cerberose
SUGAR COMPONENTS OF CARDIOACTIVNE GLYCOSIDES
O
CH2OH
OH
OH
OH
H,OH
O
CH3
OH
OH OH
H,OH
O
CH3
OH
OH
OMe H,OH
O
CH3
OH
OMe
H,OH
O
CH3
OH
OH
H,OH
O
CH3
OH
OMe
H,OH
O
CH3
OH
OH
OMe
H,OH
O
CH3
OH
OMe
H,OH
D-glucose L-rhamnose D-digitalose L-oleandrose
D-digitoxose D-cymarose L-thevetosa D-sarmentose
Influence on myocardium by effect on membrane bounded Na+, K+-ATPase
connected with sodium pump
◼ provides quiescent potential in excitable cells.
◼ inhibition of this enzyme - following depolarization of membrane and
further processes
1. Mechanical effect of sodium pump inhibition:
• Decrease of sodium concentration triggers influx of Ca2+ into cell and it also increase
deliberation of Ca2+ from cell internal storage
• High level of Ca2+ causes action myosin + actin
• Strengthened contraction
• Improvement of ventricular function, limitation of pathological feedback mechanisms
• Vasodilatation, decrease of peripheral resistance
2. Electrophysiological effect:
◼ Indirect
◼ Stimulation of nervus vagus
◼ Senzibilization of baroreceptores
◼ Negative chronotropic effect
◼ Direct
◼ Change of action potential, Ca accumulation
◼ Possibility of rise of extrasystols
◼ Bigeminia and trigeminia
CARDIOACTIVNE GLYCOSIDES
Intoxication:
◼ Extracardial symptoms:
nonspecific, nausea and vomiting,
headache, fatigue, diarrhea, colored
vision, neuropsychic disorders.
◼ Cardiac symptoms: Slowering of
conductivity - AV block I.-III. Of grade.
Increasing of automacy is manifested
often by tachycardia, nodal
tachykardia and ventricular
tachyarhytmia (bigeminia, trigeminia).
◼ Inhibition of sodium pump affects all
excitable tissues including CNS,
striated muscles and GIT.
Depolarization and spontaneous
activity in neurons and muscular fibers
is started.
Digoxine Digitoxine Strophantine
Absorption
from GIT
40-100% 90-100% 0
Binding
to plasmatic
proteins
20-30% > 90% < 5 %
t0,5 40 h 4-6 days 21 h
Enterohepat.
circulation
6,8 26 0
Penetration
through
placenta
+ + -
DIGITALIS LANATAE FOLIUM
WOOLY FOXGLOVE LEAVES
Digitalis lanata Ehrh., woolly foxglove, Grecian
foxglove
(Scrophulariaceae/Plantaginaceae). Biennial herb,
for pharmaceutical purposes cultivated as oneyear
winter-crop.
Drug: lanceolated integerrimus leaf, immediately
after harvest dried up to 60 0C.
CC: approx. 1 % of mixture of more than 60
glycosides;
half of them are lanatosides A and C, furthermore
B, D and E; minor glycosides. Lanatosides
possess acetyled hydroxyl at C-3 of third
molecule of digitoxose.
Usage: material for isolation of digoxine,
digitoxine and lanatoside C.
Cardiotonic for treatment of cardiac insufficiency.
Digitoxine/digoxine also as antidysrytmic.
Digitalis lanata EHRH.
(Scrophulariaceae/Plantaginaceae)
MAIN GLYCOSIDES DIGITALIS LANATA
OR1 O
OH
R2
OH
digitoxigenine R1=R2= H
gitoxigenine R1=OH, R2= H
gitaloxigenine R1=O-CHO, R2=H
digoxigenine R1=H, R2=OH
diginatigenine R1=R2=OH
12
16
SUGAR PART AGLYCONE
===============================================================
DIGITOXIGENINE GITOXIGENINE GITALOXIGENINE DIGOXIGENINE DIGINATIGENINE
----------------------------------------------------------------------------------------------------------------------------------------------
Glc-Dx(Ac)-Dx-Dx- lanatoside A lanatoside B lanatoside E lanatoside C lanatoside D
----------------------------------------------------------------------------------------------------------------------------------------------
Dx(Ac)-Dx-Dx- acetyldigitoxine acetylgitoxine acetylgitaloxine acetyldigoxine acetyldiginatine
----------------------------------------------------------------------------------------------------------------------------------------------
Dx-Dx-Dx- digitoxine gitoxine gitaloxine digoxine diginatine
---------------------------------------------------------------------------------------------------------------------------------------------
Glc = glukose; Dx = digitoxose; Dx(Ac) = 3-acetyldigitoxose
DIGOXINUM – DIGOXINE (ČL 2005)
O
O
O
O O
O
O
OH
CH3
CH3
O
OH
CH3
OH
CH3
CH3
OH
OH
H H
H
H
H
OH
H
Dx Dx digoxigenineDx
digoxine
DIGOXINE
• The mostly often used foxglove
preparation
• Possibility of elevation of plasmatic
concentration
• Control of plasmatic level
• High intra-individual differences in
pharmacokinetics
• Should be set in range of 0,5-0,8 ng/ml
• For this the dose 0,125 to 0,25 mg per
die is enough
• Importance of pharmacogenomics for
estimation of dose (phenotypes TT,
CC, CT)
MINOR CONTENT COMPOUNDS OF DIGITALIS LANATA
O
O
OHH
H
OH
O
Glc Glc Gal Gal Xyl
O
O
H
H
O
OH
Glc Gal Gal Xyl
digitonine
gitonine
STEROIDAL SAPONINS
O CH
CH3
O
R'
RO
OH
OH
CO
CH3
O
Dx Dx Dx
O
Dl
H
COOH
CH3
12
20
diginine diginose H
digitalonine digitalose H
digofoleine diginose OH
R R'
digipurpurine
digipronine
DERIVATIVES OF PREGNANE
DIGITANOLY
DIGITALIS PURPUREAE FOLIUM (ČL 2002)
Common foxglove leaves
Digitalis purpurea L., common foxglove
(Scrophulariaceae/Plantaginaceae);
Europe, North America. Biennial plant,
for pharmaceutical purposes is
cultivated.
Drug: leaves dried up to 60 0C
CC: ČL demands at least 0,3 % of
cardenolides, calculated as digitoxine.
More than 30 cardenolides. Further
content compounds steroid saponins,
flavonoids, anthraquinones, mucilage
Usage: material for isolation of digitoxine
and further cardenolides, used for
preparation of semisynthetic
derivatives.
Cardiotonic for treatment cardiac
insufficiency.
Digitoxine also as antidysrytmic.
MAIN GLYCOSIDES OF DIGITALIS PURPUREA
O OR
OH
OH
16
R = H digitoxigenine
R = OH gitoxigenine
R = OCHO gitaloxigenine
SUGAR PART AGLYCON
=========================================================================
DIGITOXIGENINE GITOXIGENINE GITALOXIGENINE
------------------------------------------------------------------------------------------------------------------------------
Glc-Dx-Dx-Dx- purpureaglycoside A purpureaglycoside B glucogitaloxigenine
------------------------------------------------------------------------------------------------------------------------------
Dx-Dx-Dx- digitoxine gitoxine gitaloxine
------------------------------------------------------------------------------------------------------------------------------
Gl-Dl- glucoodoroside H digitalinum verum glucoverodoxine
------------------------------------------------------------------------------------------------------------------------------
Dl- odoroside H strospeside verodoxine
------------------------------------------------------------------------------------------------------------------------------
PURPUREAGLYKOSIDE AAND DIGITOXINE (ČL 2005)
O
O
O
O
O O
O
O
OH
CH3
CH3
O
O
CH3
OH
CH3
CH3
OH
OH
OH
OH
OH
OH
H H
H
H
H
D-Glc Dx Dx digitoxigenine
purpureaglycoside A
enzyme
H+ digitoxigenine
Dx
digitoxine
MINOR CONTENT COMPOUNDS OF DIGITALIS
PURPUREA
O
OOH
RO
OH
OH
luteoline R = H
luteoline-7-glucoside R = Glc
O
O
OH
CH3
OMe
O
O
CH3
OMe
digitoluteine
3-methylalizarine-1-methylether
1-methoxy-2-methylantraquinone
MAIN GLYCOSIDES OF DIGITALIS PURPUREA
AND DIGITALIS LANATA
O O
OH
OH
OOH O
OH
OH
O O
OH
OH
OH
Digitalis lanata Ehrh.
lanatoside A lanatoside B lanatoside C
desacetyllanatoside
A
desacetyllanatoside
B
desacetyllanatoside
C
acetyldigitoxine acetylgitoxine acetyldigoxine
lanatosidaseOH- OH-
OHenzyme
enzyme
purpureaglykosid
A
purpureaglykosid
B
OH- OH- OHdigitoxine
gitoxine digoxine
H+ H+ H+
digitoxigenine gitoxigenine digoxigenine
digitoxine gitoxine gitaligenine
purpureaglycoside A
desacetyllanatoside A
gitalinepurpureaglykoside B
desacetyllanatoside B
Digitalis purpurea L.
enzyme enzyme H+
OUABAINE (STROPHANTIN-G)
Strophanthi semen
Strophanthus gratus BAILL. (Apocynaceae),
climbing liane of tropic Africa. Fruit –
follicle conaining many seeds.
Acokanthera ouabaio – tree, from which was
firstly isolated
• Seeds contain up to 8 % of cardenolides, up
to 35 % of oil, proteins
• Extracts from seeds → arrow poisons
++ Ouabainum octahydricum ČL 2002
STROPHANTHIN-g injections
• Fastly acting crdiotonic
• Low accumulation
OUABAINE (STROPHANTINE-G)
O O
OH
CH3
OHOH
OH
OH
OO
CH3
OH
OH OH
OUABAINE (G-STROPHANTINE)
L-rhamnose
Strophanthi kombé and Strophanthi hispidi semen
(up to 10 % of cardenolides expressed as K-strophantine)
O
O
O
O
O
OH
CH3
OH
O
O
OH
OH
O
OH
OH
OH OH
OH CH3
CH3
OHC
D-Glc D-cymarose strophantidineD-Glc
k-strophantoside
k-strophantine-
cymarine
SARMENTOGENINE – steroide with OH at C-11
suitable for semisynthetic preparation of corticoids
Strophanthi sarmentosi DC. var. senegambiae semen
O
CH3
OH
HCH3
HOH
H
O
OH
Sarmentogenine - aglycone of sarmentocymarine
(3,5,11)-3,11,14-trihydroxy-card-20(22)-enolide

Adonidis vernalis herba – pheasant's eye herba
Adonis vernalis L. – pheasant's
eye (Ranunculaceae).
Perennial herb native to Europe,
Asia and North America.
Leaves divided into narrow
short line- like sections.
Flowers (April, May) Ø 4 cm
lemon-like yellow colour,
shiny.
Drug: up to 60 0C dried
flowering haulm
CC: 0,2-0,25 % of cardenolides
with prevalence of
adonitoxine; furthermore 20
minor glycosides.
Antibacterial 2,6-
dimethoxybenzoquinone
Usage: Cardiotonic with
sedative and diuretic effect
Content compounds of Adonis vernalis L.
O
O
OMeMeO
2,6-dimethoxybenzoquinone
O
CH3
OH
OH OH
OH
O
CH
O
OH
O
O
ADONITOXINE
Convallariae herba – Lily of the Valley herba
Convallaria majalis L., Lily of the Valley
(Liliaceae)
Perennial plant of Europe, Asia and
North America
Lanceolated leaves and white smelling
flowers (V-VI) formatting unilateral
cluster
Drug: herb harvested during flowering
period
CC: 0,2-0,3 % of mixture of 30
cardenolides, mainly convallatoxine
and convalatoxol. Further
compounds – GIT irritating saponins
Usage: Reserve cardiotonic with diuretic
effect
Comment: flowers contain up to 0,45
% of cardenolides
Cardenolides of Convallariae herba
O
O
CH3
OH
R2
OH
OR1
convallatoxine -Rha -CHO
convalloside -Rha-Glc -CHO
convallatoxol -Rha
R1 R2
-CH2OH
Oleandri folium – oleander leaves
Nerium oleander L., oleander
(Apocynaceae). Shrub or low tree
native in Mediterranean.
Drug: dried, lanceolated, leathery,
integerrimus leaves, harvested in
VII-VIII during flowering period.
CC: cardenolides derived from
oleandrigenine, digitoxigenine and
oleagenine. Main component is
oleandrine.
Usage: highly effective cardiotonic
with diuretic effect. Slow
elimination (1 -2 weeks)
Comment: some glycosides of
oleander show antimitotic activity.
OLEANDRINE
O
O
OCOCH3
CH3
OH
CH3
O
H
O
CH3
OH
OMe
Thevetiae semen –thevetia seed
Thevetia neriifolia JUSSIEU,
(Apocynaceae). Shrub or low
tree native in Middle and South
America.
Drug: dried bright-yellow seeds,
button-shaped
CC: up to 10 % of cardenolides
derived from digitoxigenine and
canogenine. Main component is
peruvoside. It is obtained from
fermented seeds or by enzymatic
hydrolysis of triglycoside
thevetine A.
Usage: peroraly active cardiotonic,
easy dosage. Resorption from
GIT about 50 %.
Cardenolides of Thevetiae semen
O
O
CH3
OH
R2
O
H
O
CH3
O
OH
OMe
R1
peruvoside H CHO
thevetine A -Glc-Glc CHO
neriifoline H CH3
thevetin Be -Glc-Glc CH3
R1 R2
Erysimi herba – cardioactive glycosides
O O
OH
CH3
C
HO
ODx
OH
R
erysimine R = H
erysimoside R = Glc
Erysimi herba – Nať trýzele
Source: Erysimum diffusum EHRH.,
trýzel rozvětvený (Brassicaceae).
Biennial, 30-90 cm tall plant
covered with grey trichomes.
Leaves shortlined, integerrimus,
yellow flowers in bunches.
Drug: dried herb collected during
flowering period.
CC: 0,8-1,5 % of cardioactive
glycosides.
Usage: cardiotonic for treatment of
rheumatic heart diseases and
hypertension.
UZARA, UZARAE RADIX
Source: Gomphocarpus fruticosus –
ostnoplod, Xysmalobium undulatum
(Asclepiadaceae), r. Pachycarpus.
Shrubs or low trees native in South
Africa.
Effect:
• minute effect on heart muscle
(1/100 of oubaine effect)
• markedly spasmolytic effect on
guts and uterus, decreases the
gut motility
Usage: antidiarrhoic,
dysmenorrhoeic, enuresis
O
OH
RO
O
H
uzarigenine R = H
uzarine R = -Glc-Glc
uzaroside R = -Glc-Glc-Glc
O
OH
RO
O
xysmalogenine R = H
xysmalorine R = -Glc-Glc
CARDIOTONICS OF SCILLOID (BUFO) TYPE
O
CO (CH2)6CO
CH3
H
CH3
OH
O
O
O
C
O
CH3
H
H
COOH
NH C NH2
NH
NHCH(CH2)3
bufotoxine = bufotaline-3-suberoylarginine
Scillae albae bulbus – cibule mořská bílá
Zdroj: Urginea maritima (L.) BAK.,
urginea mořská (Liliaceae). Coast of
Mediterranean. Cultivated in Italy,
USA and India. Harvested after
withering the leaves up (VIII-IX).
Transversal cuts, drying.
Drug: dried, internal part of fleshy bulb.
CC: 0,2-0,4 % of mixture of cca 15
glykosides. Main are glucoscillarene
A and proscillaridine A (CARADRIN
drg.); fructosans, sterols.
Usage of proscillaridine A:
• cardiotonic with effect faster than
digitalis
• very low accumulation
• diuretic
Scillae albae bulbus – bufadienolides
O
OH
O
O
RhaGlcGlc
glucoscillarene A
scillarene A (majority)
proscillaridine A
scillarenine = scillaridine
Scillae rubrae bulbus – cibule mořská červená
Source: Urginea maritima var.
rubra, urginea mořská
červená.
Occuerence: as white variety
CC: scilliroside, scillirubroside
and glycosides same as at
white variety.
Usage: rhodenticide (killing of
rats), toxic is scilliroside.
Acting on CNS. LD for adult
rat is 0,3 mg.
O
OH
O
O
Glc OCOCH3
OH
scilliroside
scillirosidine
Hellebori nigri radix – kořen čemeřice černé
Zdroj: Helleborus niger L. – čemeřice
černá (Ranunculaceae). Perennial
plant native in Europe. Ornamental
„Christmas rose“.
Drug: dried rgizome with roots.
CC: 0,3 % of hellebrine
(glucorhamnoside of hellebrigenine)
– in exception of cumaline ring the
same structure as strophantidine.
Saponin helleborine.
Usage: deglucohellebrine as cardiotonic
Semisynthetic derivatives:
• deglucohellebrigenine-acetate is the
most active compound.
• 3-(3-methylcrotonate)-hellebrigenine
(Acrihellin).
Hellebori nigri radix – bufadienolides
O
OH
CH3
O
O
C
RhaGlc OH
HO
hellebrine
hellebrigenine
desglucohellebrine (highly active)
FURTHER EFFECTS OF CARDIOACTIVE GLYCOSIDES
• in non-toxic concentration digitoxine and digoxine inhibit
growth and induce apoptosis of different lines of human
malignant cells, and do not affect normal proliferating cells
• oleandrine, ouabaine and digoxine induce apoptosis at
cancer cells of prostate gland independent on androgen in
vitro
ANTIDYSRYTMICS
• Affect disorders of heart rate.
• Affect in prevalence heart automacy, conductivity and
often also excitability.
Biogenic therapeutics – structurally different compounds
Quinidine
Ajmaline
Sparteine
Digitoxine
Qinidini sulfas dihydricus – Quinidine sulphate dihydrate (ČL 2002)
Source: Chinae cortex – Cinchona
succirubra (Rubiaceae)
Ppreparation: isolation,
isomerisation of quinine
Usage: Antidysrytmic
• in general induce myocardial
depression
• slowering of excitement
conduction, slowering of its
formation
• decreasing of contractility
• decreasing of heart rate
N
MeO
N
H
OH H
CH2
H
H
4
6´
5
2
steric line (+)
Ajmaline – Aimalinum (ČsL 4)
Source: Rauwolfiae radix,
Rauwolfia serpentina
(Apocynaceae)
Usage: Antidysrytmic separately or
in combination
• decreases conductivity
• Used mainly during
tachysystolic dysrytmias
Comment: from ajmaline are
prepared derivatives
prajmalinium and detajmium
by the qurternization of N at
position 4
N
CH3
N
OH
OH
Sparteinum sulfuricum – Sparteine sulphate
Source: Sarothamnus scoparius –
janovec metlatý. A semi shrub
with trifoliate leaves and yellow
flowers.
Drug: dried flowering tips of
branches; for alkaloid isolation
harvested in the yearly spring.
CC: 1 – 1,5 % of quinolizidine
alkaloids with prevalent
sparteine
Usage: prophylaxis of atrial
dysrythmias and sinus
tachycardia
Sarothamni flos – contains diuretic
scoparoside – component of
diuretic herbal teas.
N
N
H
H
H
H
O
O
C Glc
OH
OH
OH
OMe
sparteine
scoparoside
DRUGS AFFECTING BLOOD VESSELS
VASODILATANTS
• dilatate veins
• eliminate vascular spasms, what makes better blood supplies of organs
• some of them lower blood pressure
VASOCONSTRINGENTS
• reduce lumen of veins
VENOPHARMACS
• affect durability of vascular wall
• affect metabolism of vascular wall
VASODILATANTS
Used for treatment of blood circulation disorders
• coronary and brain blood vessels
• muscular and skin blood vessels
spasms
atherosclerosis blood circulation disorders
inflammatory processes
VASODILATANTS
1. METHYLDERIVATIVES OF XANTHINE (theophylline, theobromine, aminophylline
(complex of theophylline with ethylendiamine) OXYPHYLLIN
2. PAPAVERINE (dilatates big veins, into them can be directly administered; also for
treatment of central and coronary blood circulation disorders - angina pectoris)
PANERGON
3. DH-ERGOT ALKALOIDS (mainly dihydroergotoxine together with etophylline – cerebral
vasodilatant, separately for peripheral circulation disorders) SECATOXIN, ERSILAN
4. KHELLINE – furanochromone derivative and VISNADINE – pyranocoumarin derivative
(coronary vasodilatants and spasmolytics)
5. VINKAMINE (cerebral vasodilatant, affects cognotive functions) CAVINTON
6. GINKGO BILOBA content compounds (cerebral and peripheral vasodilatant) TEBOKAN
7. RAUBASINE = AJMALICINE, Rauwolfia serpentina – snake root (improves blood
circulation during cerebral and peripheral disorders) LAMURAN
Papaverine
• Papaver somniferum Papaveraceae
• Benzylisoquinoline alkaloid
• Up to 1% in opium.
• Releases smooth muscles tonus in internal organs
• Effect on smooth muscles induce dilatation of veinds and
improvement of blood supplies
• Passes into mother milk, metabolized in liver, excreted by
kidneys, biological halftime is 1-2 hours.
• Indications: Gut, gallbladder colic, vascular spastic
states (increased tonus of smooth muscles of veins),
states during local insufficiency of blood supplies in tissue
of eye, inner ear, spastic states during emboli
N
MeO
MeO
MeO
MeO
• Erectile impotency – non-specific
inhibitor of phosphodiesterase,
increasing the level of cAMP and
cGMP
• Lead for semisynthetic
derivatives
Dihydrogenated ergot alkaloids
◼ DH-ergotoxine – hydergine
◼ sympatolytic, vazodilatant
◼ dilatation of veins in brain and
extremities, improvement of blood
supplies
◼ disorders of brain blood supplies, mild
psychic disorders of older people
◼ disorders of function of peripheral blood
vessels, troubles connected with high
pressure (especially headaches and
vertigoes).
◼ Ocular diseases (some disorders of
blood supplies of retina and choroid).
◼ Meniér syndrome (disease characterized
by vertigo, sounds in ears, nausea and
vomitus)
N
N
CH3
H
H
H
O N
H
O
N
N
O
H R2
OH
O
R1
R1 R2
DH-ergocrystine iPr CH2Ph
DH-ergocornine iPr iPr
DH-α-ergocryptine iPr iBu
DH-β-ergocryptine iPr secBu
Secale cornum, Claviceps purpurea Clavicipitaceae
Khelline and visnadine
◼ Ammi visnagae fructus, Ammi visnaga
Apiaceae
◼ Khelline, visnagine – furanochromones
◼ Visnadine – pyranocoumarin
◼ Dilatation of coronary arterias –
improvment of heart supplies
◼ Spasmolytic on smooth muscles –
antagonist of Ca entry into cell
◼ Againsti psoriasis
◼ Indication
◼ Ischemic heard disease
◼ Mild forms of CHOPD
◼ Antispastic of GIT (gallbladder) and
urinary tract
O O
OMe
OMeO
CH3
O O
OMeO
CH3
O
O
O
O
O
O
O
Vincamine
◼ Vinacae herba, Vinca minor
Apocynaceae
◼ Indol alkaloid of aspidospermine type
◼ Vinka contains about 50 alkaloids
(vincamine, vincamidine,
vincaminoreine, isovincamine,
pervincine), 0,1-0,7 %.
◼ Drug decrease blood pressure, it is also
used for suppression of irritation during
dry caught, it acts also as sedative, it is
used during diabetes. During
hemorrhagic states.
◼ Vincamine: Voaconga and Crioceras
◼ Blood vessels dilatation
◼ Passes through BBB
◼ Improvement of supplies of brain
by oxygen, ATP and glucose
◼ Redistribution of blood into
ischemic parts
◼ Nootropic effect
◼ Produced from tabersonine
(voakanga seeds)
N
OH
H3
COOC
H
N
H3
CH2
COOC
H
N
N
OO
H
Ginkgo folium – Jinanový list (ČL 2002)
GINKGO FOLIUM
Ginkgo biloba L. – jinan dvoulaločnatý
(Ginkgoaceae)
• dioecious gymnosperm tree
• Leaves wide wedge bilobar, veil-shaped
vasculature
• Native to eastern Asia
• Cultivated in Asia, Europe and USA
• From leaves are prepared extracts with
complex of active compounds
- flavonoids
- ginkgolides
• Application peroral and parenteral
• Usage during disorders of blood supplies
of brain and peripheral parts, mainly
atherosclerotic origin
• Antiedematic effect
Content compounds of Ginkgo folium
-
O
O
O
OH
OH
R
OH
O
OH OH
O
CH3
O
C
H2
OH
OH
OH
H
OCOC
H
CH
O
O O
O
O
R2
H
OH
H
CH3
C(CH3
)3
OH
H
CO
H
R1
O
aglycone
R=H, kaempferol
R=OH, quercetine
ginkgolide R1 R2
A H H
B OH H
C OH OH
(diterpenes with 6 rings, 3 of them
are lactones)
O
O
O
O
O
OH
O
CH3
CH3
CH3
0,2 % of gingkolides (diterpenes)
0,05 % of bilobalide (sesquiterpene)
2 % of flavonoid glykosides
2 % of biflavonoids
Proanthocyanidines, triterpenes and further
Pharmacologic effects:
• Neuroprotective
• Antioxidant, scavenger
• Membranes stabilizing effect
• Inhibitor of PAF
• Inhibition of β-amyloid deposition into tissue
(Alzheimer disease)
• Protection against the age-dependent loss of
acetylcholinergic and adrenergic receptors
• Inhibition of cGMP phosphodiesterase
• Relaxation of veins
Standardized extracts:
24 % of flavonoids
6 % of terpenoids
RAUBASINE (syn. AJMALICINE)
Source: Rauwolfia serpentina (L.)
BENTH. (Apocynaceae),
especially roots of Chinese variety
Characteristics: weakly basic
monoterpenic indol alkaloid
Usage:
• Cerebrovascular vasodilatant
• Blood supplies of peripheral tissues
during varicose complex.
• Disorders of ocular blood supplies.
• Lamuran, Circolene, Isoarteril
N
H
N
O
H
H
H
CH3
C
O
OCH3
ANTIHYPERTENSIVES
REMEDIES AGAINST INCREASED ARTERIAL BLOOD
PRESSURE
HYPERTENSION – mostly often occurring cardiovascular disease of adult,
but today described often also in children
• It is one of main factors playing role in ethipathogenesis of
atherosclerosis and its complications:
- IHD
- cerebrovascular incidents
• Needs permanent treatment
ANTIHYPERTENSIVES
REMEDIES AGAINST INCREASED ARTERIAL BLOOD
PRESSURE
• Alkaloids from Rauwolfiae radix – snake root, mainly reserpine
• Alkaloids from Veratri albi radix – kořen kýchavíce bílé, protoveratrines A and B
Antihypertensives – vasodilatants
• Content ocmpounds from Crataegi folium cum flore – list hlohu s květem
• Visci albi herba – nať jmelí (limited use becouse of side effects)
Folk medicine
• Oleae folium – olive leaves
• Allii sativi bulbus – garlic bulbs
RESERPINUM – RESERPINE (ČL 2002)
Source: different species of Rauwolfia, especially
Rauwolfia serpentina – snake root
(Apocynaceae). Small shrub with evergreen
leaves, white or pinkish flowers. For
pharmaceutical purposes is cultivated. Main
producers: India, Thailand.
Drug: dried root - Rauwolfiae radix, bark is more
rich on alkaloidal content than wood.
CC: 1-2,5 % of mixture of more than 50 indol
alkaloids. Reserpine is monoterpenic alkaloid
of yohimbane type. Obtained only by
isolation.
Dosage: Antihypertensive 0,1 – 0,25 mg pro die
Comment: also used mixture of alkaloids:
reserpine, deserpidine, rescinnamine and
syrosingopine
RESERPINUM – RESERPINE (ČL 2002)
MeO N
H
N
H
H
H3
COOC
H
OMe
O CO
OMe
OMe
OMe
Alkaloids of Rauwolfiae radix
with antihypertensive effect
N
H
N
18
11
H H
H
OOCCH3
R1
R2
OMe
O CH3
H
O CH3
OOC
OMe
OMe
OMe
OOC
OMe
OMe
OMe
C
H
OMe
O
OMe
C
H
OOC CH3
reserpine
deserpidine
rescinnamine
R1 R2
N
N
H
HH
H
CH3
OOC
OH
N
N
O
H
HH
H
CH3
OOC
CH3
N
N
H
CH3
OH
OH
H
N
N
H
CH3
OH
CH2
OH
H
N
NH
H
CH3
OH
O
O
O
H
H
O
Glukosa
N
N
H
HH
R1
H
R2CH3
OOC
OMe
Yohimbin
•Sympatolytic (peripheral
vasodilatation)
•Erectile dysfunction
Ajmalicine (raubasine)
•Vasodilatation
Reserpine
Sarpagine
•Sympatolytic (peripheral vasodilatation)
Ajmaline
•Antiarhytmic
strictosidine
Veratri albi radix – Kořen kýchavice bílé (ČsL 4)
Zdroj: Veratrum album L. – kýchavice bílá
(Liliaceae). Perennial plant, large elipsoid
leaves with parallel nervature. Flowers in
panicle (VII-VIII). Krkonoše, Nízké Tatry.
Drug: dried cylindric rhisomes with numerous
roots. Harvest in X.
CC: 1-1,5 % of alkaloid mixture (type of
cholestane, cevanine, jervanine,
veratramine and solanidanine).
Therapeutic importance possess only ester Cnor-D-homo-cevanines:
protoveratrine A
and protoveratrine B.
Usage: antihypertensive, side effects,
experimental compounds.
Veratri extractum – veterinary medicine –
stomachic, laxative
Alkaloids possess insecticidal effect.
Powdered root irritates to sneezing.
Veratri albi radix – antihypertensive active alkaloids
N
OH
CH3
COO
H H
OH
OH
CH3
OOC
OOC
O OH
H
OOC
CH3
H
H
H
C
OH
CH3
C
H
CH3
R
CH3
C
H
CH3
C
H2
CH3CH3
protoveratrine A, R = H
protoveratrine B, R = OH
Crataegi folium cum flore – Hlohový list s květem (ČL 2002)
Crataegi fructus – Hlohový plod (ČL 2002)
Source: different species of Crataegus – hloh,
especially C. monogyna, C. laevigata or
their hybrids
Drug: whole or cut dried flowering tips of
branches, collected in spring from white
flowering shrubs with simple flowers.
CC:
• At least 1,5 % of flavonoids expressed as
hyperoside (further more rutoside,
quercetine, vitexine)
• Epicatechine, procyanidine
• Triterpenic acids (oleanolic, ursolic and
crataegolic)
• Adenosine
Usageí: Antihypertensive, coronary
vasodilatant in form of herbal teas or
standardized extracts.
Crataegi fructus – dried pseudofruit
(pome). Contains at least 1,0 % of
procyanidines (expressed as cyanidine
chloride).
Crataegi folium cum flore – content compounds
O
O
O
Gal
OH
OH
OH
OH
O
O
OH
R
OH
Glc
O
O
OH
OH
OH
OH
O
OH
OH
OH
OH
OH
vitexine, R = OH
vitexine-4'-rhamnoside, R = O - Rha
hyperoside
procyanidine
O
OH
OH
OH O
Glc
O
OH
OH
OH O
O Glc-Rha
OHO
OH
OH
OH O
O Gal
OH
COOH
OH
OH
OH
OH
O
O
OH
OH
OH COOH
O
OH
OH
OH O
OH
O
OH
OH
OH O
Effect:
•Antiradical activity
•Inhibition of phosphodiesterase
•Increase of cAMP
•Relaxation of smooth muscles
•Lowering of blood pressure
•Antiarhytmic effect, improvement of energetic bilance of heart
•Improvemnt of oxygen supplies
•Hepatoprotective
•Prevention of neoplasia
•Lowering of cholesterol level
vitexine
hyperoside rutine
apigenine
luteoline
Chlorogenic acid
Caffeic acid
Visci albi herba – Nať jmelí
Source: Viscum album L. – jmelí bílé (Loranthaceae).
Dioecious epiphytic shrub with
furcated branched stems, semiparazitic on
woody plants. Thick leathery ingerrimus
leaves and small flowers, fruit - pseudo berry.
Drug: dried deciduous tips of young branches,
yellow-green, without fruits
CC:
• Lectins – high molecular glycoproteins
• Viscotoxins – proteins
• Aminoacids (GABA, valin, arginin)
• Flavonoids
• Amines (choline, acetylcholine, tyramin,
histamin)
• Triterpenes (amyrine, lupeol, oleanolic acid)
• Polysaccharides and cyclic sugars
• Lignans
Usage:
• Antihypertensive (GABA, flavonoids)
Cytotoxic (lectins – agglutination of human
erythrocytes and toxic for tumor cells)
Visci albi herba – content compounds
O C
H
C
H
CH2OHGlc
MeO
MeO
RO
MeO
MeO
O
O
OR
OMe
OMe
syringaresinol, R = H
eleutheroside E, R = Glc
syringine
VENOPHARMACS – DRUGS FOR TREATMENT OF
VASCULAR DISEASES
Vascular diseases – the most common diseases of blood circulation
• Varixes
• Vein inflammations
• Decreased elasticity of veins
• Increased permeability
• Increased fragility
• Local bleedings
• Inflammations, oedemas
Flavonoids as venopharmacs
Rusznyák L. and Szent Györgyi (1936): „Vitamin P, flavonols as vitamins“. Pvitamins
– antiPermeabile compounds.
Flavonoids (cca 6000) – biologic activity differs in dependence on:
• Oxidative degree of 2-phenyl-γ-benzopyrone
• Different number and position of hydroxyl and methoxyl (and other
substituent) groups
• Different number, character and position of glykosidic residues
Flavonoids used as venopharmacs: rutoside, quercitrine, hesperidine, diosmine and
astragaline
• normalize metabolism betwen blood and tissue – decrease permeability of
capillary walls
• decrease fragility of capillaries
• inhibit hyaluronatelyase – decrease degradation of hyaluronidase, which
cleavages proteoglycan component of intercellular cement and improve
absorption of hematoms and oedemas.
RUTOSIDE
Source: Sophora japonica L. – Japanese Pagoda
Tree (Fabaceae). Shrub or tree with green
colored branches, and to Robinia
pseudoacacia (Black Locust) similar leaves.
Small pale yellow aromatic flowers in
panicles. Producers: China, Japan.
Drug – not full-blown flower buds Sophorae flos
with content up to 20 % of rutoside.
Semisynthetic derivative tris-β-hydroxy-ethyl =
troxerutine, CILKANOL
Usage: increased fragility and permeability of
capillaries, lack of vitamin C (scorbut),
hemorhagias, hypertension, alergies, varicosal
complex, surface phlebitis, infection diseases
Source: Fagopyrum sagittatum L. – buckwheat
(Polygonaceae). One-year plant, for
pharmaceutical purposes is cultivated.
Drug: dried herb harvested during flowering
period.
OL: 1-2 % of rutoside, difficult isolation
O
O
OH
OH
OH
O
OOH
OH
OH
OH
CH2 O
O
OH OH
OH
H
CH3
glucose rhamnose
rutinose
rutoside
quercetine
VENOPHARMACS – DRUGS FOR TREATMENT OF
VASCULAR DISEASES
FLAVONOIDS
DIOSMINE (Folium bucco, Cortex xanthoxylli)
TOVENE, DAFLON, FLEBOSTEN, VENOTREX
HESPERIDINE (fruits of Citrus spp. plants)
HESPEROSIDE
QUERCITRINE (Quercus tinctoria)
ARIVEN
O
O
Rha-GLc-O
O
OH
CH3
O
O
Rha-GLc-O
O
OH
CH3
O
OH
OH
O
OH
OH
O-Rha
Xanthoxylli avicenae cortex, Rutaceae
Bucco folium
Rutaceae fructi
Quercus tinctorie cortex
diosmine
hesperidine
quercitrine
antiinflammatory, antimutagenic and antioxidative
properties
Inhibition of prostaglandine and tromboxane –
rheologic
rapid metabolisation to aglycon
inhibition of ACAT, HMG-CoA reductase
antihistamine effect
KVERCITRINUM
Source: Quercus tinctoriae cortex
ARIVEN
O
OOH
OH
OH
OH
O Rha
quercitrine
LEUKOCYANIDOL
Source: Pini maritimae cortex –
maritime pine; Cacao semen;
Gossypii flos; Corylli avelanae
fructus – common hazel fruit
PYCNOGENOL
O
OH
OH
OH
OHOH
OH
leucocyanidol
ANTHOCYANOSIDES – MIXTURE
Source: Myrtilli fructus
hemeralopia, xerophtalmia
DIFRAREL, MYRTOCYAN
O
O
OH
OH
cukr
OMe
OMe
OMe
anthocyanosides
+
Hippocastani semen – horse chestnut seed
Source: Aesculus hippocastanum L.– horse
chestnut (Hippocastanaceae). Large tree
with arched treetop. Fruit is rounded
spinose capsule with 1-3 seeds with shiny
brown testa.
Drug: frsh or dried seeds. Dried bark.
CC: Seeds contain at least 3 % o f mixture of
triterpenic saponins, called as aescine
(aglycons protoaescigenine and
baringtogenol C).
Usage:
• decreases permeability of capillaries,
suppresses development of oedemas
• used also during vascular brain accidents,
comotion, contusion, encephalitis
YELLON, REPARIL, ANAVENOL
In testa and bark described presence of
aesculine (coumarin derivative)
EVERCIL
Hippocastani semen – content compounds
3 4
12
13
14
15
16
18
17
22
21
20
19
CH3
25
H
H
R
23
CH3 24
OH
CH3
26
CH3
27
CH2
OH
28
H
CH3CH3
OH
OH
OH
O
CH2OH
OH
OH
OH
O
O OOH
protoaescigenine, R = CH2OH
barringtogenol C, R = CH3
aesculine
O
CH2OH
OH
OH
OH
OO
CH2OH
OH
OH
OH
O
O
OH
O
H
CH2OH
CH2OH
O
O
OH
C
O
CH3
C
O C C
CH3
CH3
CH3
COOH
aescin
COMPOUNDS AFFECTING DYSLIPIDEMIA (DLP)
[HYPERLIPOPROTEINEMIA (HLP)]
Dyslipidemia – a panel of metabolic deviations leading to increase of
proatherogenic, and procoagulative acting lipoproteins:
DLP – risk factor of development of atherosclerosis and its complications
DLP – in connection with pancreas, liver and billiard tract diseases
DLP – increased number of low density lipoproteins (LDL), lipoproteins (a) Lp(a),
triglycerides together with total cholesterol in serum, or decreased number of
antiaterogenic high density lipoprotein (HDL)
Prevention
• strict diet with limited amount of animal fat
• Increased energetic output
• Biogenic compounds
- cellulose, lignin, pectins, gums – high molecular plant compounds
vegetables, fruits
- heparinoids activating lipoprotein lipases, splitting non-atherogenic fatty acids
COMPOUNDS AFFECTING DYSLIPIDEMIA
• Biogenic compounds - continued
- β-sitosterol lowers the level of blood cholesterol; it is used also for
treatment of benign hyperplasia of prostate gland
- soya lecithin = side product of oil manufacturing from soya seeds,
it contains phosphatidylcholine
- choleretics (cynarine and others) and compounds preventing
resorption of bile acids
- product blocking synthesis of cholesterol skeleton – inhibitors
of enzyme 3-OH-3-Me-glutaryl-CoA reductase (HMG-CoA reductase) –
statins
- products blocking resorption of cholesterol and its
esterification: inhibitors of acetylcoenzym-A-cholesterol
acyltransferase - ACAT
- development of inhibitors of squalene synthase, inhibiting last
stage of chlesterol synthesis
β-SITOSTEROL
Source: slices of sugar beet,
defatted soya seeds, oil from
cereal sprouts.
Plant sterols are absorbed by
human in minimal rate.
High doses considerable inhibit
cholesterol absorption
Usage: hypercholesterolemia,
benign adenoma of prostate
gland.
OH
R
-sitosterol R = CH2-CH3
campesterol R = CH3
cholesterol R = H
SOYA LECITHIN
Source: side product of
manufacturing of soya oil
from soya seeds. Purified on
ion exchangers.
Yellowish hygroscopic mass
containing 90-95 % of
phosphatidylcholine. Linoleic
acid content cca 70 %.
Usage: lowering of cholesterol
level.
C
H2
O P O
CH
CH2 OCO C17H34
C
H2
C
H2
N
+
CH3
CH3
CH3
O
O
OC
O
H32C17
phosphatidylcholin
-
CHOLERETICS
Source: Cynara scolymus and others ◼ cynarin
OH
OH
O
O
OH
OH
O
O
OH
OH
O
OH
Products of moulds – originally antimycotics
MEVINOLIN
Source: Aspergillus terreus
• Lowers blood cholesterol about
18 – 34 %
• blocks key enzyme reductase of
3-OH-3-Me-glytarylCoA (HMGCoA)
which participates on
cholesterol biosynthesis
CH3
CH3
O
CH3
CH3
H
O
OOH
mevinolin