Toxicology of alkaloids
I.
• Alkaloids
– Nitrogenous compounds
– Metabolic transformation of aminoacids or /and other
precursors (pseudoalkaloids)
– One or more atoms of nitrogen
• built into cycle (heterocyclic alkaloids)
• aliphatic (protoalkaloids)
– Heterocyclic alkaloids:
• Quinolizidine, piperidine, pyridine, pyrrolizidine,
• Isoquinoline, indol, quinoline, imidazol, terpenic, steroid
– Important pharmacological and toxikological activity
– Quinolizidine alkaloids
• Activity similar to quinidine
• Activity on ion channals (Na,
K), nicotinic and muscarinic
receptors, affection of
proteosynthesis
– Anagyrine
• Anagyris foetida, Cytisus spp.,
Genista spp., Lupinus spp.,
Sophora spp. Fabaceae
• Vasoconstriction
– Central
– Increased release of
adrenalin
• Teratogenic
– Skeletal contractive
deformation
– Cleft palate
– Mainly described for calfs
– Inhibition of foetus
movement in uterus
– U lidí
» Erythrocytary
aplazia
» Vascular
anomalies
» Skeletal dysplazia
N
N
O
H
H
•Cytisine, N-
methylcytisine
–Laburnum
anagyroides, Cytisus
spp., Genista spp.,
Sophora spp.
Fabaceae
– Common intoxications
– Similar to nicotine
intoxications
• Mydriazis, salivation,
sweting
• Burning in mouth
• Central irritation causing
vomiting
– Large amount
• Delirium, excitation
• Tonic-clonic convulsions
• Respiratory distress
N
N
O
H
H
N
N
O
H
H
CH3
• Lupanine, lupinine,
isolupinine
– Lupinus spp.,
Genista spp.,
Cytisus spp.
Fabaceae
– Mostly pasturing
animals
– Lupinosis
• Anxiety,
convulsions
• Icterus
N
N
O
H
N
OH
• Sparteine
– Sarothomnus scoparius,
Genista tinctoria Fabaceae
– Effect most similar to
quinidine
• Delay and slowering of
excitement transfer
– Ventricular arrhythmia to
arrest
• Minimal effect on CNS
• Peripherial:
– Paralyse terminations of
motoric nerves
– Curare-phormous affection
of sympathic ganglia
• Image of intoxication:
– Nausea, diarrhea, vomiting
– Vertigo
– Tachycardia?
– Circulatory collapse
– Decrease of glycaemia
» Increased release of
insulin
N
N
• Metabolism of sparteine
– Genetic polymorphism
CYP2D6
– 5-10% of population slow
metabolisers
– 2,3-dehydrosparteine
– Hydroxylation, conjugation
– Excretion via kidneys
• Piperidine and pyridine alkaloids
– Toxicologic importance
– Coniine, nicotine, tropane alkaloids
• Actinidine
– Actinidia polygama
Actinidiaceae silver vine
– Similar to kiwi, edible fruits
– Poisonous leaves
• Sedative effect
• Excitation of Felidae beast
– Toxic substance of
defensive secret of some
insects
• N-(p-OH-phenylethyl)-
actinidine
– Inhibitor of cholinesterase
– Valeriana officinalis
Valerianaceae
CH3
N
CH3
• Anabasine
– Nicotiana spp.
Solanaceae
– Anabasis aphylla
Chenopodiaceae
– Similar to nicotine
– Highly toxic
– Often intoxications
– Teratogen
• Poultry, cattle, pigs
• tzv. arthrogryposes
• Anabaseine
– Aphaenogaster rudis
N
N
N
N
• Arecoline
– Areca catechu betel
Arecaceae
– Muscarinic effect
– Higher dosage affects
also nicotinic receptors
– Salivation,
perspiration, miosis
• Dioscorine
– yam
– Dioscorea spp.
Dioscoreaceae
– Anticholinergic
– Convulsions
N O
O
O
N
O
– Lobeline
• Lobelia spp. Lobeliaceae
• Campanula medium
Campanulaceae
• Nausea
• Stimulation of CNS and
GIT
– 4´-O-methylpiridoxine
• B6-antivitamin
• Hypersensitivity,
convulsions, death
• Mainly cattle
– Pasture of Albizia spp.
• Gingko biloba
N
CH3
OHO
• Coniine, N-methylconiine
• γ-coniceine (Aloe
globuligemma)
– Conium maculatum Apiaceae
– Local irritation
– Paralysis of snesoric and
motoric nerves
– Typical ascending paralysis of
skeletal muscles
– Terminal stage
• Respiratory arrest in full
consciousness nad heart
action
– Symtoms
• Nausea, salivation, vomitus
• Stomach pain with diarrea
• Landry´s ascending
polyneuritis
– Chronic intoxication
• teratogenic
N
• Cocaine
• Erythroxylon cocca,
Erythroxylaceae
– History
• Indians of Chibcha tribe
• Incas
• Spanish
• Coca-cola till 1904
• 1860 Albert Niemann –
pure cocaine
• Sigmund Freund, Carl
Coller
–Metabolism
–Formation of ethylderivative during intoxication by ethanol
– Mechanism of rffect
• Indirect sympathomimetic (inhibitor of
noradrenaline reuptake)
• Block of ion channels of neurons
(disorder of excitement transmission)
• Adrenergic stimulation
– Peripheral effects
• Vasoconstriction, hypertermia,
mydriazis
• Low dosage - ↓ of heart rate
• High dosage - ↑ of heart rate, cardial
arrest
– Central stimulation
• Euphoria, depletion of
neutransmiters (NA), short
depressive effect
• Rise of psychic dependence
– Does not induces physical
dependence
• Intelectual stimulation, hyperactivity,
hyperlucidity
• Self-deceit, paranoid psychosis
N
O
O
O
O
H
• Cocaine
– Complications during
usage
• Cardiovascular failure
– Way of use
• As salt (chloride) or base
• Chloride
– Snuffing, i.v.
• Base
– Smoking (crack),
inhalation
• Mixture with heroine
– snowball
• Mixture with alcohol
– Cardiotoxic
– Highly euphoric
• Tropane alkaloids
– Azabicyklo[3,2,1]octane
– Apoatropine, atropine,
hyoscyamine, scopolamine
– Solanaceae
– Parasympatholytic
• Competitive antagonists of
acetylcholinergic receptors
– Muscarine type
– Intoxication
• Facial redness, dry mucose,
thirst
• Tachycardia, mydriasis
• Hypertermia, central
excitation, halucination
• Coma, respiratory distress
N
O
O
O
• Pyrrolizidine alkaloids
– Asteracea, Fabaceae, Boraginaceae
– Ester bonded alkaloids
• Necine part (base, bicyclic pyrrolizidine, sometimes 1,2
dehydroform)
• Necic acid or fragment
– Dehydroform more toxic
– 360 compounds
• Makrocyclic diesters
• Open diesters
• Monoesters
– Metabolism in plant:
• Synthesis in roots via N-oxides
• Transport through phloem
• Storage in vacuoles, in water as N-oxides
• Loss of water – tertiary bases
Senecio spp.
Heliotropium spp.
Symphytum officinalis
–Metabolism in vertebrae
•N-oxides polar and non-
toxic
–Do not cross membranes
–Unstable
–Reduction in gut to
tertiary amines
–Crossing membranes
thanks to lipophilicity
»Non-protonated
•Partially cleaved to base
and acid
–Non-specific blood
esterase
–Non-toxic (no
metabolites)
–Conjugation and urine
excretion
–Steric protection – not
cleaved
•In liver
–Oxidation to pyrrol,
hydrolýsis
–Derivatives with
exocyclic methylene
E. Röder. Pharmazie 50 (1995), 83-98.
• Toxicity
– N-oxides similarly toxic to tertiary alkaloids
– Polar – therefore rapid excretion
– Acute toxicity
• Hepatotoxicity
– Megalocytosis of hepatocytes (upto 30 times bigger)
– Enlargement of hepatocytes nuclei
– Disorder of hepatocyte metabolism
– Disorder of mitosis
– Cellular destruction
– Fat degeneration
• Intake of 10-20 mg of alkaloids
• Larger scale of cells destruction – liver failure, death.
– Chronic toxicity
• Proliferation of bile ducti epitel
• Inflammatory changes
• Centrilobular necrosis
• Cirrhosis, ascites
• Venooclusive disease
– seneciosis
– Clinical symptoms
• Pain in underbelly
• Vomiting, diarrhea
• Ascites
• Swelling of liver
• Vasomotoric collapse
• Blood regurgitation, blood diarrhea
• After liver damage
– Pulmonary damage, stimulation of pulmonary arterial epithelium
– Cor pulmonale
• Intake of sub-toxic doses for long time (about 1 mg)
– Megalocytosis
– VOD
– Fat degeneration of liver
– Adenomas or carcinomas
• Middle and South Africa
– Usage of several medicinal plants
– Crotalaria, Cynoglossum, Heliotropium and Senecio
• Mutagenicity
– senkirkine > monocrotaline > seneciphylline > senecionine >
7-acetyl-intermedine > heliotrine > retrorsine > 7acetyllycopsamine
> symphytine > jacoline > symlandine >
intermedine > indicine > lycopsamine > indicin N-oxide >
supinine
– Hydroxylation of structure decrease mutagenicity
• Teratogenity
– 50 to 200 mg alkaloid/kg of body weight
• Damage and changes
– Death of fetus
• More than 200 mg/kg
• Isoquinoline alkaloids
– Different structures
– Different biogenetic pathways
– Wide occurrence
– Isoquinoline nucleus
– Derived from tyrosine
– Tetrahydroisoquinoline
– Benzyltetrahydroisoquinoline
– Bis(Benzyltetrahydroisoquinoline)
– Amaryllidaceae
– Monoterpenoid
• Adlumine
– Phtalidoisoquinoline
alkaloid
– Adlumia fungosa, Fumaria
a Coryldalis spp.
Fumariaceae
– Convulsions, cardial
depression
– Gut stimulation
– Uterotonic
• Bicuculine
– Phtalidisoquinoline alkaloid
– Corydalis, Fumaria,
Adluminia Fumariaceae
– Antagonist of GABAA
– For experimental purposes
Adlumia fungosa
Fumaria officinalis
Corydalis lutea
• Allocryptopine
– Benzylisoquinoline alkaloid of
protoberberine type
– Bocconia spp., Chelidonium spp.,
Glaucium spp. Papaveraceae
– Corydalis spp. Fumariaceae
– Zanthoxylum spp., Fagara spp.
Rutaceae
– Thalictrum spp. Ranunculaceae
– Increases bond of GABA to
receptors (benzodiazepine
activity)
– Inhibition of phosphodiesterases
– Bond to adrenergic α-receptors
– Toxicity
• Non-specified cardial toxicity
N
O
O
OMe
OMe
CH3
O
Escholzia californica
Bocconia spp.
Chelidonium majus
• Androcymbine
– Androcymbium melanthoides Liliaceae
– Homomorphinan alkaloid
• Colchicine
– Colchicum spp., Gloriosa superba,
Merendera spp. Liliaceae
– Exocyclic amine derived from tyrosine
– Toxicity
• Toxin of cell division
– Inhibition
» Transport of proteins and
saccharides in neural cells
» Transport of vesicules to
memebranes
» Transport of chromosomes from
equatorial position to poles
– GIT, heart, neural tissue, haemopoiesis
• After consumation rapid absorption,
strong linkage to plasmatic proteins,
later biliar elimination
– Gut reabsorpce (lonf termed toxicity,
cumulation of low dosage)
O
MeO
OMe
MeO
MeO
N
CH3
OMe
MeO
MeO
N CH3
O
O
OMe
Androcymbium spp.
Merendera spp. Gloriosa superba
• Symptoms
– Similar to arsenic intoxication
• Burning of oral and throat mucosa
• Nausea, vomitus
• Stomach pain, colics, convulsive urination
• Watery and bloody bowel movement,
hemorrhage to GIT
• Loss of liquids, plasma, electrolytes
• Circulatory disorders, hypotension, tachycardia,
shock
• Toxicity
– Damage of liver tissue
– Damage of nerves
• Mental confusion, tonic-clonic convulsions
• Loss of tendinous reflexes
– Alopecia
– Lethal dosage variable
• 7 mg to 50 mg, 20-30 mg in average
– Acts slowly
• First symptoms in several hours
• Death comes first in 12 hours
• Bulbocapnine
– Aporphine type of alkaloid
– Corydalis spp., Fumaria spp.
– Glaucium spp. Papaveraceae
– Toxicity
• So called bulbocapnine
numbness
– Catatonia
– Slowering of cognitive
function
– Bizarre movements of
extremities
– High dosage
» Tremor, convulsions
» Circulatory disorders,
respiratory paralysis
• Inhibition of peristaltic
• Stimulation to paralysis of
uterus
• Hyperglycemia
NCH3
O
O
OH
MeO
• Erythrina alkaloids
– β-erythroidine, erysonine, erythratidine
– Erythrina spp. Fabaceae
• Mostly Erythrina americana
– Highest concentration in seeds
– Boiling lowers toxicity
– Toxicity
• Used as halucinogenic (Mexico)
• Vomiting and diarrhea
• Peroral administration of pure substances
– Neuromuscular blockator
» Curare-forming effect
» Sedative effect on CNS
» Depression of respiratory centre
N
O
O
MeO
•Morphine, codeine, heroine
–Morphinan alkaloids
–Effective levorotary form
–Morphinan type of alkaloids
• Typical for Papaver spp. Papaveraceae
• Morphine
–P. somniferum, P. setigerum Papaveraceae
–Stereospecific, reversibile linkage to opioid receptors
• At diiferent levels of CNS
–Agonist at presynaptic receptors of myelinized fibers
of small diameter
• Nociception, inhibition of substance P release
• Uprise of physical dependance
–Inhibition of enkephaline production and
simultaneous occupation of receptors
–Insufficiency of natural ligands and
morphinans
» Withdrawal syndrome
–Effect on respiration
• Depression of respiratory centre
–Decrease of sensitivity to hypoxia and pCO2
–Dependent on dose
–Tempo of onset dependent on way of
administration
–Miosis of central origin
–Depression of centre for cough
–Complex effect on centre for vomiting
• Nausea and vomiting
–Influence on hypophysis
• ↓secretion of FSH, LH, ACTH
–Influence on hypothalamus
• ↑secretion of ADH
–Influence on fibers of smooth muscles
• Constipation and urinary retention
• Morphine metabolism
• Symptoms of withdrawal
– Chronic users
• Nasal bleeding, perspiration,
lachrymation, anxiety
• Mydriasis, myalgia and pain of joints
• Insomnia, tachycardia, arrhythmias,
polypnoe, dispnoe
• Nausea, diarrhea
• Acute intoxication
– Usually overdose from different
reasons
– High dosage
• Immediate depression of CNS
– Lower dosage
• Initial short stimulation
• Successive malaise, fatigue,
somnolence
• Heart rate decreases and tends to fade
• Respiration slow and shallow
• Loss of consciousness
• Relaxation of muscles, extinction of
reflexes
• Cold, pale, wet skin
– If the dose high enough
• Coma, relaxation of muscles
• Circulatory failure, cyanosis
• Death caused by CNS depression
– Respiratory arrest
• Chronic intoxication
– Morphinism
• Short time of uprise
– Strong analgetic
– Experiments with drug
• Tolerance to dosage
• Combination of health
problems
– Social excomunication
» Psychical and
physical
dilapidation
– Criminality
– Prognosis adverse
» Accompanying
diseases
» Suicidal tendences
http://www.mujweb.cz/www/jpdepot/danger/Drugs.htm
• Thebaine
– Morphinane type of alkaloid
– Papaver somniferum, Papaver
bracteatum Papaveraceae
– Metabolism
• oripavine, nororipavine and codeine
– Symptoms similar to strychnine
• Higher doses convulsion
– Inhibitor of cholinesterase
– Stimulation of CNS
– ↑ deliberation of histamine
– More toxic than morphine, lower risk of
triggering dependence
O O
N
O H
O O
N
OH H
• Papaverine
– Benzylisoquinolin alkaloid
– Papaver somniferum
• In opium cca 1 %
– No effect on CNS
– Relaxation of smooth muscles
• Vessels, lungs, GIT
– Quinidine effect on heart
• Risc hypotension and
arrhythmias
– Symptoms of intoxication
• Cardiovascular system
• Headache
• Constipation, vomiting
• Sweating
N
MeO
MeO
OMe
OMe
• Sanguinarine
– Benzophenanthridine alkaloid
– Sanguinaria canadensis,
Papaver somniferum,
Chelidonium majus
Papaveraceae
– Fumaria officinalis
Fumariaceae
– Peroraly only low toxicity
– Parenteral administration
• Much higher toxicity
• Depressor of heart function
• Effect on CNS
– Symptoms
• Vomiting, gastritis, stomach
pain
• More difficult respiration
• Miosis, syncope
• Cardiac arrest
– Epidemiologic studies
• Higher incidence of glaucoma
O
O
O
O
N
+
• Tubocurarine
– Chondrodendron spp., mostly Ch.
tomentosum Menispermaceae
– Part of curare
• Active after parenteral administration only
– Competition with acetylcholine
• On the nicotine receptor of
neuromuscular disc
• Prevent formation of excitement
• No influence of other type of excitement
formation
• Do not prevent muscle contraction
triggered by direct stimulation
– Effect of curare
• Lowering of muscle tonus
• Advancing atonia
• Muscular paralysis
– Firstly face and eye lid
– Neck and numbs
– Abdominal and respiratory muscles
– Diaphragm
• Peripheral myorelaxant
• Effect not persisting
– Teratogenic
N
+
O
CH3
CH3
OH
OCH3
OOH
O
N
+
CH3
CH3
CH3
• Alkaloids of Amaryllidaceae
– Galanthus, Leucojum, Narcissus, Lycoris,
Amaryllis, Hippeastrum
– More than 100 of toxic alkaloids
– Several sub-groups
• Most important lycorine, galanthamine,
narciclasine
Lycoris radiata Amaryllis spp.
Hippeastrum equestre
Haemanthus spp.
• Galanthamine
– Reverse inhibitor of acetylcholinesterase
• Mostly in CNS
• Less on peripheria
– Disorders of atrioventricular transmission
– Bradycardia
– Nausea, vomiting, hypotension,
analgesia
• Lycorine
– Respiratory depression, death caused by
respiratory arrest
– Strong emetic
– Symptoms
• Vomiting, diarrhea, congestion of GIT
musosa
• Congestion of pleura and endocardium
– It is cytotoxic
• Narciclasine
– Antimitotic activity
• Inhibition of protein synthesis by blocking
the bigger ribosome subunit
N
OH
MeO
N
O
O
OH
OH
N
O
O
OH
OH
OOH
OH
• Monoterpenic
isoquinoline alkaloids
– Emetine
• Cephaelis spp. Rubiaceae
• Hedera spp. Araliaceae
– Intoxication
• Usually overdose of drug
• Muscular weakness,
tachycardia, abnormalities
on ECG
• Changes in ALT, AST
levels
• GIT malaise
– vomiting, diarrhea, pyloric
inflammation
• Lethal dose cca 1 gram
N
N
OMe
OMe
MeO
MeO