Download Plant Drugs that Affect the Autonomic Nervous System

Plant Drugs that Affect the
Autonomic Nervous System
Major Divisions of the Nervous System
• Central nervous system (CNS)
– brain and spinal column
• Peripheral nervous system (PNS)
– somatic nervous system: innervates skeletal muscle
during voluntary movement (efferent system) &
sensory nerve endings for touch and pain (afferent
system)
– Autonomic nervous system (ANS): controls
involuntary responses that maintain homeostasis
Major Divisions of the Autonomic Nervous
System
• Sympathetic Nervous System &
• Parasympathetic Nervous System
– the two systems work antagonistically: inhibition
of one system tends to produce effects that
resemble the stimulation of the other system
Sympathetic Nervous System
• Catabolic system that expends (burns) energy
• Nerves in this system originate from the thoracolumbar regions
• “Fight or flight” responses to danger:
–
–
–
–
–
–
–
increase in heart rate & force of ventricular contractions
shunting blood to muscles and heart
increase in sweat gland secretion
dilates pupils
dilates bronchial tubes
inhibits GI motility and secretions, contracts GI sphincters
stimulates secretion of adrenaline from adrenal medulla
Parasympathetic Nervous System
• Anabolic system that promotes the conservation and
storage of energy
• Nerves in this system originate from the cranial and
sacral regions
• promotes digestion and storage of food
–
–
–
–
contracts pupils
stimulates secretion from lacrimal and salivary glands
decreases heart rate and force of ventricular contractions
constricts bronchia and stimulates bronchial gland
secretion
– stimulates motility and secretion of GI tract
– relaxes GI sphincters
– contracts bladder
Peripheral (Efferent) Nervous System:
Neurotransmitters & Receptors
CNS
Sympathetic
nicotinic receptor
adrenergic receptor
Parasympathetic
muscarinic receptor
Somatic Motor
nicotinic receptor
nicotinic and muscarinic receptors = cholinergic receptors
Sympathetic Nervous System Adrenergic
Receptors (Stimulated by Endogenous
Norepinephrine)
• alpha receptors – reduce glandular secretions, GI
motility, increase constriction of certain arterioles
and veins
• beta receptors – increase heart rate,
contractions, increase kidney renin secretion,
relax trachea and bronchioles, dilate some
arterioles and veins (not in skin or brain),
increase breakdown of fats to release energy
• Epinephrine (adrenaline) – main neurohormone
produced by the adrenal medulla – the most
potent endogenous stimulator of adrenergic
alpha and beta receptors
Parasympathetic Nervous System Receptors
(Stimulated by Endogenous Acetylcholine)
• Nicotinic receptors – are located in the
autonomic ganglia of both the sympathetic
and parasympathetic systems (and the nerve
endings of the somatic motor system)
Parasympathetic Nervous System Receptors
(Stimulated by Endogenous Acetylcholine)
• Muscarinic receptors - are associated with
parasympathetic functions and are located at
the ends of postganglionic neurons in
peripheral tissues (effectors, e.g., glands,
smooth muscle) innervated by the
parasympathetic system
Parasympathetic Nervous System Receptors
(Stimulated by Acetylcholine)
• Nicotinic receptor - a channel protein that,
upon binding by acetylcholine, opens to allow
diffusion of cations
• Muscarinic receptor - a membrane protein:
upon stimulation by neurotransmitter, it
causes the opening of ion channels indirectly,
through a second messenger. For this reason,
the action of a muscarinic synapse is relatively
slow.
Drugs that affect the autonomic nervous system:
• agonists – substances that stimulate receptors
• antagonists – substances that block a receptor
• drugs that have chemical or molecular
resemblance to endogenous
neurotransmitters (acetylcholine or
norepinephrine) of the ANS can stimulate or
inhibit this system
Parasympathetic Agonists
• Modes of action:
– direct agonistic action on the receptor
– inactivation of acetylcholinesterase (enzyme that
breaks down acetylcholine), resulting in
accumulation of acetylcholine in synaptic cleft
Muscarinic Cholinergic Receptor Agonists
• Acetylcholine (endogenous neurotransmitter)
• Synthetic choline esters (methacholine,
carbachol, betanechol)
• Cholinomimetic plant (and fungal) alkaloids:
– muscarine
– pilocarpine
– arecoline (also affects nicotinic cholinergic
receptors)
Muscarine
• compound isolated from various species of
fungi:
• Amanita muscaria, Amanita spp., Inocybe spp.
and Clitocybe spp.
• common name: amanita, fly agaric
• origin: Siberia, North America
• habit: mushroom with red, orange, yellow or
cream colored cap with white spots. Grows on
forest floor
Muscarine, cont.
• Ethnomedical/cultural uses:
– mushroom eaten by Siberian indigenous people as
hallucinogen
– dried mushrooms repel flies
• compounds with hallucinogenic (CNS) activity:
– ibotenic acid, muscimole, muscazone
• PSN principle active compound: muscarine
Muscarine, cont.
• chemical class: quaternary ammonium alkaloid
• chemical derivatives: muscarine  oxotremorine
• Muscarine effects: diaphoretic, salivation, lacrimation,
vision problems, nausea, vomiting, diarrhea,
hypotension, brachycardia, bronchiospasm
• Oxotremorine effects: stimulates receptors in basal
ganglia and produces parkinsons-like effects (spasticity
or tremor)
• Modern medical uses: neurobiological research
(understanding muscarinic receptors)
• Antedote: 1 – 2 mg of atropine IM every 30 min
Pilocarpine
• Isolated from Pilocarpus jaborandi, P.
microphyllus
• Plant family: Rutaceae (citrus family)
• Common name: Jaborandi (means slobber
mouth plant in Tupi language)
• Origin: lowland wet forests of Tropical
America, West Indies
• Ethnomedical uses: members of the Tupi
culture in Brazil chew leaves to induce
salivation and sweating
Pilocarpine, cont.
• Chemical class: tertiary amine alkaloid
• Mechanism of action: cholinergic receptor
agonist with strong postganglionic (muscarinic
receptor) stimulation and mild ganglionic
(nicotinic receptor) stimulation
• Muscarinic receptor stimulation effects:
– salivation
– intestinal motility
– pupil constriction
Pilocarpine, cont.
Therapeutic uses:
• Topical application to eye constricts pupils
– treats open-angle glaucoma by reducing
intraocular pressure
• Oral administration treats dry mouth
(xerostoma)
• Also used to reduce side effects of
morphine treatment, including:
– dry mouth
– constipation
– urinary retention
• Overdose may cause cardiovascular collapse
• Antedote is atropine (conversely,
pilocarpine is sometimes used as an
antedote in cases of atropine poisoning)
Arecoline
•
•
•
•
From Areca catechu
Plant family: Arecaceae (palm family)
Common name: betelnut, betel, areca nut
Origin: tree in wet forests of S Asia,
Indomalaysia, Oceania, probably originally
from Sulawesi (Indonesia)
• Ethnobotanical use: Used as a masticatory
(chew): the areca seed is rolled in leaves of
Piper betel and mixed with gambir (a spice
made from the boiled leaves of Unicaria
gambir) and shell lime (which changes pH to
release active compounds)
Arecoline, cont.
• Ethnomedical uses:
– euphoretic
– cardiac tonic
– energizer
– antihelminthic
• Chemical structure: arecoline is an alkaloid
• Chemical derivative: arecoline  aceclidine
(glaucoma treatment in Europe)
• Arecoline stimulates both muscarinic and
nicotinic receptors (in ANS and CNS)
Parasympathetic Agonists: Anticholinesterase
Compounds
• prevent hydrolysis of acetylcholine by
acetylcholinesterase at cholinergic
transmission sites, resulting in an
accumulation of the transmitter
• some synthetic compounds with this type of
activity include:
– insecticides (parathion, malathion)
– nerve poisons (sarin, tabun)
Physostigmine
• From Physostigma venemosum
• Plant family: Fabaceae (pea or bean family)
• Common names: calabar, ordeal, or esere
bean
• Origin: rainforests of West Africa
• Habit: a perennial woody vine (liana)
• Cultural origins: used by the Efik people of the
Calabar region of SE Nigeria
Physostigmine, cont.
• Ethnomedical uses:
– dry beans as ordeal poison in witchcraft trials
– perceived ability to “reveal” and “destroy”
witchcraft…suspected witch is given a drink of
ground up beans in water: if guilty, mouth shakes
and mucous comes out of nose (and/or the
person dies), if innocent, the suspect will only
vomit
• beans still carried today for protection against
witchcraft
Physostigmine, cont.
• Chemical class: indole alkaloid
• Chemical derivatives:
• neostigmine
• pyridostigmine
• edrophonium
• demecarium
Physostigmine, cont.
• Mechanism of action:
– inhibits acetylcholinesterase in postganglionic
nerves & myoneural nerve endings (somatic
motor neurons)
• Physiological cholinergic effects:
– diaphoresis (sweating)
– reduced heart rate
– smooth muscle stimulation in intestines and
bladder
Physostigmine, cont.
Modern medical uses of physostigmine and derivatives –
• Physostigmine:
• glaucoma
• antedone for anticholinergic (e.g., atropine) poisoning
• Neostigmine, pyridostigmine, demercarium:
• intestinal stimulant
• treatment of myasthenia gravis (muscle weakness
disease with defect in myoneural conduction)
• Edrophonium:
• used to diagnose and treat myasthenia gravis
Intermission
Peripheral Nervous System:
Neurotransmitters & Receptors
CNS
Sympathetic
nicotinic receptor
adrenergic receptor
Parasympathetic
muscarinic receptor
Somatic Motor
nicotinic receptor
nicotinic and muscarinic receptors = cholinergic recepto
Antimuscarinic (Anticholinergic)
Compounds
• Parasympathetic depressants – substances
that are muscarinic receptor antagonists
• The plant family Solanaceae is the major
natural source of antimuscarinic compounds
• Tropane alkaloids
Solanaceae
Antimuscarinic (Anticholinergic)
Compounds
• Tropane alkaloids from the Solanaceae:
– atropine
– scopolamine
– hyoscyamine
Antimuscarinic (Anticholinergic)
Compounds
Tropane Alkaloids:
• Resemble chemical structure of acetylcholine, but
act as antagonists at receptor
• Bind to postganglionic parasympathetic receptors
and block access of acetylcholine
• Interfere or block the normal transmission of
postganglionic parasympathetic messages
• Also can have a CNS effect (especially
scopolamine)
• Synthetic muscarinic receptor antagonists include
tricyclic antidepressants
Atropa belladona
Atropa belladonna
• Common name: belladonna
• historically used as a cosmetic to
enlarge pupils
• also used to poison various Roman
emperors
• Origin: Europe
• Also traditionally used as an:
– analgesic
– intestinal antispasmodic
– hallucinogen (a component of witches
“flying ointment” in the Middle Ages
in Europe)
Atropa belladonna
Active compounds:
• atropine (first isolated in 1831)
– anticholinergic at muscarinic receptors
– pupil dilator (mydriatic)
– cardiac stimulant
• Hyoscyamine
– anticholinergic at muscarinic receptors
– analgesic
– antispasmodic
• Scopolamine
– anticholinergic and has CNS effects
– pupil dilator
– hallucinogen
Atropa belladonna
Therapeutic uses of belladonna and its tropane alkaloids:
• A. belladonna tincture:
– used as an intestinal antispasmodic and analgesic
• Scopolamine:
– used to dilate pupils, used to treat motion sickness (unfortunate side
effect of hallucinations)
• Hyoscyamine:
– used as an analgesic, sedative, and antispasmodic
• Atropine:
– used as a pupil dilator, cardiac stimulant, treatment for brachycardia,
treatment for organophosphate or insecticide poisoning (counteracts
effects of muscarinic agonists)
– Lomotil (atropine-diphenoxylate): reduces intestinal motility to treat
diarrhea
– Atrovent (ipatropium bromide): a bronchodilator used to treat asthma
Hyoscyamus niger & H. muticus
Hyoscyamus niger & H. muticus
• Common name: Henbane
• Hyoscyamus niger:
– from Eurasia, N. Africa
• Hyoscyamus muticus:
– from India to Egypt, grown in CA
• Habit:
– herbaceous plant in open fields and
disturbed areas
• Plant parts used:
– leaves, flower tops (rich in hyoscyamine)
– leaves seeds (rich in scopolamine)
Hyoscyamus niger & H. muticus
Ethnomedical uses:
• used in many cultures in Europe, Egypt, Near
East and Asia as an:
– antispasmodic
– analgesic
– mydriatic (pupil dilator)
– inebriant / hallucinogen
Hyoscyamus niger & H. muticus
Active compounds:
• hyoscyamine
– anticholinergic at muscarinic receptors
– analgesic, sedative, intestinal
antispasmodic
• scopolamine
– anticholinergic, also CNS effects
– pupil dilator and treatment for motion
sickness
Mandragora officinarum
Mandragora officinarum
• Common name: Mandrake
• Origin: Europe to the Himalayas
• Habit: herb with thick tuberous
roots that sometimes resemble a
human
• Cultural origins: used by many
cultures in Europe and Asia
Mandragora officinarum
Mandragora officinarum
“The root was to be picked before dawn on a
Friday morning by a black dog, then washed
and "fed" with milk and honey and, in some
prescriptions, blood, whereupon it would fully
develop into a miniature human which would
guard and protect its owner.”
Mandragora officinarum
• All parts of plant contain
hyoscyamine
• Therapeutic uses:
– intestinal antispasmodic
– analgesic
– sedative
– used as an anesthetic in surgery
until the introduction of ether in
the mid 1800s
Datura stramonium
Datura stramonium
• Common names:
– Algonquin: wysoccan
– English: Jimson weed,
Jamestown weed, thorn apple
• Origin: North America, now
naturalized around the world
• Habit: herb with erect flowers
that grows in open fields and
disturbed areas
Datura stramonium
Ethnomedical uses:
• leaves, fruits taken orally for:
– asthma
– sedative
– hallucinogen (esp. the seeds)
• Algonquins of the eastern US gave wysoccan
to boys as a hallucinogen for 18-20 days in
adolescent ceremony…after completion of
ceremony, they were considered adults
Datura stramonium
Active compounds:
• Scopolamine
• Hyoscyamine
Therapeutic uses:
• pupil dilation,
antispasmodic, analgesic
other Datura species
• Ethnomedical uses: sacred psychogenic &
hallucinogen
• D. innoxia – sacred hallucinogen in SW US and
Mexico
• D. ceratocaula – used by Aztecs
• D. candida – Colombia & South America
• D. metel – native to India, used by Hindu
sadhus for spiritual experience…this painting
sometimes present in paintings of Shiva
Datura innoxia – US Southwest & Mexico
Datura ceratocaula – Central America
Datura candida – Colombia, South America
Datura metel - India
Datura metel - India
Brugmansia spp.
• Common name: trumpet flower
• Perennial shrubs and trees with pendulous
flowers
• Chemistry: tropane alkaloids, especially
scopolamine
• Ethnomedical uses: sacred psychoactive with
intense intoxication followed by hallucinations
Brugmansia spp.
• Brugmansia aurea – different varieties with
different hallucinogenic properties are
propagated vegetatively by shamans in South
America
Brugmansia aurea
Brugmansia spp.
• Brugmansia sanguinea – used as a
hallucinogen and medicine by South American
cultures from Chile to Colombia
Brugmansia sanguinea