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 thoraco-

lumbar 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

nicotinic receptor

nicotinic receptor

muscarinic receptor

adrenergic receptor

Sympathetic

Parasympathetic

Somatic Motor

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

nicotinic receptor

nicotinic receptor

muscarinic receptor

adrenergic receptor

Sympathetic

Parasympathetic

Somatic Motor

nicotinic and muscarinic receptors = cholinergic receptors

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 belladonnaActive 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 belladonnaTherapeutic 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