Bot 380: Stimulants II

What are the Cholinergic stimulants we discus?

Nicotine

Arecoline

What genus and family does tobacco belong to?

Genus Nicotiana ; Family Solanacea

How did Nicotene get its name?

In 1500: Jean Nicot introduces tobacco to France as ground leaves and seeds

In 1700 Linnaeus named the genus after Nicot

Where was the first tobacoo plantation in america?

In 1612 a Virginian colony obtains the seeds of Tobacco which becomes known as ‘Virginian Tabacco’

Why is harvesting tobacco dangerous? what are the symtoms?

Green Tobacco Sickness

• Essentially nicotine poisoning

• Occurs in contact with wet tobacco or sweat

Symptoms:

• Nausea

• Vomiting

• Headache

• Dizziness

Where is nicotene stored and synthesized in tobacco?

• Stored in leaf

• Synthesized in the root

• Derived from aspartic acid

Who first isolated Nicotene?

 Wilhelm Passel and Karl Reinmann in 1828, Germany

What are the phsyiological responses to nicotene?

• Stimulant, depressant, tranquilizer and narcotic

• Analgesic like effects

What is the difference between a low vs high dose of nicoteine?

Low nicotine

• Increased BP

• Increased HR

• Nausea, dizziness and general weakness

• Muscle relaxant

High nicotine

• Convulsions

• Death by suffocation; paralysis of breathing muscles

What does nicotine do in the CNS?

• Appetite suppression

• Reduces anxiety

• Actives dopaminergic reward system

What is the primary vs secondary MOA of nicotine?

Primary mechanism:

Mimics acetylcholine at nicotinic receptors that are present throughout the body

Secondary mechanism

May cause release of epinephrine from adrenal glands, norepinephrine and dopamine in the brain

How does nicotine act at cholinergic synapses?

Nicotine competes with acetylcholine for binding to the receptor; acts as an agonist, desensitizes the receptor, then acts as an antagonist

How efficent is smoking tobacco?

Efficient drug delivery; 90% potential to be absorbed; 12 mg of nicotine in a cigarette 1 mg delivered

What is the lethal dose for nicotine?

•  60 mg

What does the addiction to tobacco look like?

• Addiction = 15 cigarettes/day 7.5 -30 mg

Withdrawal symptoms may include craving, mood changes, cognitive deficits and sleep disturbance

→ Increased correlation of depression and smoking

How is tobacco habit forming?

• Positive reinforcement: causes mood elevation and cognitive enhancement due to stimulation of dopamine limbic system

• Negative reinforcement: anxiety reduction

T/F Nicotine can cause cancer?

True

There are toxic compounds in tobacco smoke

→ Increase in cancer, pulmonary and cardiovascular disease (inhibit cancer suppressor gene P53)

What is betel?

• A palm tree cultivated in India, Asia and Africa

• Fruit contains a nut with a single seed

• The nuts are chewed with lime as betel

• 100s of millions of people chew Betel

T/F Betel is a depressant?

False

It is a stimulant

Agonist of muscarinic acetylcholine receptors

What are the effects of betel?

• Increased HR and BP

• Increases memory and mental processing

• Adduction

• Health issues

• Oral cancer

What are the adrenergic stimulants we discuss?

Cocaine

Cathinone

Ephedrine

What is the coca plant?

Native to Columbia, Ecuador, Bolivia and Western Bolivia

→ Grows in small bushy trees that grow in warm, moist valleys

A very limited niche!

The leaves produce cocaine

Where was the coca plant first domesticated?

• Large scale cultivation in Peru, Bolivia and Columbia

• First cultivated in the eastern Andes of Bolivia ~7000 years ago

• Grown on mountain terraces called cocales

How was the coca plant historically used?

• Leaves are highly valued; used for centuries by Andes and Amazon regions people to allay hunger and fatigue and as a source of nutrients (high in vitamins)

• Chew dried leaves with mineral lime (aids in absorption)

• Distances measured in Cocadas

Who used Coca leaves as a currency?

The Inca Culture of Peru

Later adopted by the Spanish to pay workers

How was the coca plant introduced to European Society?

Vin Mariani

• Mix of red Bordeaux wine and coca leaf extract

• This was popular between 1844 and 1913

• Produced in Paris ‘strengthens, refreshes and restores the vital forces”

• Dispensed by prescription

Who endorsed vin mariani?

Jules Verne " a single bottle guarantees 100 years of life”

Pope Leo XIII : gave Mariani a gold medal as a token of esteem for the product

How was the Vin Mariani modified in the USA?

In the 1880s: An American pharmacist concocts an ‘intellectual’ beverage based on Vin Mariani; Pemberton's French wine coca

In 1886 during prohibition the wine is replaced with sugar syrup

What did coca cola originally contain?

• Coca leaf extract + African cola nuts

• High in caffeine

• Cocaine is removed in 1904

• Modern flavors contain a de-cocainized leaf extract for flavour

When was cocaine first isolated in its purified form?

In 1915 it was purified by Merck Co. In Germany

How was cocain initially used in the states?

As a local anesthetic

To alleviate depression and overcome withdrawl symptoms

In nerve tonics, patent medicines and elixirs

When was cocaine restricted?

• In 1914: the Harrison Narcotic Act classified cocaine as a restricted substance

How many kg per year does Peru produce per year legally and illegally?

50 million kg of leaves produced per year, and only 5 million kg exported legally

How many people are addicted to cocaine?

• 2 million people in America addicted to Cocaine

What does Evo Marales believe?

• Former coca grower; wishes to legalize coca for medicinal uses

• He proposes a zero cocaine not zero coca policy

What pathways are used for coco alkaloid synthesis?

Aliphatic or Aromatic amino acids = Alkaloids

Shikimic pathway or TCA pathway

What is the precursor to cocaine?

Ornithine

How is cocaine extracted from coca leaves?

• Mash leaves with alkali, kerosine or gasoline to form a free base form of alkaloids

• Coca paste is converted into water soluble from cocaine hydrochloride which is used medicinally or legall

What are the derivates to cocaine we discus?

ecgonine, tropine and hygrine

Why do people use cocaine?

• Exhilaration and vivid euphoria

• Greater capacity for work

• Long lasting mental or physical work without fatigue

• Complete elimination for food or sleep

What is the difference between low and high dose of cocaine?

Low Dose

• Increased HR, BP and temperature 

Increasing Use

• Convulsions and respiratory failure

• Cardiovascular collapse

• Liver damage

Extreme Dose

• Depression during withdrawal

• Suicidal thoughts

How can cocaine be used medicinally?

• Acts as a local anesthetic and vasoconstrictor

• Blocks conduction of sensory nerve impulses and constricts blood vessels

• Used as a local anesthetic in eye surgery and dentistry

• Replaced with novocaine which is non addictive

• Can be used in modern times as a local anesthetic

What is the MOA of cocaine?

Blocks reuptake transporters of dopamine and norepinephrine

Results in increased levels of neurotransmitters in the synapse

What is the difference between Dopamine and Norepinepherine?

D = brain neurotransmitter; affects limbic system and pleasure center and stimulates memory and emotions

N = stimulates heart and muscle contraction

Why do people get addicted to cocaine?

• Affects dopamine reuptake

• Associated with reward system in the brain 

• More dopamine = reward

• This means psychological and physical dependence

Why is cocaine overdose fatal?

Vasoconstriction of blood vessels

What is Chat?

• A small shrub endemic to Arabia and Ethiopia; brought to NA by african immigrants

• Leaves and green twigs chewed and infused into tea

What are the effects of Chat?

• General boost; alleviation of hunger and fatigue, euphoria and suppresses sexual drive

• Traditional uses = asthma, cough and fever

• Side effects = hypertension, aggression and personality changes

What plant does ephedra come from? where is it found?

Gnetophyta gymnosperms

• Small evergreen shrubs; Numerous species

• Found in Eastern Mediterranean, West Pakistan, North India, Tibet, Szechwan and Yunnan Provinces of China

• North American Ephedra found in American Southwest and Mexico

Where is ephedrine found?

Found in green branches, twigs and leaves

What are the natural amphetamines in ephedra?

70% Ephedrine + 20% Pseudoephedrine + 10% other

What is ephedrine derived from?

Phenylalanine

How was ephedra used Traditionally?

Chinese Herbal medicine; used for >5000 years for coughing fits, fevers and improved circulation

In Shen Nung Herbal: Ma Huang used to treat asthma

Used to create mormon tea

Who first isolated ephedrine?

•  Yamanashi a Japanese Chemist

What is the MOA of ephedrine?

• Sympathomimetic drug

• Mimics Nts normally active in the sympathetic nervous system

• Agonist at alpha and beta adrenergic receptors; where norepinephrine and epinephrine usually bind

• Promotes bronchial dilation and increases HR and BP

What are some other uses of ephedrine?

• Stimulates the CNS: counteract depressant effects during drug or alcohol induced comas

• Act as a vasoconstrictor and heart stimulator; treatment for hypotension

• Used in weight loss and cold medicines

Why is ephedrine no longer used in weight loss medicine?

Linked to stroke, increased HR and BP

What ae amphetamines? when were they discovered?

Synthetic Epinephrine

In the 1920s synthetic and discovery of amphetamines and derivatives

These are used as substitutes for ephedrine

What is an example of an early amphetamine?

 Benzedrine is the first synthetic amphetamine used in 1932 to clear nasal passages and to treat narcolepsy. It becomes known for its euphoric effects.

What is the MOA of amphetamines?

• Travels into nerve terminal through reuptake transporters; displaces NTs from vesicles in the synapse

• Inhibits intracellular metabolism of NTs

• Increase in nerve terminal Nts cases reuptake transporters to run in reverse = floods synapse with the NT

= Increases in dopamine and norepinephrine in synapse