Nicotine and tobacco toxicity

Laboratory of Toxicology

College of Pharmacy
2016
Nicotine and Tobacco Toxicity

• Nicotine is a bitter-tasting compound that naturally occurs in large amounts in the leaves of tobacco plants
• Leaves of Nicotiana tobacum dried and (usually) smoked
nicotine







• Cigarette smoke contains thousands of different chemicals, or 'smoke constituents,' also referred to as 'smoke emissions'
• The most commonly known smoke constituents are tar, nicotine and carbon monoxide (CO). In addition to these, more than 7,000 chemicals have been identified in tobacco smoke to date
• Tobacco and nicotine can be addictive like alcohol, cocaine, and morphine
Nicotine and tobacco

Nicotine and tobacco

• Nicotine use can have many different effects on the body:
• Decreases the appetite
• Increases activity of the intestines
• Creates more saliva and phlegm
• Increases heart rate
• Increases blood pressure
• Sweating, nausea, and diarrhea
• Boosts mood and may even relieve minor depression
• Stimulates memory and alertness
Nicotine and tobacco

• Absorption

• Lungs, oral mucosa, skin, Intestinal tract increase in in more alkaline environment
• Volume of distribution
• Approximately 1 L/kg
• Protein binding
• 5-20%
• Metabolism
• 80-90% hepatic, rest in lung, kidney.
• principle (inactive) metabolite is cotinine
• Half-life
• Nicotine 1-4 h decrease with repeated exposure, cotinine 19-20h
• Excretion
• 2-35%excretea unchanged in urine
Pharmacokinetics of nicotine


Pharmacokinetics of nicotine
Nicotine absorption
• Lungs (nicotine enters the brain with in 7 seconds)
• Skin (slower absorption, more constant blood levels)
• Stomach, poor ( acid- base interaction), better in intestine
• Treatment options: Behavior modification
• Nicotine lozenges
• Nicotine gum
• Nicotine patches
• Nicotine inhaler
• Nicotine nasal spray

Pharmacodynamics of nicotine

• Nicotine is a direct agonist for nicotinic ACh receptors (nAchRs)
• Low dose: Stimulate receptors
• High dose: Block receptors
• nAchRs found in brain, Muscles, Lymphoid tissue, Macrophages, Skin, Lung cells, Vascular tissue
•

Pharmacodynamics of nicotine

• nAChRs found in limbic system (e.g. striatum, hippocampus, accumbens), midbrain (e.g. VTA, substantia nigra), various cortical areas (frontal lobe)

• nAChRs are involved in a wide range of physiological and pathological processes

• Learning and memory
• Motor control and analgesia
• nAChRs both postsynaptic and presynaptic, facilitating ACh, DA, 5-HT and Glutamate action
• Nicotine also increases release of various neurohormones
• Has powerful effects on peripheral nervous system, heart, and other organs
Pharmacodynamics of nicotine


• Nicotine initially causes a rapid release of adrenaline, the "fight-or-flight" hormone
• NE, Ach, glutamate, serotonin, GABA, and dopamine are released by nicotine and associated with mood enhancement , appetite suppression and energy expenditure and anxiety reduction

Pharmacodynamics of nicotine

Low blood nicotine level
Pharmacodynamics of nicotine
Craving to nicotine
Dopamine release
Inhale more nicotine

Neuromuscular System

Many of the effects of nicotine result from its effects on the neuromucular system which is made up of the brain and muscle. In order to understand the physiological response to nicotine, I would like to review with you some of the physiology of the neuromuscuar system. The neuromuscular system is consists of the connections between the brain and muscle. The brain connects to the muscle fiber by a special neuron called the motoneuron. The place of contact between the motoneuron and the muscle is called the NEUROMUSCULAR JUNCTION.

Motorneuron

Muscle Fiber

Signal from

the Brain


Nerve Terminal
Neuromuscular System
Normally, a signal from the brain stimulates a signal in the motorneuron. The signal travels down the motorneuron to the nerve terminals (the ends of the neuron).

Motorneuron

Muscle Fiber

Signal from

the Brain

Acetylcholine (ACh)

Neuromuscular System
A chemical called acetylcholine is then released from the motorneuron terminal and binds to proteins called receptors on the muscle fiber

Motorneuron

Muscle Fiber

Signal from

the Brain

Acetylcholine (ACh)

Neuromuscular System
Binding of acetylcholine to its receptor results in muscle contraction. Normally, folowing its release and action at its receptor, acetylcholine is broken down and can no longer exert its effects allowing the muscle to relax.


Motorneuron
Muscle Fiber

Signal from

the Brain

Nicotine

Neuromuscular System
Nicotine, however is not broken down but is able to mimic the effects of acetylcholine at its receptor thus it is as if acetylcholine is always in the synapse and the muscle remains is unable to relax.

Nicotinic Syndrome

• Acute exposure to high dose nicotine produces a syndrome or set of specific symptoms called the nicotinic syndrome
Nicotine toxicity
The neuromuscular system controls the muscle in many body organs via the acetylcholine receptor. Thus, nicotine produces effects in multiple body organs but the response is different depending on length of exposure. The nicotinic syndrom is characterized by...

Nicotine produces

tachycardia
And increase the blood pressure
through its action in
the sympathetic
nervous system or
the “Fight or Flight”
system
Increases in heart rate or tachycardia and blood pressure due to nicotine’s action in the branch of the neuromuscular system called the sympathetic nervous system or the fight or flight system which controls heart rhythm.


Nicotine decreases appetite

Acute action of nicotine in the enteric branch of the neuromuscular system which controls muscle tone in the GI tract results in loss of appetite.

Nicotine’s action on

skeletal muscles
and the diaphragm
to produice paralysis
and asphyxiation

paralysis and asphyxiation due to nicotine’s action on the diaphragm and skeletal muscle (muscle attached to the bone).

Chronic Effects of Nicotine

Chronic exposure to low dose nicotine also effects the neuromuscular system but leads to a different set of consequences.


Chronic administration
leads to coronary artery
disease and
hypertension

Nicotine produces peptic

ulcer disease, and esophageal
reflux through its influences
on the Gastrointestinal tract.

Nicotine enhances

learning and memory

Nicotine’s influences

in the brain also
produces its addictive
properties

• Acute nicotine toxicity

• N/V, Salivation, diarrhea, dizziness, mental confusion, and weakness.
• Fatal exposure (60 mg for adults, oral LD50=0.8mg/kg)
• Decreased blood pressure, breathing difficulty, irregular pulse, convulsions, respiratory depression, and death
• Death is usually due to paralysis of respiratory muscles and/or central respiratory failure
Nicotine toxicity


• GIT
• Respiratory
• Cardiovascular
• Neurologic
• Early (0.25-1 h)
• Nausea
• Vomiting
• Salivation
• Abdominal pain
• Bronchorrhea
• hyperpnea
• Pallor
• Tachycardia
• hypertension
• Agitation
• Anxiety
• Tremors
• Seizures
• Late (0.5-4 h)
• Diarrhea
• Hypoventilation
• apnea
• Bradycardia
• Hypotension
• Dysrhythmias
• shock
• Lethargy
• Weakness
• paralysis
Nicotine toxicity


• Withdrawal effects
• Restlessness
• Anxiety, hostility
• Irritability
• Weight gain
• Depression
Nicotine toxicity

Acute Inhalation Toxicity - Acute Toxic Class Method

2mg/L, 5 mins

10mg/L, 25 mins