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CNS Stimulants

Chapter 10
CNS Stimulants
- Psychomotor stimulants and hallucinogens

- Pyschomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, increase motor activity

- Hallucinogens or psychotomimetic drugs produce changes in though patterns and mood with little effect on brainstem and spinal cord
Psychomotor Stimulants
- Methylxantines
- Nicotine
- Varenicline
- Cocaine
- Amphetamine
- Methylphenidate
- Theophylline which is found in tea
- Theobromine which is found in cocoa
- Caffeine in coffee, cola, chocolate, cocoa
Mechanism of action of Methylxantines
- Different actions proposed
- Translocation of extracellular calcium, increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate, blockade of adenosine receptors
Actions of Methylxantines
CNS - decrease in fatigue, increased mental alertness, in excess can produce anxiety and tremors, spinal cord stimulated at very high doses, tolerance can develop, withdrawal consists of fatigue and sedation

Cardiovascular system - at high doses it has positive inotropic and chronotropic effects on heart

Diuretic action - increases urinary output of sodium, chloride and potassium

Gastric mucosa - stimulate secretion of hydrochloric acid from the gastric mucosa, people with peptic ulcers should avoid foods and beverages containing methylxanthines
Therapeutic uses of Methylxanthines
relax smooth muscle of bronchioles
Pharmacokinetics of Methylxanthines
- well absorbed orally and distribute throughout the body including the brain
- cross placenta to fetus and are secreted into mothers milk
- metabolized in liver by CYP1A2 pathways, excreted in urine
Adverse effects
- moderate doses cause insomnia, anxiety, agitation
- high doses required for toxicity, manifested by emesis and convulsions
- 10 g of caffeine causes cardiac arrhythmias
- headaches occur from withdrawal
- active ingredient in tabacco
- second to caffeine for most used CNS stimulant
- risk factor with lung and cardiovascular disease, cancer, etc
- dependency not easily overcome
- not currently used therapeutically
Nicotine Mechanism of Action
- in low doses, can cause ganglionic stimulation by depolarization
- at high doses, causes ganglionic blockade
- receptors exist at number of sites in CNS which participle in stimulant attributes of the drug
Actions of Nicotine
1. On CNS
- highly lipid soluble and readily crosses blood brain barrier
- produces euphoria and arousal and relaxation at lose doses, as well as improving attention, learning, problem solving
- at high doses, results in paralysis and hypotension
- appetite suppressant

2. On Peripheral
- inc blood pressure and heart rate
- harmful in people with hypertension
- vasonconstriction and inc bowel activity
Pharmacokinetics of Nicotine
- highly lipid soluble
- absorbs readily via oral mucosa, lungs, GI, skin
- crosses placental membrane, secreted in milk
- 1 to 2 mg of nicotine per cigarette
- lethal dose is 60 mg
- 90% inhaled is absorbed
- tolerance develops
Adverse effects of Nicotine and Withdrawal syndrome
- irratability and tremors, intestinal cramps, diarrhea, inc heart rate and inc blood pressure
- inc the rate of metabolism of other drugs

- dependence develops rapidly and is severe
- Buproprion, an antidepressant, can reduce craving
- partial agonist at neuronal nicotinic acetylcholine receptors in CNS
- produces less euphoric effects than nicotine
- useful in adjunct management of smoking cessation in patients with withdrawal symptoms from nicotine
- should be monitored for suicidal thoughts, nightmares and mood changes
- widely available and highly addictive drug that is currently abused daily by more than 3 million people in US
- Schedule II drug by DEA
Cocaine Mechanism of Action
- blockade of reuptake of the monoamines (norepinephrine, serotonin, dopamine) into the presynaptic terminals from which these neurotransmitters were released
- prolongs effects of neurotransmitters
- chronic intake of cocaine depletes dopamine which triggers vicious cycle of craving for cocaine that temporarily relieves severe depression
Actions of Cocaine
1. CNS
- stim cortex and brainstem
- increases mental awareness and produce feeling of wellbeing and euphoria
- produce hallucinations and delusions, paranoia
- tremors and convulsions at high doses with respiratory and vasomotor depression

2. Sympathetic nervous system
- potentiates the action of norepinephrine and produces fight or flight syndrome characteristic or adrenergic stimulation
- tachycardia, hypertension, pupillary dilation, peripheral vasoconstriction

3. Hyperthermia
- death from dose or from hyperthermia
- deaths rise in hot weather
- impairs sweating and cutaneous vasodilation
- perception of thermal discomfort is impaired
Therapeutic uses for Cocaine
- local anesthetic action
Pharmacokinetics of Cocaine
- self administered by chewing, snorting, smoking, IV
- peak effect 15 to 20 mins after, high disappears after 1 to 1.5 hours
- rapid but short lived
- excreted in urine
- deesterfied and demethylated to benzoylecgonine
Adverse effects of Cocaine
- Anxiety
- Depression
-Toxic effects
- seizures, cardiac arrhythmias
- sympathetic amine that shows neurologic and clinical effects like cocaine
- Dextroamphetamine, Methamphetamine
Mechanism of Action of Amphetamine
- effects of CNS and peripheral nervous system are indirect
- depend on elevation of level of catecholamine neurotransmitters in synaptic spaces
- Amphetamine releases intracellular stores of catecholamines and inhibits monoamine oxidase (MAO)
Actions of Amphetamine
1. On CNS
-dopamine and norepinephrine release enhancing properties
- stimulates cerebrospinal axis, cortex, brainstem, medulla
- increased alertness, decreased fatigue, depressed appetite, insomnia
- use in hyperactive kids, narcolepsy, appetite control

2. On sympathetic nervous system
- acts on adrenergic system, indirectly stimulating receptors through norepinephrine release
Therapeutic uses of Amphetamine
- limited due to psychological and physiological dependence

- attention deficit hyperactivity disorder (ADHD)
- narcolepsy
Pharmacokinetics of Amphetamine
- completely absorbed in GI tract, metabolized in liver and excreted in urine
- euphoria lasts 4 to 6 hours
Adverse effects of Amphetamine
- cause addition, leading to dependence, tolerance, drug seeking behavior

1. On CNS
- insomnia, irratability, weakness, dizziness, tremor, confusion, delirium, panic, suicide

2. On cardiovascular
- palpitations, cardiac arrhythmias, hypertensions, anginal pain, circulatory collapse, headache, chills, excessive sweating
- can't give to cardiovascular disease patients or people taking MAOI

3. On GI system
- anorexia, nausea, vomitting, abdominal cramps, diarrhea
- Sodium bicarbonate increases reabsorption of dextroamphetamine from renal tubules to bloodstream

4. Contraindications
- patients with hypertension, cardiovascular disease, hyperthyroidism, glaucoma should not be treated
- don't give to drug addicts
- may lead to abuse, although addictive potential is controversial
- Schedule II drug
- most prescribed in kids, 4 to 6 million take it for ADHD
Mechanism of Action of Methylphenidate
- dopamine transport inhibitor and acts by increasing dopamine for synaptic space
Therapeutic uses for Methylphenidate and Pharmacokinetics
- used for treating ADHD in children
- methylphenidate for treatment of narcolepsy

- methylphenidate and dexmethylphenidate absorbed upon oral administration
- have extended release capsules and patches
- ritalinic acid excreted in urine
Adverse reactions and Drug interactions with Methylphenidate
- GI effects common, ab pain, nausea
- anorexia, insomnia, nervousness, fever
- can increase seizure frequency
- Methylphenidate contraindicated in patients with glaucoma

- Methylphenidate can interfere in metabolism of warfarin, phenytoin, phenobarbital, prim done, tricyclic antidepressants
- ability to induce altered perceptual states reminiscent of dreams
- visions of bright colorful changes in environment, changing shapes and color
- people under the influence are incapable of normal decision making bc it interferes with rational thought
- called hallucinogens or psychotomimetic drugs
- Lysergic acid diethyl amide
- tetrahydrocannabinol
- phencyclidine
Lysergic acid diethylamide
- multiple sites in CNS affects
- shows serotonnin agonist activity of presynaptic receptors in midbrain
- pupillary dilation, increased blood pressure, piloerection, increased body temp
- taken orally
- true dependence rare
- can cause hyperreflexia, nausea, muscular weakness
- haloperidol and neuroleptics can block hallucinatory action of LSD and abort syndrome
- psychoactive alkaloid contained in weed is drocannabinol
- to treat emesis and stimulate appetite
- THC can produce euphoria, followed by drowsiness, relaxation
- adversely effect short term memory and mental activity
- peak of 2 to 4 hours
- cause increased heart rate, decreased blood pressure, reddening of conjuctiva
- tolerance and mild dependence develop

- Rimonabant not currently available in US, may treat obesity but cause psychiatric disturbances like anxiety and depression
- angel dust
- inhibits reuptake of dopamine, norepinephrine
- anticholinergic activity but produces hyper salivation
- numbness to extremities, staggered gait, slurred speech, muscular rigidity
- hostile and bizarre behavior
- coma with eyes open
- no therapeutic applications, manufacture is illegal in US
- tolerance with continued use
- CNS actions last a week