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Defination

“Stimulants are a substance which tends to increase behavioral activity when administered”

Few clinical uses, Important as drugs of abuse.Factors that limit the therapeutic usefulness include:1.Dependence: Psychological and physiological.2.Tolerance to the euphoric and anorectic effects

are classified according to their action into:Psychomotor stimulantsHallucinogen (psychotomimetic or psychedelics) drugs

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1. Psychomotor stimulants cause: Excitement, Euphoria, Decrease feeling of fatigue & Increase motor activityEx., Methylxanthines (caffeine, theobromine, theophylline), nicotine, cocaine, amphetamine, atomoxetine, modafinil, methylphenidate.

2. Hallucinogens (psychotomimetic):Affect thought, perception, and mood, therefore produce profound changes in thought patterns & mood, little effect on the brain stem & spinal cord Ex., Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol (THC), Rimonabant.

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Q. What are Stimulants?Answer. Chemical stracture are similar to

monoamine neurotransmitters. All are indirect-acting sympathomimetics:

1. Many CNS stimulants release catecholamines, Therefore, their effects are abolished by prior treatment with reserpine or guanethidine

Ex: amphetamine, dextroamphetamine, methamphetamine, methylphenidate (Ritalin), ephedrine, pseudoephedrine (a stereoisomer of ephedrine), tyramine.

2. Other CNS stimulants block the reuptake of catecholamines (NE and DA) and serotonin:

EX. Cocaine, sibutramine (reduct)®, modafinil

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Attention Deficit Hyperactivity Disorder (ADHD); lack the ability to be involved in any one activity for longer than a few minutes. Narcolepsy: It is a relatively rare sleep disorder, that is characterized by uncontrollable bouts of sleepiness during the day. It is sometimes accompanied by catalepsy, a loss in muscle control, or even paralysis brought on by strong emotion, such as laughter.Contraindications: patients with anorexia, insomnia, asthenia, psychopathic personality, a history of homicidal or suicidal tendencies.

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I. Cocaine, Crack (free base or hydrochloride).II. Amphetamines:

D-Amphetamine, Methamphetamine, methylphenidate (use to treat attention deficit disorders in children), phenmetrazine (Preludin) - used to treat obesity,

III. Methylxanthines: caffeine (coffee), theophyline (tea), theobromide (chocolate).

Alkaloid from Erythroxylon coca

Indigenous to western South America

Coca leaves used for religious, mystical, social, stimulant, and medicinal purposes

Main stimulant uses: endurance, feeling of well-being, alleviate hunger

Medical uses: local anesthetic, vasoconstrictor

alertness/vigilance, concentration

mental acuity, sensory awareness

euphoria/elevated mood

brain electrical activity

self-confidence, grandiosity

need for sleep (insomnia)

appetite

brain blood flow, glucose metabolism

London et al., 1999

sexual desire, but cocaine can performance anxiety, suspiciousness

convulsions, tremor, seizure

psychosis, delirium

locomotion at low/moderate doses

repetitiveness, stereotypy at high doses

reinforcement/addiction

judgement, complex multi-tasking

Blood pressure

Blood sugar

Heart rate

Irregular heart beat

Vasoconstriction

Body temperature Bronchodialation

& Impaired breathing

Fight/Flight/Fright Syndrome(sympathetic nervous system arousal)

Routes of administration◦ Insufflated (snorted)◦ IV (mainlined)◦ Inhaled (freebased)◦ Oral

Cocaine has a local anesthetic action that represents the only current rationale for the therapeutic use of cocaine.

For example, cocaine is applied topically as a local anesthetic during eye, ear, nose, and throat surgery.

Whereas the local anesthetic action of cocaine is due to a block of voltage-activated sodium channels, an interaction with potassium channels may contribute to the ability of cocaine to cause cardiac arrhythmias.

Both cocaine and amphetamines penetrate BBB easily

Half-lives◦ Cocaine: ~ 50-90 min

◦ Amphetamine: ~ 5-10 hours

◦ Meth: ~ 12 hours

Metabolites include active and inactive compounds Cocaine is unusual in that it “autometabolizes” in

the blood in addition to normal liver metabolism.◦ Cocaine ----> norcocaine, ecgonine methyl ester, benzoylecgonine

High abuse potential Physical and psychological dependence Tolerance to euphoria, appetite suppression;

sensitization to psychomotor Withdrawal

◦ Physically mild to moderate (hunger, fatigue, anxiety, irritability, depression, panic attacks, dysphoric syndrome) Dysphoric syndrome (1-5 days after the crash): characterized by

decreased activity, amotivation, intense boredom and anhedonia, intense “craving” for cocaine. May last 1-10 weeks.

Intense cravings Route of administration important to addiction risk

Synthetic analog of ephedrine, active ingredient in mahuang

Mahuang used in China for asthma

◦ Chinese (Mandarin) má huáng : má, hemp + huáng, yellow

Methamphetamine and Methylphenidate (Ritalin) are very similar

Medical uses: obesity, ADHD, narcolepsy

Amphetamine is a noncatecholaminergic sympathetic amine that shows neurologic and clinical effects quite similar to those of cocaine. Dextroamphetamine is the major member of this class of compounds.

Methamphetamine is a derivative of amphetamine that can be smoked, and it is preferred by many abusers.

Adverse effects: - Cardiovascular: Hypertension (7% to

22%, pediatric ) - Endocrine metabolic: Weight loss (4% to

9%, pediatric; 11%, adults ) - Gastrointestinal: Abdominal pain (11%

to 14%, pediatrics ), Loss of appetite (22% to 36%), Xerostomia (35% )

- Neurologic: Headache (26% ), Insomnia ( to 17%, pediatric; 27%, adults %12) ارق

- Psychiatric: Feeling nervous (6% ) 

After injecting,  the mice with amphetamine you well notice: - Hair erection

- Licking, gnawing. - Stereotype - Sniffing 

Methylxanthines The methylxanthines include theophylline

which is found in tea; theobromine found in cocoa; and caffeine .

Caffeine, the most widely consumed stimulant in the world, is found in highest concentration in coffee, but it is also present in tea, cola drinks, chocolate candy, and cocoa.

Several mechanisms have been proposed for the actions of methylxanthines, including translocation of extracellular calcium, increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate caused by inhibition of phosphodiesterase, and blockade of adenosine receptors.

The latter most likely accounts for the actions achieved by the usual consumption of caffeine-containing beverages

CNS: The caffeine contained in one to two cups of coffee causes a decrease in fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain.

Consumption of 1.5 g of caffeine (12 to 15 cups of coffee) produces anxiety and tremors.

The spinal cord is stimulated only by very high doses of caffeine.

Tolerance can rapidly develop to the stimulating properties of caffeine; withdrawal consists of feelings of fatigue and sedation.

Cardiovascular system: A high dose of caffeine has positive inotropic

and chronotropic effects on the heart. Diuretic action: Caffeine has a mild diuretic action that

increases urinary output of sodium, chloride, and potassium.

Gastric mucosa: Because all methylxanthines stimulate

secretion of hydrochloric acid from the gastric mucosa, individuals with peptic ulcers should avoid beverages containing methylxanthines

The methylxanthines are well absorbed orally.

Caffeine distributes throughout the body, including the brain.

The drugs cross the placenta to the fetus and is secreted into the mother's milk.

All the methylxanthines are metabolized in the liver,

generally by the CYP1A2 pathway, and themetabolites are then excreted in the urine.

Moderate doses of caffeine cause insomnia, anxiety, and agitation.

The lethal dose is about 10 g of caffeine (about 100 cups of coffee), which induces cardiac arrhythmias; death from caffeine is thus highly unlikely.

Lethargy, irritability, and headache occur in users who have routinely consumed more than 600 mg of caffeine per day (roughly six cups of coffee per day) and then suddenly stop.

Nicotine is the active ingredient in tobacco. Although this drug is not currently used

therapeutically, nicotine remains important, because it is second only to caffeine as the most widely used CNS stimulant and second only to alcohol as the most abused drug.

In combination with the tars and carbon monoxide found in cigarette smoke, nicotine represents a serious risk factor for lung and cardiovascular disease, various cancers, as well as other illnesses. Dependency on the drug is not easily overcome.

In low doses, nicotine causes ganglionic stimulation by depolarization.

At high doses, nicotine causes ganglionic blockade.

Nicotine receptors exist at a number of sites in the CNS, which participate in the stimulant attributes of the drug.

Nicotine is highly lipid soluble and readily crosses the blood-brain barrier.

Cigarette smoking or administration of low doses of nicotine produces some degree of euphoria and arousal as well as relaxation.

It improves attention, learning, problem solving, and reaction time.

High doses of nicotine result in central respiratory paralysis .

Because nicotine is highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, mucosa, and skin.

Nicotine crosses the placental membrane and is secreted in the milk of lactating women.

By inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette (most cigarettes contain 6 to 8 mg of nicotine). The acute lethal dose is 60 mg. More than 90 percent of the nicotine inhaled in smoke is absorbed.

The CNS effects of nicotine include irritability and tremors.

Nicotine may also cause intestinal cramps, diarrhea, and increased heart rate and blood pressure.

In addition, cigarette smoking increases the rate of metabolism of number of drugs.