1. CNS Stimulants Asst Prof Dr Inam S. Arif isamalhaj@yahoo.com

2. Psychomotor stimulants and hallucinogens
Two groups of drugs act primarily to stimulate CNS
Psychomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity
Hallucinogens produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord

6. Psychomotor Stimulants
Methylxanthines
Theophylline, found in tea; Theobromine, found in cocoa; and Caffeine
Caffeine, the most widely consumed stimulant in the world, is found in highest conc. in certain coffee products (e.g. espresso, tea, cola drinks, energy drinks, chocolate candy, and cocoa).
Mechanism of action: Several/including:
translocation of EC calcium
increase in cAMP & cGMP caused by inhibition of PDEs
blockade of adenosine receptors

8. CNS of caffeine:
1-2 cups of coffee (100 to 200 mg) causes a decrease in fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain
12 to 15 cups of coffee/ 1.5 g of caffeine produces anxiety and tremors
2 to 5 g / spinal cord stimulation / only by very high doses
Tolerance can rapidly develop to the stimulating properties of caffeine
Withdrawal consists of feelings of fatigue and sedation
CVS: A high dose of caffeine has +ve inotropic and chronotropic
Diuretic action: Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and potassium
Gastric mucosa: Because methylxanthines stimulate secretion of gastric acid / peptic ulcers should avoid foods and beverages containing methylxanthines.

9. Therapeutic uses:
Caffeine and its derivatives relax SMs of the bronchioles
Recently replaced by other drugs???
Used in combination with the analgesics acetaminophen and aspirin for the management of headaches in both prescription and OTC
Pharmacokinetics:
well absorbed orally, distributes throughout the body, including the brain, cross the placenta to the fetus and are secreted into the breast milk, metabolized by CYP1A2 pathway, and excreted in the urine.
Adverse effects:
Moderate doses of caffeine cause insomnia, anxiety, and agitation
A high dosage is required for toxicity, which is manifested by emesis and convulsions
The lethal dose is 10 g of caffeine (about 100 cups of coffee), which induces cardiac arrhythmias
Death from caffeine is, therefore, highly unlikely
Lethargy, irritability, and headache occur in users who routinely consume more than 600 mg of caffeine per day (roughly six cups of coffee per day) and then suddenly stop.

10. Nicotine/tobacco Uses: Mechanism of action:
I- CNS: highly lipid solublity & readily crosses the BBB
Cigarette smoking or low doses produces euphoria and arousal, as well as relaxation
It improves attention, learning, problem solving, and reaction time
High doses result in central resp. paralysis & severe hypotension / medullary paralysis
Nicotine is also an appetite suppressant.
II- Peripheraleffects:
Stimulation of symp. ganglia & adrenal medulla / BP & HR/ hypertensive patients???
Many patients with peripheral vascular disease / exacerbation of symptoms with smoking
Nicotine- induced vasoconstriction decrease coronary BF / patient with angina ???
Stimulation of parasympathetic ganglia also increases motor activity of the bowel
At higher doses, BP falls & both GIT & bladder musculature???

11. Pharmacokinetics:
Highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, GI mucosa, and skin, the placental membrane and is secreted in the breast milk
By inhaling tobacco smoke, smoker takes in 1 to 2 mg of nicotine /cigarette
The acute lethal dose is 60 mg
More than 90% of the nicotine inhaled in smoke is absorbed
Clearance of nicotine involves metabolism in the lung and the liver and urinary excretion
Tolerance to the toxic effects of nicotine develops rapidly, often within days.
Adverse effects:
The CNS effects /irritability and tremors
Intestinal cramps, diarrhea, and increased HR & BP
Cigarette smoking increases the rate of metabolism for a number of drugs.

12. Withdrawal syndrome:
Nicotine is an addictive substance, and physical dependence develops rapidly and can be severe
Withdrawal symptoms / irritability, anxiety, restlessness, difficulty concentrating, headaches, and insomnia
Appetite is affected, and GI upset often occurs
The transdermal patch and chewing gum containing nicotine have been shown to reduce nicotine withdrawal symptoms and to help smokers stop smoking

13. Other forms of nicotine replacement used for smoking cessation include the inhaler, nasal spray, and lozenges
Bupropion, an antidepressant, can reduce the craving for cigarettes.

14. Varenicline A partial agonist at neuronal N Ach Rs in CNS
Less euphoric effects than nicotine (nicotine is a full agonist)
Useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptoms
Attenuate the rewarding effects of nicotine if a person relapses and uses tobacco
Patients taking varenicline should be monitored for suicidal thoughts, vivid nightmares, and mood changes

15. Cocaine Addictive drug/ because of its abuse potential
Block reuptake of the monoamines (NE, 5-HT, & DA) into the presynaptic terminals/ potentiates and prolongs the CNS and peripheral actions of these monoamines /prolongation of DA effects in the brain’s pleasure system (limbic system) produces the intense euphoria
Chronic intake of cocaine depletes DA/ triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression

16. Amphetamine a sympathetic amine / similar cocaine Dextroamphetamine
Methamphetamine / can be smoked and is preferred by many abusers
3,4-Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties

17. Mechanism of action
Indirect effects on the CNS and peripheral nervous system
Elevation of the level of catecholamine
Amphetamine enhances release of catecholamine stores
Inhibits monoamine oxidase (MAO) and is a weak reuptake transport inhibitor
As a result: the behavioral effects of amphetamine and its derivatives are similar to those of cocaine.

18. Actions
CNS:
The major behavioral effects of amphetamine result from a combination of its DA & NE release-enhancing properties
Stimulates the entire cerebrospinal axis, cortex, brainstem, & medulla
leads to increased alertness, decreased fatigue, depressed appetite, and insomnia
Used in hyperactivity in children, for narcolepsy, and for appetite control
At high doses, psychosis and convulsions can ensue.
Sympathetic NS: indirectly stimulating the receptors through NE release.

19. Therapeutic uses
chronic use/development of tolerance to the euphoric and anorectic effects.
I-Attention deficit hyperactivity disorder (ADHD): Some young children are hyperkinetic and lack the ability to be involved in any one activity for longer than a few minutes
Dextroamphetamine, methamphetamine, the mixed amphetamine salts, & methylphenidate help improve attention & alleviate behavioral problems
Lisdexamfetamine a prodrug converted to the active component dextroamphetamine after GI absorption and metabolism
Atomoxetine is a nonstimulant drug approved for ADHD in children and adults.
This drug should not be taken by individuals on MAO inhibitors and by patients with angle- closure glaucoma.]
Atomoxetine is more selective for inhibition of NE reuptake
Therefore, it is not considered habit forming and is not a controlled substance.

20. II-Narcolepsy: rare sleep disorder characterized by uncontrollable bouts of sleepiness during the day, sometimes accompanied by catalepsy, a loss in muscle control, and even paralysis brought on by strong emotions such as laughter
The sleepiness can be treated with drugs, such as the mixed amphetamine salts or methylphenidate
Modafinil and its R-enantiomer derivative, Armodafinil, are considered first-line agents for the treatment of narcolepsy (mechanism!!!)
promotes wakefulness, fewer psychoactive and euphoric effects and fewer alterations in mood, perception, thinking, and feelings typical of other CNS stimulants.
effective orally, extensive hepatic metabolism, excreted in urine
SE: Headaches, nausea, and nervousness
Modafinil and armodafinil may have some potential for abuse and physical dependence, and both are classified as controlled substances.

21. III- Appetite suppression:
Phentermine and Diethylpropion are sympathomimetic amines that are related structurally to amphetamine
Used as epitite-suppressants in obesity
Pharmacokinetics:
completely absorbed from the GI, metabolized by liver
Alkalization of urine???
Euphoria caused by amphetamine lasts 4 to 6 hours, or four- to eightfold longer than the effects of cocaine.

22. Adverse effects:
may cause addiction, leading to dependence, tolerance
a. CNS effects: insomnia, irritability, weakness, dizziness, tremor, and hyperactive reflexes
can also cause confusion, delirium, panic states, and suicidal tendencies / BZDs ( lorazepsam, are often used in the management of agitation and CNS stimulation secondary to amphetamine overdose)
Chronic amphetamine /“Amphetamine Psychosis” resembles psychotic episodes, psychic and physical dependence, tolerance within a few weeks
The anorectic effect of amphetamine is due to its action in the lateral hypothalamic feeding center.
b. CVS: palpitations, cardiac arrhythmias, hypertension, anginal pain, etc.
c. GIT: anorexia, nausea, vomiting, abdominal cramps, and diarrhea.
d. CI: Patients with hypertension, cardiovascular disease, hyperthyroidism, glaucoma, or a history of drug abuse or those taking MAOIs

23. Methylphenidate
CNS-stimulant properties similar to amphetamine and may also lead to abuse, although its addictive potential is controversial
Is now one of the most prescribed medications in children
The pharmacologically active isomer, dexmethylphenidate, is also a used for the treatment of ADHD.
Mechanism of action:
increasing both DA & NE in the synaptic space
less potential for abuse than cocaine, because it enters the brain much more slowly than cocaine and, thus, does not increase DA levels

24. Therapeutic uses:
ADHD, narcolepsy.
Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy.
Pharmacokinetics: Both methylphenidate and dexmethylphenidate are readily absorbed after oral administration
Methylphenidate is available in extended-release oral formulations and as a transdermal patch for once-daily application
The deesterified product, ritalinic acid, is excreted in urine.

25. Adverse Effects GI: include abdominal pain and nausea
Anorexia, insomnia, nervousness, and fever
In seizure patients, methylphenidate may increase seizure frequency, especially if the patient is taking antidepressants. It is contraindicated in patients with glaucoma
Methylphenidate can inhibit the metabolism of warfarin, phenytoin, phenobarbital, primidone, and the tricyclic antidepressants.

26. Hallucinogens
A few drugs have, as their primary action, the ability to induce altered perceptual states reminiscent of dreams
Many of these altered states are accompanied by visions of bright, colorful changes in the environment and by a plasticity of constantly changing shapes and color
The individual under the influence of these drugs is incapable of nor- mal decision making because the drug interferes with rational thought
These cpds are known as hallucinogens, and lysergic acid diethylamide (LSD) and tetrahydrocannabinol (from marijuana) are examples of agents in this class.